Materiały źródłowe

• #1 Androgen insensitivity syndrome: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/androgen-insensitivity-syndrome/

  Androgen insensitivity syndrome is a condition that affects sexual development before birth and during puberty. […] Variants (also called mutations) in the AR gene cause androgen insensitivity syndrome. This gene provides instructions for making a protein called an androgen receptor. Androgen receptor proteins interact with androgen hormones, such as testosterone, and help direct male sexual development. Specifically, the androgen receptor attaches (binds) to androgen hormones to form an androgen-receptor complex. This complex then binds to DNA to regulate the activity of certain genes that play a role in male sexual development. Androgens and androgen receptors also have other important functions in both males and females, such as regulating hair growth and sex drive. […] Variants in the AR gene prevent androgen receptors from working properly, which makes them less able to bind to testosterone and regulate gene activity. If androgen receptors cannot bind to androgens, the body cannot use androgens, even if there are normal levels of these hormones in the body.

• #2 Androgen Insensitivity Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK542206/

  Androgen insensitivity syndrome arises from loss-of-function mutations in the coding sequence of the androgen receptors (AR). This X-linked genetic mutation of the androgen receptor gene results in the dysfunction of androgen receptors and hormone resistance. These mutations lead to a loss in virilization or infertility in 46XY males in individuals with functional testes and adequate testosterone production. CAIS and PAIS encompass variability in phenotypic expression; however, both these conditions have similar genetic, endocrine, and pathophysiologic mechanisms. […] Androgen insensitivity syndrome (AIS) is a common etiology of sexual developmental disorders and results in varying phenotypes. These disorders of androgen action present as 46 XY disorders or differences in sex development (DSD).

• #3 Androgen insensitivity syndrome: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/androgen-insensitivity-syndrome/

  Androgen insensitivity syndrome is a condition that affects sexual development before birth and during puberty. […] Variants (also called mutations) in the AR gene cause androgen insensitivity syndrome. This gene provides instructions for making a protein called an androgen receptor. Androgen receptor proteins interact with androgen hormones, such as testosterone, and help direct male sexual development. Specifically, the androgen receptor attaches (binds) to androgen hormones to form an androgen-receptor complex. This complex then binds to DNA to regulate the activity of certain genes that play a role in male sexual development. Androgens and androgen receptors also have other important functions in both males and females, such as regulating hair growth and sex drive. […] Variants in the AR gene prevent androgen receptors from working properly, which makes them less able to bind to testosterone and regulate gene activity. If androgen receptors cannot bind to androgens, the body cannot use androgens, even if there are normal levels of these hormones in the body.

• #4 Androgen Insensitivity Syndrome: Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/924996-overview

  Androgen insensitivity syndrome (AIS), formerly known as testicular feminization, is an X-linked recessive condition resulting in a failure of normal masculinization of the external genitalia in chromosomally male individuals. This failure of virilization can be either complete androgen insensitivity syndrome (CAIS) or partial androgen insensitivity syndrome (PAIS), depending on the amount of residual receptor function. […] The basic etiology of androgen insensitivity syndrome is a loss-of-function mutation in the androgen receptor (AR) gene. This AR gene has been localized to the long arm of the X chromosome (ie, Xq11-13). Over 1000 such mutations have been described, including complete and partial gene deletions, point mutations, and small insertions/deletions. […] Loss of AR function means that, despite normal levels of androgen synthesis, the typical postreceptor events that mediate the effects of hormones on tissues do not occur.

• #5 Androgen Insensitivity: Symptoms, Causes, and Treatment

  https://www.verywellhealth.com/androgen-insensitivity-4173975

  Androgen insensitivity is caused by mutations in the androgen receptor gene. As such, it is an inherited condition that runs in families as an X-linked trait. That means it occurs on the X chromosome and follows the maternal line. Over one thousand mutations have been identified to date. […] Historically, androgen insensitivity syndrome was known as testicular feminization syndrome. This is because it often was not discovered until seemingly normal females did not undergo menarche. When such girls continued to not menstruate, it was discovered that some of them had testes instead of ovaries. It was not until later that it was discovered that androgen insensitivity was caused by mutations in the androgen receptor gene.

• #6 Androgen Insensitivity Syndrome: Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/924996-overview

  Androgen insensitivity syndrome (AIS), formerly known as testicular feminization, is an X-linked recessive condition resulting in a failure of normal masculinization of the external genitalia in chromosomally male individuals. This failure of virilization can be either complete androgen insensitivity syndrome (CAIS) or partial androgen insensitivity syndrome (PAIS), depending on the amount of residual receptor function. […] The basic etiology of androgen insensitivity syndrome is a loss-of-function mutation in the androgen receptor (AR) gene. This AR gene has been localized to the long arm of the X chromosome (ie, Xq11-13). Over 1000 such mutations have been described, including complete and partial gene deletions, point mutations, and small insertions/deletions. […] Loss of AR function means that, despite normal levels of androgen synthesis, the typical postreceptor events that mediate the effects of hormones on tissues do not occur.

• #7 Different Clinical Presentations and Management in Complete Androgen Insensitivity Syndrome (CAIS)

  https://www.mdpi.com/1660-4601/16/7/1268

  Complete androgen insensitivity syndrome (CAIS) is an X-linked recessive genetic disorder resulting from maternally inherited or de novo mutations involving the androgen receptor gene, situated in the Xq11-q12 region. […] An AR gene mutation is found in more than 95% of patients with CAIS: 70% of them result from maternally inherited mutations, while the remaining 30% are de novo mutations. […] Mutations in AR may lead to several abnormalities, such as a deficit/alteration in AR synthesis or an inability to bind the ligand. […] Currently, approximately 900 different mutations have been associated with AIS according to an AR gene mutations database. […] Four types of mutations have been widely investigated in patients with AIS: (1) single point mutations that result in stop codons or in amino acid substitutions, (2) deletions and insertions that lead to shifts in the translation reading frame, (3) partial or complete gene deletions involving a large part of the gene sequence, and (4) mutations that involve introns, altering RNA splicing.

• #8 Different Clinical Presentations and Management in Complete Androgen Insensitivity Syndrome (CAIS)

  https://www.mdpi.com/1660-4601/16/7/1268

  Complete androgen insensitivity syndrome (CAIS) is an X-linked recessive genetic disorder resulting from maternally inherited or de novo mutations involving the androgen receptor gene, situated in the Xq11-q12 region. […] An AR gene mutation is found in more than 95% of patients with CAIS: 70% of them result from maternally inherited mutations, while the remaining 30% are de novo mutations. […] Mutations in AR may lead to several abnormalities, such as a deficit/alteration in AR synthesis or an inability to bind the ligand. […] Currently, approximately 900 different mutations have been associated with AIS according to an AR gene mutations database. […] Four types of mutations have been widely investigated in patients with AIS: (1) single point mutations that result in stop codons or in amino acid substitutions, (2) deletions and insertions that lead to shifts in the translation reading frame, (3) partial or complete gene deletions involving a large part of the gene sequence, and (4) mutations that involve introns, altering RNA splicing.

• #9 Complete androgen insensitivity syndrome caused by a deep intronic pseudoexon-activating mutation in the androgen receptor gene | Scientific Reports

  https://www.nature.com/articles/srep32819

  Mutations in the X-linked androgen receptor (AR) gene underlie complete androgen insensitivity syndrome (CAIS), the most common cause of 46,XY sex reversal. […] Here, we describe a novel mechanism of AR disruption leading to CAIS in two 46,XY sisters. […] Our results show that patients with CAIS and normal AR coding region need to be examined for deep intronic mutations that can lead to pseudoexon activation. […] Mutations of variable severity in AR, the X-linked gene encoding the androgen receptor, cause the different forms of AIS, which total more than 500 mutations reported by 2012 in the Androgen Receptor Gene Mutations Database. […] About 80 to 100% of CAIS patients are found to have an AR mutation, whereas in PAIS, the percentage may be as low as 16%. […] The identification of a pathogenic mutation in AR confirms the diagnosis of AIS, especially in the milder forms which have some phenotypic overlap with other disorders of sex development.

