Materiały źródłowe

• #1