• #10 Complete androgen insensitivity syndrome caused by a deep intronic pseudoexon-activating mutation in the androgen receptor gene | Scientific Reports

  https://www.nature.com/articles/srep32819

  The deep intronic mutation causes the aberrant splicing of AR mRNA, creating two abnormally long products and a significantly reduced amount of the normal-sized mRNA. […] The destruction of the aberrant mRNA products by the NMD pathway cannot be ruled out, however, especially since the half-life of the PTC-containing mRNA products is not known. […] Regardless, AR protein was undetectable in the patient fibroblasts, which suggests that even if the aberrantly-spliced mRNAs are translated into protein, the stability of the aberrant AR protein is compromised, and that the low amount of correct mRNA does not yield significant levels of AR protein. […] In conclusion, AR cDNA together with intronic sequences should be examined in CAIS patients with normal coding region and conserved splice sites of AR. […] Other deep intronic or regulatory region mutations, often missed in routine genetic screenings, may underlie CAIS in patients who still lack a molecular genetic diagnosis.

• #11 LINE1-mediated epigenetic repression of androgen receptor transcription causes androgen insensitivity syndrome | Scientific Reports

  https://www.nature.com/articles/s41598-024-65439-w

  Androgen insensitivity syndrome (AIS) is a difference of sex development (DSD) characterized by different degrees of undervirilization in individuals with a 46,XY karyotype despite normal to high gonadal testosterone production. Classically, AIS is explained by hemizygous mutations in the X-chromosomal androgen receptor (AR) gene. Nevertheless, the majority of individuals with clinically diagnosed AIS do not carry an AR gene mutation. […] We show that this insertion causes a strongly reduced AR mRNA expression both through the disruption of regulatory sequences in the 5UTR and through DNA methylation at the insertion site, thus explaining the clinical phenotype. […] Over 50% of individuals with the clinical diagnosis AIS do not harbor mutations within the coding region of the AR gene. This significantly complicates the counseling and clinical care of these individuals and raises fundamental questions such as sex assignment.

• #12 LINE1-mediated epigenetic repression of androgen receptor transcription causes androgen insensitivity syndrome | Scientific Reports

  https://www.nature.com/articles/s41598-024-65439-w

  We here report a patient with an L1 insertion in the 5UTR of the AR causative for AIS. This is the second report of a patient with AIS caused by a L1 insertion in the AR 5UTR. […] We show that an insertion in the AR 5UTR per se can reduce AR mRNA expression or stability in vitro, likely due to the disruption of regulatory sequences. Specific insertion of the truncated L1 element reduced AR/AR (mRNA and protein, respectively) expression even further, indicating that L1 insertion triggered transcriptional silencing rather than further mRNA instability probably due to DNA methylation, as we observed high DNA methylation in GSF-derived patient DNA surrounding the insertion site.

• #13 SciELO Brazil – Androgen insensitivity syndrome: a review Androgen insensitivity syndrome: a review

  https://www.scielo.br/j/aem/a/98DLW9RbrG7knCMNdRcGdtM/

  Androgenic insensitivity syndrome is the most common cause of disorders of sexual differentiation in 46,XY individuals. It results from alterations in the androgen receptor gene, leading to a frame of hormonal resistance, which may present clinically under 3 phenotypes: complete (CAIS), partial (PAIS) or mild (MAIS). […] Mutations in the androgen receptor gene (AR) are found in most individuals with CAIS but in less individuals with PAIS. […] The AIS diagnosis is confirmed by the presence of allelic variants in the AR gene. About 30% of AR mutations in AIS are de novo and sequencing of the entire AR gene is recommended for all 46,XY DSD newborns, regardless of a familial history of DSD or AIS. […] There is not a perfect correlation between genotype and phenotype in AIS. In the AR mutation database, there are some AR allelic variants that can cause different phenotypes. The explanation for this is not completely understood. It is hypothesized that AR co-regulators (activators and repressors) are implicated with this phenomenon. Other possibilities are variations in the level of 5-reductase type 2 activity resulting in different DHT availability, and the presence of germ-line AR allelic variants at a post zygote stage conferring somatic mosaicism.

• #14 SciELO Brazil – Androgen insensitivity syndrome: a review Androgen insensitivity syndrome: a review

  https://www.scielo.br/j/aem/a/98DLW9RbrG7knCMNdRcGdtM/

  Androgenic insensitivity syndrome is the most common cause of disorders of sexual differentiation in 46,XY individuals. It results from alterations in the androgen receptor gene, leading to a frame of hormonal resistance, which may present clinically under 3 phenotypes: complete (CAIS), partial (PAIS) or mild (MAIS). […] Mutations in the androgen receptor gene (AR) are found in most individuals with CAIS but in less individuals with PAIS. […] The AIS diagnosis is confirmed by the presence of allelic variants in the AR gene. About 30% of AR mutations in AIS are de novo and sequencing of the entire AR gene is recommended for all 46,XY DSD newborns, regardless of a familial history of DSD or AIS. […] There is not a perfect correlation between genotype and phenotype in AIS. In the AR mutation database, there are some AR allelic variants that can cause different phenotypes. The explanation for this is not completely understood. It is hypothesized that AR co-regulators (activators and repressors) are implicated with this phenomenon. Other possibilities are variations in the level of 5-reductase type 2 activity resulting in different DHT availability, and the presence of germ-line AR allelic variants at a post zygote stage conferring somatic mosaicism.

• #15 SciELO Brazil – Androgen insensitivity syndrome: a review Androgen insensitivity syndrome: a review

  https://www.scielo.br/j/aem/a/98DLW9RbrG7knCMNdRcGdtM/

  Androgenic insensitivity syndrome is the most common cause of disorders of sexual differentiation in 46,XY individuals. It results from alterations in the androgen receptor gene, leading to a frame of hormonal resistance, which may present clinically under 3 phenotypes: complete (CAIS), partial (PAIS) or mild (MAIS). […] Mutations in the androgen receptor gene (AR) are found in most individuals with CAIS but in less individuals with PAIS. […] The AIS diagnosis is confirmed by the presence of allelic variants in the AR gene. About 30% of AR mutations in AIS are de novo and sequencing of the entire AR gene is recommended for all 46,XY DSD newborns, regardless of a familial history of DSD or AIS. […] There is not a perfect correlation between genotype and phenotype in AIS. In the AR mutation database, there are some AR allelic variants that can cause different phenotypes. The explanation for this is not completely understood. It is hypothesized that AR co-regulators (activators and repressors) are implicated with this phenomenon. Other possibilities are variations in the level of 5-reductase type 2 activity resulting in different DHT availability, and the presence of germ-line AR allelic variants at a post zygote stage conferring somatic mosaicism.

• #16 Diverse phenotypes and fertility outcomes of patients with androgen insensitivity syndrome in a Chinese family harboring identical AR gene variant | BMC Medical Genomics | Full Text

  https://bmcmedgenomics.biomedcentral.com/articles/10.1186/s12920-024-01990-9

  The proband was diagnosed with PAIS, his old sibling was diagnosed with CAIS, whereas his two maternal uncles were both diagnosed with MAIS. […] Despite that the semen sample was not obtained, the older uncle (II-3) of proband fathered two girls naturally. […] The younger uncle (II-5) was infertile because of severe oligoasthenozoospermia (SOZ), and conceived a son by utilizing assisted reproductive technology. […] The nonsynonymous p.Phe755Leu (c.2265 CA) mutant of AR protein was first reported in PAIS by Hiort et al. in 1994. […] In the present study, we identified the same AR gene variant (c.2263TC; p.Phe755Leu) in four AIS patients from a single Chinese family with highly diverse clinical phenotypes and fertility outcomes, which expanded the phenotypic spectrum of AIS. […] Thus, phenotypic heterogeneity of AIS with identical AR variant indicated that other factors, independent of AR sequence alterations, contributed to the diverse AIS phenotypes.

• #17 Diverse phenotypes and fertility outcomes of patients with androgen insensitivity syndrome in a Chinese family harboring identical AR gene variant | BMC Medical Genomics | Full Text

  https://bmcmedgenomics.biomedcentral.com/articles/10.1186/s12920-024-01990-9

  Androgens concentration may play an important role in the phenotypic diversity of AIS, and deserve further investigation. […] Furthermore, we presented a clear insight into different fertility potential of AIS patients with the AR p.Phe755Leu, which provided the evidence that males harboring this variant may obtain biological offspring naturally or in combination with assisted reproductive technology.

• #18 Androgen Insensitivity Syndrome – GeneReviews® – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK1429/

  Androgen insensitivity syndrome (AIS) is inherited in an X-linked manner. […] Each offspring of a female known to carry an AR pathogenic variant (heterozygote) is at a 25% risk for each of the following: Having a 46,XY karyotype and being affected; Having a 46,XY karyotype and being unaffected; Having a 46,XX karyotype and being a carrier; Having a 46,XX karyotype and not being a carrier. […] The diagnosis of AIS is established in an individual with a 46,XY karyotype who has: undermasculinization of the external genitalia, impaired spermatogenesis with otherwise normal testes, absent or rudimentary mullerian structures, evidence of normal or increased synthesis of testosterone and its normal conversion to dihydrotestosterone, and normal or increased luteinizing hormone (LH) production by the pituitary gland; AND/OR a hemizygous pathogenic variant in AR identified by molecular genetic testing.

• #19 Androgen insensitivity syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Androgen_insensitivity_syndrome

  As of 2010, over 400 AR mutations have been reported in the AR mutation database, and the number continues to grow. […] Inheritance is typically maternal and follows an X-linked recessive pattern; individuals with a 46,XY karyotype always express the mutant gene since they have only one X chromosome, whereas 46,XX carriers are minimally affected. […] Some individuals with CAIS or PAIS do not have any AR mutations despite clinical, hormonal, and histological features sufficient to warrant an AIS diagnosis; up to 5% of women with CAIS do not have an AR mutation, as well as between 27 and 72% of individuals with PAIS. […] Mutations in the androgen receptor gene can cause problems with any of the steps involved in androgenization, from the synthesis of the androgen receptor protein itself, through the transcriptional ability of the dimerized, androgen-AR complex. […] AIS can result if even one of these steps is significantly disrupted, as each step is required for androgens to activate the AR successfully and regulate gene expression.

• #20 Androgen insensitivity syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Androgen_insensitivity_syndrome

  As of 2010, over 400 AR mutations have been reported in the AR mutation database, and the number continues to grow. […] Inheritance is typically maternal and follows an X-linked recessive pattern; individuals with a 46,XY karyotype always express the mutant gene since they have only one X chromosome, whereas 46,XX carriers are minimally affected. […] Some individuals with CAIS or PAIS do not have any AR mutations despite clinical, hormonal, and histological features sufficient to warrant an AIS diagnosis; up to 5% of women with CAIS do not have an AR mutation, as well as between 27 and 72% of individuals with PAIS. […] Mutations in the androgen receptor gene can cause problems with any of the steps involved in androgenization, from the synthesis of the androgen receptor protein itself, through the transcriptional ability of the dimerized, androgen-AR complex. […] AIS can result if even one of these steps is significantly disrupted, as each step is required for androgens to activate the AR successfully and regulate gene expression.

• #21 Androgen Insensitivity Syndrome – GeneReviews® – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK1429/

  Androgen insensitivity syndrome (AIS) is inherited in an X-linked manner. […] Each offspring of a female known to carry an AR pathogenic variant (heterozygote) is at a 25% risk for each of the following: Having a 46,XY karyotype and being affected; Having a 46,XY karyotype and being unaffected; Having a 46,XX karyotype and being a carrier; Having a 46,XX karyotype and not being a carrier. […] The diagnosis of AIS is established in an individual with a 46,XY karyotype who has: undermasculinization of the external genitalia, impaired spermatogenesis with otherwise normal testes, absent or rudimentary mullerian structures, evidence of normal or increased synthesis of testosterone and its normal conversion to dihydrotestosterone, and normal or increased luteinizing hormone (LH) production by the pituitary gland; AND/OR a hemizygous pathogenic variant in AR identified by molecular genetic testing.

• #22 Androgen Insensitivity Syndrome – GeneReviews® – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK1429/

  Androgen insensitivity syndrome (AIS) is inherited in an X-linked manner. […] Each offspring of a female known to carry an AR pathogenic variant (heterozygote) is at a 25% risk for each of the following: Having a 46,XY karyotype and being affected; Having a 46,XY karyotype and being unaffected; Having a 46,XX karyotype and being a carrier; Having a 46,XX karyotype and not being a carrier. […] The diagnosis of AIS is established in an individual with a 46,XY karyotype who has: undermasculinization of the external genitalia, impaired spermatogenesis with otherwise normal testes, absent or rudimentary mullerian structures, evidence of normal or increased synthesis of testosterone and its normal conversion to dihydrotestosterone, and normal or increased luteinizing hormone (LH) production by the pituitary gland; AND/OR a hemizygous pathogenic variant in AR identified by molecular genetic testing.

• #23

  https://www.nhs.uk/conditions/androgen-insensitivity-syndrome/

  Androgen insensitivity syndrome (AIS) affects the development of a person’s genitals and reproductive organs. […] AIS is caused by a genetic alteration that is passed along the female line to the child. […] Although people with AIS have XY (usual male pattern) chromosomes, the body does not respond to testosterone (the sex hormone) fully or at all. […] Women who carry the genetic alteration will not have AIS themselves, but there’s a 1 in 4 chance each child they have will be born with AIS. […] These are: complete androgen insensitivity syndrome (CAIS) where testosterone has no effect on sex development, so the genitals are entirely female; partial androgen insensitivity syndrome (PAIS) where testosterone has some effect on sex development, so the genitals are often not as expected for boys or girls.

• #24 Androgen Insensitivity Syndrome Symptoms, Doctors, Treatments, Advances & More | MediFind

  https://www.medifind.com/conditions/androgen-insensitivity-syndrome/257

  Androgen insensitivity syndrome (AIS) is when a person who has one X and one Y chromosome (typically seen in males) is resistant to hormones that produce a male appearance (called androgens). As a result, the person has some of the physical traits of a female, but the genetic makeup of a male. […] AIS is caused by genetic defects on the X chromosome. These defects make the body unable to respond to the hormones that produce a male appearance. […] The syndrome is passed down genetically (X-linked recessive inheritance). People with two X chromosomes are not affected if only one copy of the X chromosome carries the genetic variant. Males who inherit the gene from their mothers will have the condition. There is a 50% chance that a male child of a mother with the genetic trait will be affected. Every female child of a mother with the genetic trait has a 50% chance of carrying the genetic trait. Family history is important in determining risk factors of AIS.

• #25 SciELO Brazil – Androgen insensitivity syndrome: a review Androgen insensitivity syndrome: a review

  https://www.scielo.br/j/aem/a/98DLW9RbrG7knCMNdRcGdtM/

  Androgenic insensitivity syndrome is the most common cause of disorders of sexual differentiation in 46,XY individuals. It results from alterations in the androgen receptor gene, leading to a frame of hormonal resistance, which may present clinically under 3 phenotypes: complete (CAIS), partial (PAIS) or mild (MAIS). […] Mutations in the androgen receptor gene (AR) are found in most individuals with CAIS but in less individuals with PAIS. […] The AIS diagnosis is confirmed by the presence of allelic variants in the AR gene. About 30% of AR mutations in AIS are de novo and sequencing of the entire AR gene is recommended for all 46,XY DSD newborns, regardless of a familial history of DSD or AIS. […] There is not a perfect correlation between genotype and phenotype in AIS. In the AR mutation database, there are some AR allelic variants that can cause different phenotypes. The explanation for this is not completely understood. It is hypothesized that AR co-regulators (activators and repressors) are implicated with this phenomenon. Other possibilities are variations in the level of 5-reductase type 2 activity resulting in different DHT availability, and the presence of germ-line AR allelic variants at a post zygote stage conferring somatic mosaicism.

• #26 Orphanet: Complete androgen insensitivity syndrome

  https://www.orpha.net/en/disease/detail/99429

  Complete androgen insensitivity syndrome (CAIS) is a form of androgen insensitivity syndrome (AIS), a disorder of sex development (DSD), characterized by the presence of female external genitalia in a 46,XY individual with normal testis development but undescended testes and unresponsiveness to age-appropriate levels of androgens. […] The condition is due to mutations in the androgen receptor (AR) gene which is located on the long arm of the X-chromosome (Xq11-12). The AR is a nuclear transcription factor comprising three functional domains. Mutations are distributed throughout the gene, predominantly in 5 of the 8 exons that code for the ligand binding domain. The CAIS phenotype is associated with an AR mutation that completely disrupts AR function; target cells do not respond to testosterone or dihydrostosterone (DHT). An AR mutation is found in more than 95% of patients with CAIS; 30% are de novo mutations.

• #27 Complete Androgen Insensitivity Syndrome: From Bench to Bed

  https://www.mdpi.com/1422-0067/22/3/1264

  Complete androgen insensitivity syndrome (CAIS) is due to complete resistance to the action of androgens, determining a female phenotype in persons with a 46,XY karyotype and functioning testes. CAIS is caused by inactivating mutations in the androgen receptor gene (AR). Hundreds of genetic variants in the AR gene have been reported in CAIS. The majority of AR mutations (about two-thirds) are of germline origin inherited from asymptomatic mothers; in other cases, CAIS is due to somatic and de novo mutations. It has been estimated that up to one-third of the de novo mutations may arise in the postzygotic phase, which could partly explain the phenotypic variability observed in subjects with the same genetic defects. […] According to some AR mutation databases, hundreds of pathogenetic mutations related to CAIS are known. Complex rearrangement has been rarely reported.

• #28 Androgen insensitivity syndrome: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/androgen-insensitivity-syndrome/

  Androgen insensitivity syndrome is a condition that affects sexual development before birth and during puberty. […] Variants (also called mutations) in the AR gene cause androgen insensitivity syndrome. This gene provides instructions for making a protein called an androgen receptor. Androgen receptor proteins interact with androgen hormones, such as testosterone, and help direct male sexual development. Specifically, the androgen receptor attaches (binds) to androgen hormones to form an androgen-receptor complex. This complex then binds to DNA to regulate the activity of certain genes that play a role in male sexual development. Androgens and androgen receptors also have other important functions in both males and females, such as regulating hair growth and sex drive. […] Variants in the AR gene prevent androgen receptors from working properly, which makes them less able to bind to testosterone and regulate gene activity. If androgen receptors cannot bind to androgens, the body cannot use androgens, even if there are normal levels of these hormones in the body.

• #29 Androgen Insensitivity Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK542206/

  Androgen insensitivity syndrome arises from loss-of-function mutations in the coding sequence of the androgen receptors (AR). This X-linked genetic mutation of the androgen receptor gene results in the dysfunction of androgen receptors and hormone resistance. These mutations lead to a loss in virilization or infertility in 46XY males in individuals with functional testes and adequate testosterone production. CAIS and PAIS encompass variability in phenotypic expression; however, both these conditions have similar genetic, endocrine, and pathophysiologic mechanisms. […] Androgen insensitivity syndrome (AIS) is a common etiology of sexual developmental disorders and results in varying phenotypes. These disorders of androgen action present as 46 XY disorders or differences in sex development (DSD).

• #30 Androgen Insensitivity Syndrome | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/17524

  Androgen insensitivity syndrome arises from loss-of-function mutations in the coding sequence of the androgen receptors (AR). This X-linked genetic mutation of the androgen receptor gene results in the dysfunction of androgen receptors and hormone resistance. These mutations lead to a loss in virilization or infertility in 46XY males in individuals with functional testes and adequate testosterone production. CAIS and PAIS encompass variability in phenotypic expression; however, both these conditions have similar genetic, endocrine, and pathophysiologic mechanisms.[2] […] Androgen resistance results in complete androgen insensitivity syndrome (CAIS), characterizing XY sex reversal with normal female phenotype, whereas phenotype diversity is variable with residual androgen receptor activity, which leads to partial androgen insensitivity syndrome (PAIS).

• #31 Androgen insensitivity syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Androgen_insensitivity_syndrome

  As of 2010, over 400 AR mutations have been reported in the AR mutation database, and the number continues to grow. […] Inheritance is typically maternal and follows an X-linked recessive pattern; individuals with a 46,XY karyotype always express the mutant gene since they have only one X chromosome, whereas 46,XX carriers are minimally affected. […] Some individuals with CAIS or PAIS do not have any AR mutations despite clinical, hormonal, and histological features sufficient to warrant an AIS diagnosis; up to 5% of women with CAIS do not have an AR mutation, as well as between 27 and 72% of individuals with PAIS. […] Mutations in the androgen receptor gene can cause problems with any of the steps involved in androgenization, from the synthesis of the androgen receptor protein itself, through the transcriptional ability of the dimerized, androgen-AR complex. […] AIS can result if even one of these steps is significantly disrupted, as each step is required for androgens to activate the AR successfully and regulate gene expression.

• #32 Androgen insensitivity syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Androgen_insensitivity_syndrome

  As of 2010, over 400 AR mutations have been reported in the AR mutation database, and the number continues to grow. […] Inheritance is typically maternal and follows an X-linked recessive pattern; individuals with a 46,XY karyotype always express the mutant gene since they have only one X chromosome, whereas 46,XX carriers are minimally affected. […] Some individuals with CAIS or PAIS do not have any AR mutations despite clinical, hormonal, and histological features sufficient to warrant an AIS diagnosis; up to 5% of women with CAIS do not have an AR mutation, as well as between 27 and 72% of individuals with PAIS. […] Mutations in the androgen receptor gene can cause problems with any of the steps involved in androgenization, from the synthesis of the androgen receptor protein itself, through the transcriptional ability of the dimerized, androgen-AR complex. […] AIS can result if even one of these steps is significantly disrupted, as each step is required for androgens to activate the AR successfully and regulate gene expression.

• #33 Partial or Complete Androgen Insensitivity Syndrome

  https://www.urology-textbook.com/androgen-insensitivity.html

  A defective androgen receptor causes androgen insensitivity syndrome (AIS) in men (46, XY, leading to infertility and, to a varying degree, a male or female phenotype. The production of androgens is not disturbed. The extent of the disease depends on the severity of the androgen receptor dysfunction. […] Different mutations of the androgen receptor gene on the X chromosome lead to a minimal impairment, partial response, or complete lack of androgen response (androgen resistance). Different mutations with various effects are known, but molecular alterations cannot predict the resulting phenotype (MAIS, PAIS, or CAIS). Some mutations inhibit the binding of testosterone or DHT to the receptor; some impede the binding of the activated androgen-receptor complex to the DNA. If there is a complete loss of the androgen receptor gene, complete androgen insensitivity syndrome (CAIS) is certain.

• #34 Partial or Complete Androgen Insensitivity Syndrome

  https://www.urology-textbook.com/androgen-insensitivity.html

  A defective androgen receptor causes androgen insensitivity syndrome (AIS) in men (46, XY, leading to infertility and, to a varying degree, a male or female phenotype. The production of androgens is not disturbed. The extent of the disease depends on the severity of the androgen receptor dysfunction. […] Different mutations of the androgen receptor gene on the X chromosome lead to a minimal impairment, partial response, or complete lack of androgen response (androgen resistance). Different mutations with various effects are known, but molecular alterations cannot predict the resulting phenotype (MAIS, PAIS, or CAIS). Some mutations inhibit the binding of testosterone or DHT to the receptor; some impede the binding of the activated androgen-receptor complex to the DNA. If there is a complete loss of the androgen receptor gene, complete androgen insensitivity syndrome (CAIS) is certain.

• #35 Complete androgen insensitivity syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Complete_androgen_insensitivity_syndrome

  Androgen insensitivity syndrome is the largest single entity that leads to 46, XY undermasculinization. […] The gonads in people with CAIS are testes; during the embryonic stage of development, testes form in an androgen-independent process that occurs due to the influence of the SRY gene on the Y chromosome. […] Testosterone produced by the testes cannot be directly used due to the mutant androgen receptor that characterizes CAIS; instead, it is aromatized into estrogen, which effectively feminizes the body and accounts for the normal female phenotype observed in CAIS. […] The receptor in question is encoded by the AR gene located on the X chromosome at Xq1112. At least 15 different mutations were known in 2003, and they are all recessive, which makes the disease follow X-linked recessive inheritance. […] Immature sperm cells in the testes do not mature past an early stage, as sensitivity to androgens is required in order for spermatogenesis to complete. […] CAIS is associated with an increased risk for gonadal tumors (e.g. germ cell malignancy) in adulthood if gonadectomy is not performed.

• #36

  https://www.archivesofmedicalscience.com/The-challenges-of-androgen-insensitivity-syndrome,125584,0,2.html

  According to the literature, an AR gene mutation can be identified in 95% of complete AIS (CAIS) cases, out of which approximately two thirds of these mutations are inherited through the maternal line, while the remaining one third are de novo mutations. […] The differentiation of the human embryo into the male sex is regulated by the sex-determining region Y gene (SRY), which is located on Yp 11.2. SRY encodes the testes determining factor (TDF), which has a crucial role in the initiation of male sex determination. […] In 46XY embryos with AIS, the activity of the SRY gene and TDF protein is normal, favours the development of the male gonads and inhibits the development of the uterus, fallopian tubes, cervix and upper part of the vagina via AMH action. […] Considering the degree of AR sensitivity to androgen stimulation, this condition can be divided into three different entities: CAIS, partial AIS (PAIS) and mild AIS (MAIS).

• #37 Complete androgen insensitivity syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Complete_androgen_insensitivity_syndrome

  Androgen insensitivity syndrome is the largest single entity that leads to 46, XY undermasculinization. […] The gonads in people with CAIS are testes; during the embryonic stage of development, testes form in an androgen-independent process that occurs due to the influence of the SRY gene on the Y chromosome. […] Testosterone produced by the testes cannot be directly used due to the mutant androgen receptor that characterizes CAIS; instead, it is aromatized into estrogen, which effectively feminizes the body and accounts for the normal female phenotype observed in CAIS. […] The receptor in question is encoded by the AR gene located on the X chromosome at Xq1112. At least 15 different mutations were known in 2003, and they are all recessive, which makes the disease follow X-linked recessive inheritance. […] Immature sperm cells in the testes do not mature past an early stage, as sensitivity to androgens is required in order for spermatogenesis to complete. […] CAIS is associated with an increased risk for gonadal tumors (e.g. germ cell malignancy) in adulthood if gonadectomy is not performed.

• #38 Complete androgen insensitivity syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Complete_androgen_insensitivity_syndrome

  Androgen insensitivity syndrome is the largest single entity that leads to 46, XY undermasculinization. […] The gonads in people with CAIS are testes; during the embryonic stage of development, testes form in an androgen-independent process that occurs due to the influence of the SRY gene on the Y chromosome. […] Testosterone produced by the testes cannot be directly used due to the mutant androgen receptor that characterizes CAIS; instead, it is aromatized into estrogen, which effectively feminizes the body and accounts for the normal female phenotype observed in CAIS. […] The receptor in question is encoded by the AR gene located on the X chromosome at Xq1112. At least 15 different mutations were known in 2003, and they are all recessive, which makes the disease follow X-linked recessive inheritance. […] Immature sperm cells in the testes do not mature past an early stage, as sensitivity to androgens is required in order for spermatogenesis to complete. […] CAIS is associated with an increased risk for gonadal tumors (e.g. germ cell malignancy) in adulthood if gonadectomy is not performed.

• #39 Androgen insensitivity syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Androgen_insensitivity_syndrome

  Androgen insensitivity syndrome (AIS) is a condition involving the inability to respond to androgens, typically due to androgen receptor dysfunction. […] The condition results in the partial or complete inability of cells to respond to androgens. […] The insensitivity to androgens is therefore clinically significant only when it occurs in genetic males, (i.e. individuals with a Y-chromosome, or more specifically, an SRY gene). […] AIS is divided into three categories that are differentiated by the degree of genital masculinization: Mild androgen insensitivity syndrome (MAIS), Partial androgen insensitivity syndrome (PAIS), and Complete androgen insensitivity syndrome (CAIS). […] Androgen insensitivity syndrome is the largest single entity that leads to 46,XY undermasculinized genitalia.

• #40 Androgen Insensitivity Syndrome | Embryo Project Encyclopedia

  https://embryo.asu.edu/pages/androgen-insensitivity-syndrome

  Androgen Insensitivity Syndrome (AIS) is a human disorder in which an individual’s genetic sex (genotype) differs from that individual’s observable secondary sex characteristics (phenotypes). […] Due to a defect on the androgen receptor gene (AR) located on the X chromosome, a fetus with AIS cannot process male sex hormones or androgens. […] Although most cases of AIS are in individuals with families that have had other individuals with AIS, scientists estimate that thirty percent of AIS cases result from spontaneous, or de novo, mutations to AR genes. […] AIS is classified into three categories based on the degree of altered sex differentiation: complete AIS (CAIS), partial AIS (PAIS), and mild AIS (MAIS). […] During development, an 46,XY embryo with CAIS cannot process the androgens produced by the testes, but it responds to other hormones.

• #41 Complete androgen insensitivity syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Complete_androgen_insensitivity_syndrome

  Complete androgen insensitivity syndrome (CAIS) is an AIS condition that results in the complete inability of the cell to respond to androgens. […] The unresponsiveness of the cell to the presence of androgenic hormones prevents the masculinization of male genitalia in the developing fetus, as well as the development of male secondary sexual characteristics at puberty, but does allow, without significant impairment, female genital and sexual development in those with the condition. […] CAIS is one of the three categories of androgen insensitivity syndrome (AIS) since AIS is differentiated according to the degree of genital masculinization: complete androgen insensitivity syndrome (CAIS) when the external genitalia is that of a typical female, mild androgen insensitivity syndrome (MAIS) when the external genitalia is that of a typical male, and partial androgen insensitivity syndrome (PAIS) when the external genitalia is partially, but not fully masculinized.

• #42 Orphanet: Complete androgen insensitivity syndrome

  https://www.orpha.net/en/disease/detail/99429

  Complete androgen insensitivity syndrome (CAIS) is a form of androgen insensitivity syndrome (AIS), a disorder of sex development (DSD), characterized by the presence of female external genitalia in a 46,XY individual with normal testis development but undescended testes and unresponsiveness to age-appropriate levels of androgens. […] The condition is due to mutations in the androgen receptor (AR) gene which is located on the long arm of the X-chromosome (Xq11-12). The AR is a nuclear transcription factor comprising three functional domains. Mutations are distributed throughout the gene, predominantly in 5 of the 8 exons that code for the ligand binding domain. The CAIS phenotype is associated with an AR mutation that completely disrupts AR function; target cells do not respond to testosterone or dihydrostosterone (DHT). An AR mutation is found in more than 95% of patients with CAIS; 30% are de novo mutations.

• #43 Pediatric androgen insensitivity syndrome (AIS) – Children’s Health Dallas and Plano

  https://www.childrens.com/specialties-services/conditions/androgen-insensitivity-syndrome

  Androgen insensitivity syndrome is an example of disorders of sex development (DSD). An androgen is a hormone that causes a male child to develop male characteristics. Testosterone is the most well known androgen and is made by the testes (and also in smaller amounts in the ovaries and adrenal glands of females). […] There are two general types of androgen insensitivity syndromes: Complete androgen insensitivity syndrome (CAIS) and Partial androgen insensitivity syndrome (PAIS). […] CAIS is a syndrome where the body is completely resistant to the effects of androgens. When these children are born, they generally appear to be normal females and often the diagnosis is not suspected. […] These patients have male chromosomes (46XY), but because androgens have no effect they develop normal female external genitalia.

• #44 Orphanet: Complete androgen insensitivity syndrome

  https://www.orpha.net/en/disease/detail/99429

  Complete androgen insensitivity syndrome (CAIS) is a form of androgen insensitivity syndrome (AIS), a disorder of sex development (DSD), characterized by the presence of female external genitalia in a 46,XY individual with normal testis development but undescended testes and unresponsiveness to age-appropriate levels of androgens. […] The condition is due to mutations in the androgen receptor (AR) gene which is located on the long arm of the X-chromosome (Xq11-12). The AR is a nuclear transcription factor comprising three functional domains. Mutations are distributed throughout the gene, predominantly in 5 of the 8 exons that code for the ligand binding domain. The CAIS phenotype is associated with an AR mutation that completely disrupts AR function; target cells do not respond to testosterone or dihydrostosterone (DHT). An AR mutation is found in more than 95% of patients with CAIS; 30% are de novo mutations.

• #45 ANDROGEN INSENSITIVITY SYNDROME (AIS)

  https://medicover-genetics.com/product/androgen-insensitivity-syndrome-ais/

  Androgen insensitivity syndrome (AIS) is characterized by feminization of the external genitalia at birth, impaired pubertal development, and subsequent infertility in a 46,XY karyotype. […] The most common cause is missense variants in the androgen receptor gene (AR) leading to AR transcription factor dysfunction. The detection rate of pathogenic variants is 95% in CAIS patients, less than 50% in PAIS patients and even lower in MAIS patients. AIS is inherited in an X-linked recessive pattern. Offspring of heterozygous mothers have a 50% probability to inherit the trait. […] AIS belongs to the heterogeneous group of Disorders of sex development (DSD). In 46,XY-DSD, pathogenic variants have been described in a number of other genes: SRY, NR5A1, SRD5A2, HSD3B2, HSD17B3, MAMLD1, NROB1, WNT4, DMRT1, SOX9, DHH, TSPYL, WWOX, and WT1.

• #46

  https://www.archivesofmedicalscience.com/The-challenges-of-androgen-insensitivity-syndrome,125584,0,2.html

  Partial androgen insensitivity syndrome is the result of an incomplete cellular response to androgen stimulation. The phenotype of these patients depends on the degree of androgen receptors responsiveness to androgen stimulation. […] Mild androgen insensitivity syndrome is associated with a small degree of androgen insensitivity; these patients present a male phenotype. This type of androgen insensitivity is also the result of an androgen receptor mutation, but these patients, in contrast to those with PAIS and CAIS, present normally developed male genitalia. […] In the case of AIS patients, the risk for germ cell cancer in gonads varies across the subtypes. It is considered that the number of germ cell tumours increases in individuals, simultaneous with AIS, because of the Y chromosome and presence of the testis-specific protein Y-linked 1 (TSPY) gene. […] In patients with CAIS, prostate development and masculinization are inhibited by the impaired androgen receptor function, the prostate remaining practically undeveloped.

• #47 Pediatric androgen insensitivity syndrome (AIS) – Children’s Health Dallas and Plano

  https://www.childrens.com/specialties-services/conditions/androgen-insensitivity-syndrome

  PAIS is another form of androgen insensitivity. As the name suggests, PAIS patients are only partially sensitive to androgens. […] Externally, the patients have ambiguous genitalia ranging from mostly female to almost completely normal male. Internally, the patients do not have a uterus or fallopian tubes. […] The diagnosis of PAIS is sometimes difficult to make and the management of patients with PAIS can be challenging.

• #48 Orphanet: Partial androgen insensitivity syndrome

  https://www.orpha.net/en/disease/detail/90797

  A difference of sex development (DSD) distinct from complete AIS (CAIS) characterized by the presence of abnormal genital development in a 46,XY individual with normal testis development and partial responsiveness to age-appropriate levels of androgens. […] The condition is due to missense mutations in the androgen receptor (AR) gene (Xq11-12) coding for the AR nuclear transcription factor, and results in variable degrees of AR function. An AR mutation is found in only approximately 20% of patients with PAIS. […] There are no available data on the prevalence of PAIS in the general population. Nevertheless, resistance to androgens is the most frequent cause of XY DSD.

• #49 ANDROGEN INSENSITIVITY SYNDROME (AIS)

  https://medicover-genetics.com/product/androgen-insensitivity-syndrome-ais/

  Androgen insensitivity syndrome (AIS) is characterized by feminization of the external genitalia at birth, impaired pubertal development, and subsequent infertility in a 46,XY karyotype. […] The most common cause is missense variants in the androgen receptor gene (AR) leading to AR transcription factor dysfunction. The detection rate of pathogenic variants is 95% in CAIS patients, less than 50% in PAIS patients and even lower in MAIS patients. AIS is inherited in an X-linked recessive pattern. Offspring of heterozygous mothers have a 50% probability to inherit the trait. […] AIS belongs to the heterogeneous group of Disorders of sex development (DSD). In 46,XY-DSD, pathogenic variants have been described in a number of other genes: SRY, NR5A1, SRD5A2, HSD3B2, HSD17B3, MAMLD1, NROB1, WNT4, DMRT1, SOX9, DHH, TSPYL, WWOX, and WT1.

• #50

  https://www.archivesofmedicalscience.com/The-challenges-of-androgen-insensitivity-syndrome,125584,0,2.html

  Partial androgen insensitivity syndrome is the result of an incomplete cellular response to androgen stimulation. The phenotype of these patients depends on the degree of androgen receptors responsiveness to androgen stimulation. […] Mild androgen insensitivity syndrome is associated with a small degree of androgen insensitivity; these patients present a male phenotype. This type of androgen insensitivity is also the result of an androgen receptor mutation, but these patients, in contrast to those with PAIS and CAIS, present normally developed male genitalia. […] In the case of AIS patients, the risk for germ cell cancer in gonads varies across the subtypes. It is considered that the number of germ cell tumours increases in individuals, simultaneous with AIS, because of the Y chromosome and presence of the testis-specific protein Y-linked 1 (TSPY) gene. […] In patients with CAIS, prostate development and masculinization are inhibited by the impaired androgen receptor function, the prostate remaining practically undeveloped.

• #51 Androgen Insensitivity Syndrome | Embryo Project Encyclopedia

  https://embryo.asu.edu/pages/androgen-insensitivity-syndrome

  The testes secrete MIS, which causes the Mullerian ducts to regress, so the uterus, fallopian tubes, and the cervix do not develop. […] The Wolffian ducts don’t respond to the androgens released by the testes, and the ducts either regress or remain in a rudimentary form, but they do not develop into a prostate gland, vas deferens, or seminal vesicles. […] Because the defect in the AR gene is linked to the X chromosome, all 46,XY embryos that have an X chromosome with a defective AR gene and a normal Y chromosome exhibit varying degrees of sex differentiation. […] In infants born with MAIS, parents often raise the children as male, as those infants exhibit mild alteration of normal male genitalia.

• #52 Androgen insensitivity syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Androgen_insensitivity_syndrome

  As of 2010, over 400 AR mutations have been reported in the AR mutation database, and the number continues to grow. […] Inheritance is typically maternal and follows an X-linked recessive pattern; individuals with a 46,XY karyotype always express the mutant gene since they have only one X chromosome, whereas 46,XX carriers are minimally affected. […] Some individuals with CAIS or PAIS do not have any AR mutations despite clinical, hormonal, and histological features sufficient to warrant an AIS diagnosis; up to 5% of women with CAIS do not have an AR mutation, as well as between 27 and 72% of individuals with PAIS. […] Mutations in the androgen receptor gene can cause problems with any of the steps involved in androgenization, from the synthesis of the androgen receptor protein itself, through the transcriptional ability of the dimerized, androgen-AR complex. […] AIS can result if even one of these steps is significantly disrupted, as each step is required for androgens to activate the AR successfully and regulate gene expression.

• #53 LINE1-mediated epigenetic repression of androgen receptor transcription causes androgen insensitivity syndrome | Scientific Reports

  https://www.nature.com/articles/s41598-024-65439-w

  Androgen insensitivity syndrome (AIS) is a difference of sex development (DSD) characterized by different degrees of undervirilization in individuals with a 46,XY karyotype despite normal to high gonadal testosterone production. Classically, AIS is explained by hemizygous mutations in the X-chromosomal androgen receptor (AR) gene. Nevertheless, the majority of individuals with clinically diagnosed AIS do not carry an AR gene mutation. […] We show that this insertion causes a strongly reduced AR mRNA expression both through the disruption of regulatory sequences in the 5UTR and through DNA methylation at the insertion site, thus explaining the clinical phenotype. […] Over 50% of individuals with the clinical diagnosis AIS do not harbor mutations within the coding region of the AR gene. This significantly complicates the counseling and clinical care of these individuals and raises fundamental questions such as sex assignment.

• #54 Complete androgen insensitivity syndrome caused by a deep intronic pseudoexon-activating mutation in the androgen receptor gene | Scientific Reports

  https://www.nature.com/articles/srep32819

  Mutations in the X-linked androgen receptor (AR) gene underlie complete androgen insensitivity syndrome (CAIS), the most common cause of 46,XY sex reversal. […] Here, we describe a novel mechanism of AR disruption leading to CAIS in two 46,XY sisters. […] Our results show that patients with CAIS and normal AR coding region need to be examined for deep intronic mutations that can lead to pseudoexon activation. […] Mutations of variable severity in AR, the X-linked gene encoding the androgen receptor, cause the different forms of AIS, which total more than 500 mutations reported by 2012 in the Androgen Receptor Gene Mutations Database. […] About 80 to 100% of CAIS patients are found to have an AR mutation, whereas in PAIS, the percentage may be as low as 16%. […] The identification of a pathogenic mutation in AR confirms the diagnosis of AIS, especially in the milder forms which have some phenotypic overlap with other disorders of sex development.

• #55 Complete androgen insensitivity syndrome caused by a deep intronic pseudoexon-activating mutation in the androgen receptor gene | Scientific Reports

  https://www.nature.com/articles/srep32819

  The deep intronic mutation causes the aberrant splicing of AR mRNA, creating two abnormally long products and a significantly reduced amount of the normal-sized mRNA. […] The destruction of the aberrant mRNA products by the NMD pathway cannot be ruled out, however, especially since the half-life of the PTC-containing mRNA products is not known. […] Regardless, AR protein was undetectable in the patient fibroblasts, which suggests that even if the aberrantly-spliced mRNAs are translated into protein, the stability of the aberrant AR protein is compromised, and that the low amount of correct mRNA does not yield significant levels of AR protein. […] In conclusion, AR cDNA together with intronic sequences should be examined in CAIS patients with normal coding region and conserved splice sites of AR. […] Other deep intronic or regulatory region mutations, often missed in routine genetic screenings, may underlie CAIS in patients who still lack a molecular genetic diagnosis.

• #56 Complete androgen insensitivity syndrome caused by a deep intronic pseudoexon-activating mutation in the androgen receptor gene | Scientific Reports

  https://www.nature.com/articles/srep32819

  The deep intronic mutation causes the aberrant splicing of AR mRNA, creating two abnormally long products and a significantly reduced amount of the normal-sized mRNA. […] The destruction of the aberrant mRNA products by the NMD pathway cannot be ruled out, however, especially since the half-life of the PTC-containing mRNA products is not known. […] Regardless, AR protein was undetectable in the patient fibroblasts, which suggests that even if the aberrantly-spliced mRNAs are translated into protein, the stability of the aberrant AR protein is compromised, and that the low amount of correct mRNA does not yield significant levels of AR protein. […] In conclusion, AR cDNA together with intronic sequences should be examined in CAIS patients with normal coding region and conserved splice sites of AR. […] Other deep intronic or regulatory region mutations, often missed in routine genetic screenings, may underlie CAIS in patients who still lack a molecular genetic diagnosis.

• #57 Androgen Insensitivity Syndrome | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/17524

  Androgen insensitivity syndrome and individuals with cryptorchid testes have an increased risk of tumorigenesis. Cryptorchidism in partial androgen insensitivity syndrome (PAIS) should be corrected surgically soon after diagnosis to maintain testicular function and minimize the risk of malignancy. […] Studies have suggested an increased tumor risk of greater than 30% in late adulthood if a gonadectomy is not done.[19]

• #58 Complete androgen insensitivity syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Complete_androgen_insensitivity_syndrome

  Androgen insensitivity syndrome is the largest single entity that leads to 46, XY undermasculinization. […] The gonads in people with CAIS are testes; during the embryonic stage of development, testes form in an androgen-independent process that occurs due to the influence of the SRY gene on the Y chromosome. […] Testosterone produced by the testes cannot be directly used due to the mutant androgen receptor that characterizes CAIS; instead, it is aromatized into estrogen, which effectively feminizes the body and accounts for the normal female phenotype observed in CAIS. […] The receptor in question is encoded by the AR gene located on the X chromosome at Xq1112. At least 15 different mutations were known in 2003, and they are all recessive, which makes the disease follow X-linked recessive inheritance. […] Immature sperm cells in the testes do not mature past an early stage, as sensitivity to androgens is required in order for spermatogenesis to complete. […] CAIS is associated with an increased risk for gonadal tumors (e.g. germ cell malignancy) in adulthood if gonadectomy is not performed.

• #59 Androgen Insensitivity Syndrome | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/17524

  Androgen insensitivity syndrome and individuals with cryptorchid testes have an increased risk of tumorigenesis. Cryptorchidism in partial androgen insensitivity syndrome (PAIS) should be corrected surgically soon after diagnosis to maintain testicular function and minimize the risk of malignancy. […] Studies have suggested an increased tumor risk of greater than 30% in late adulthood if a gonadectomy is not done.[19]

• #60 Different Clinical Presentations and Management in Complete Androgen Insensitivity Syndrome (CAIS)

  https://www.mdpi.com/1660-4601/16/7/1268

  The CAIS condition has been related to a higher incidence of TGCT than in the general population. […] The exact incidence of cancer in patients with CAIS is very difficult to estimate because of the frequent change in management of this disorder over the years, particularly regarding the correct time of gonadectomy. […] Data from the literature review report a general risk of approximately 5% in AIS disorder overall and a prevalence of <1% in CAIS. [...] These data suggest that malignant progression from pre-GCNIS to invasive TCGT is very infrequent and probably takes place only in late adulthood. [...] In summary, CAIS is a condition associated with an increased risk of cancer, although cancer results less frequently in CAIS compared to other DSD.

• #61 Different Clinical Presentations and Management in Complete Androgen Insensitivity Syndrome (CAIS)

  https://www.mdpi.com/1660-4601/16/7/1268

  The CAIS condition has been related to a higher incidence of TGCT than in the general population. […] The exact incidence of cancer in patients with CAIS is very difficult to estimate because of the frequent change in management of this disorder over the years, particularly regarding the correct time of gonadectomy. […] Data from the literature review report a general risk of approximately 5% in AIS disorder overall and a prevalence of <1% in CAIS. [...] These data suggest that malignant progression from pre-GCNIS to invasive TCGT is very infrequent and probably takes place only in late adulthood. [...] In summary, CAIS is a condition associated with an increased risk of cancer, although cancer results less frequently in CAIS compared to other DSD.

• #62

  https://www.archivesofmedicalscience.com/The-challenges-of-androgen-insensitivity-syndrome,125584,0,2.html

  Partial androgen insensitivity syndrome is the result of an incomplete cellular response to androgen stimulation. The phenotype of these patients depends on the degree of androgen receptors responsiveness to androgen stimulation. […] Mild androgen insensitivity syndrome is associated with a small degree of androgen insensitivity; these patients present a male phenotype. This type of androgen insensitivity is also the result of an androgen receptor mutation, but these patients, in contrast to those with PAIS and CAIS, present normally developed male genitalia. […] In the case of AIS patients, the risk for germ cell cancer in gonads varies across the subtypes. It is considered that the number of germ cell tumours increases in individuals, simultaneous with AIS, because of the Y chromosome and presence of the testis-specific protein Y-linked 1 (TSPY) gene. […] In patients with CAIS, prostate development and masculinization are inhibited by the impaired androgen receptor function, the prostate remaining practically undeveloped.

• #63

  https://www.archivesofmedicalscience.com/The-challenges-of-androgen-insensitivity-syndrome,125584,0,2.html

  Partial androgen insensitivity syndrome is the result of an incomplete cellular response to androgen stimulation. The phenotype of these patients depends on the degree of androgen receptors responsiveness to androgen stimulation. […] Mild androgen insensitivity syndrome is associated with a small degree of androgen insensitivity; these patients present a male phenotype. This type of androgen insensitivity is also the result of an androgen receptor mutation, but these patients, in contrast to those with PAIS and CAIS, present normally developed male genitalia. […] In the case of AIS patients, the risk for germ cell cancer in gonads varies across the subtypes. It is considered that the number of germ cell tumours increases in individuals, simultaneous with AIS, because of the Y chromosome and presence of the testis-specific protein Y-linked 1 (TSPY) gene. […] In patients with CAIS, prostate development and masculinization are inhibited by the impaired androgen receptor function, the prostate remaining practically undeveloped.

• #64 Androgen Insensitivity Syndrome: Complete & Partial

  https://my.clevelandclinic.org/health/diseases/22199-androgen-insensitivity-syndrome

  Androgen insensitivity syndrome (AIS) occurs when someone is genetically male but is insensitive to androgens (male sex hormones). […] AIS is the result of an abnormal X-linked gene, meaning its a gene on the X chromosome and the mother passes it to her child. The gene cant produce androgen receptors. These are cells that allow your body to respond to androgens, such as testosterone. […] Males who inherit an abnormal gene, called the androgen receptor (AR) gene, from their mothers have a 1 in 4 chance of developing AIS. […] Androgen insensitivity syndrome is rare. About 1 in 99,000 male infants are born with partial androgen insensitivity syndrome and 2 to 5 per 100,000 are born with complete androgen insensitivity syndrome.

• #65 Orphanet: Partial androgen insensitivity syndrome

  https://www.orpha.net/en/disease/detail/90797

  A difference of sex development (DSD) distinct from complete AIS (CAIS) characterized by the presence of abnormal genital development in a 46,XY individual with normal testis development and partial responsiveness to age-appropriate levels of androgens. […] The condition is due to missense mutations in the androgen receptor (AR) gene (Xq11-12) coding for the AR nuclear transcription factor, and results in variable degrees of AR function. An AR mutation is found in only approximately 20% of patients with PAIS. […] There are no available data on the prevalence of PAIS in the general population. Nevertheless, resistance to androgens is the most frequent cause of XY DSD.

• #66 Diverse phenotypes and fertility outcomes of patients with androgen insensitivity syndrome in a Chinese family harboring identical AR gene variant | BMC Medical Genomics | Full Text

  https://bmcmedgenomics.biomedcentral.com/articles/10.1186/s12920-024-01990-9

  Androgen insensitivity syndrome (AIS) is a rare genetic disorder characterized by resistance to androgens, mainly due to mutations in the androgen receptor (AR) gene. […] The pathogenic mutations within the AR gene commonly disrupt the normal structure of AR protein, affecting its ability to bind with ligands or downstream responsive elements, thereby leading to the occurrence of AIS. […] Approximately 600 mutations in the AR gene have been reported to be related to AIS, of which missense mutations occurring in LBD or DBD are the most common. […] Different types of mutations are reported to be associated with diverse phenotypes of AIS. […] Notably, different phenotypes of AIS with the same AR gene mutation have also been previously described. […] In this study, we observed diverse intrafamilial variabilities of AIS phenotypes in the degrees of undervirilization and spermatogenesis from four affected patients within a single Chinese family.

• #67 Diverse phenotypes and fertility outcomes of patients with androgen insensitivity syndrome in a Chinese family harboring identical AR gene variant | BMC Medical Genomics | Full Text

  https://bmcmedgenomics.biomedcentral.com/articles/10.1186/s12920-024-01990-9

  The proband was diagnosed with PAIS, his old sibling was diagnosed with CAIS, whereas his two maternal uncles were both diagnosed with MAIS. […] Despite that the semen sample was not obtained, the older uncle (II-3) of proband fathered two girls naturally. […] The younger uncle (II-5) was infertile because of severe oligoasthenozoospermia (SOZ), and conceived a son by utilizing assisted reproductive technology. […] The nonsynonymous p.Phe755Leu (c.2265 CA) mutant of AR protein was first reported in PAIS by Hiort et al. in 1994. […] In the present study, we identified the same AR gene variant (c.2263TC; p.Phe755Leu) in four AIS patients from a single Chinese family with highly diverse clinical phenotypes and fertility outcomes, which expanded the phenotypic spectrum of AIS. […] Thus, phenotypic heterogeneity of AIS with identical AR variant indicated that other factors, independent of AR sequence alterations, contributed to the diverse AIS phenotypes.

• #68 Diverse phenotypes and fertility outcomes of patients with androgen insensitivity syndrome in a Chinese family harboring identical AR gene variant | BMC Medical Genomics | Full Text

  https://bmcmedgenomics.biomedcentral.com/articles/10.1186/s12920-024-01990-9

  The proband was diagnosed with PAIS, his old sibling was diagnosed with CAIS, whereas his two maternal uncles were both diagnosed with MAIS. […] Despite that the semen sample was not obtained, the older uncle (II-3) of proband fathered two girls naturally. […] The younger uncle (II-5) was infertile because of severe oligoasthenozoospermia (SOZ), and conceived a son by utilizing assisted reproductive technology. […] The nonsynonymous p.Phe755Leu (c.2265 CA) mutant of AR protein was first reported in PAIS by Hiort et al. in 1994. […] In the present study, we identified the same AR gene variant (c.2263TC; p.Phe755Leu) in four AIS patients from a single Chinese family with highly diverse clinical phenotypes and fertility outcomes, which expanded the phenotypic spectrum of AIS. […] Thus, phenotypic heterogeneity of AIS with identical AR variant indicated that other factors, independent of AR sequence alterations, contributed to the diverse AIS phenotypes.

• #69 ANDROGEN INSENSITIVITY SYNDROME (AIS)

  https://medicover-genetics.com/product/androgen-insensitivity-syndrome-ais/

  Androgen insensitivity syndrome (AIS) is characterized by feminization of the external genitalia at birth, impaired pubertal development, and subsequent infertility in a 46,XY karyotype. […] The most common cause is missense variants in the androgen receptor gene (AR) leading to AR transcription factor dysfunction. The detection rate of pathogenic variants is 95% in CAIS patients, less than 50% in PAIS patients and even lower in MAIS patients. AIS is inherited in an X-linked recessive pattern. Offspring of heterozygous mothers have a 50% probability to inherit the trait. […] AIS belongs to the heterogeneous group of Disorders of sex development (DSD). In 46,XY-DSD, pathogenic variants have been described in a number of other genes: SRY, NR5A1, SRD5A2, HSD3B2, HSD17B3, MAMLD1, NROB1, WNT4, DMRT1, SOX9, DHH, TSPYL, WWOX, and WT1.

• #70 ANDROGEN INSENSITIVITY SYNDROME (AIS)

  https://medicover-genetics.com/product/androgen-insensitivity-syndrome-ais/

  Androgen insensitivity syndrome (AIS) is characterized by feminization of the external genitalia at birth, impaired pubertal development, and subsequent infertility in a 46,XY karyotype. […] The most common cause is missense variants in the androgen receptor gene (AR) leading to AR transcription factor dysfunction. The detection rate of pathogenic variants is 95% in CAIS patients, less than 50% in PAIS patients and even lower in MAIS patients. AIS is inherited in an X-linked recessive pattern. Offspring of heterozygous mothers have a 50% probability to inherit the trait. […] AIS belongs to the heterogeneous group of Disorders of sex development (DSD). In 46,XY-DSD, pathogenic variants have been described in a number of other genes: SRY, NR5A1, SRD5A2, HSD3B2, HSD17B3, MAMLD1, NROB1, WNT4, DMRT1, SOX9, DHH, TSPYL, WWOX, and WT1.

• #71 Androgen Insensitivity Syndrome | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/17524

  The diagnosis of CAIS and PAIS includes assessing clinical and biochemical features, 46 XY karyotype, and exclusion of defects in testosterone synthesis. Furthermore, confirmation is possible with genetic testing. […] In addition to clinical features, biochemical testing may not be adequate to establish the diagnosis of CAIS or PAIS. Therefore, molecular genetic studies become imperative to diagnose CAIS or PAIS. CAIS confirmation is possible with genetic testing locations where the typical loss-of-function mutations in the coding sequence of the androgen receptor exist. […] The differential diagnosis of CAIS includes disorders of androgen biosynthesis or Leydig cell dysfunction, Mullerian agenesis, mixed gonadal dysgenesis, etc. Defects in testosterone synthesis can be the result of a defect in any of the enzymes in the pathway of testosterone synthesis or dysfunction of the LH receptor.

• #72

  https://link.springer.com/article/10.14310/horm.2002.1201

  The end-organ resistance to androgens has been designated as Androgen Insensitivity Syndrome (AIS), an X-linked disorder caused by mutations in the Androgen Receptor (AR) gene. […] More than 400 different AR gene mutations have thus far been reported but the receptor structure-function relationship and its phenotypic outcome is not yet fully understood. […] This review focuses on the clinical features and molecular pathophysiology of AIS and explores the relationship of the molecular defects in the AR gene to their clinical expression.

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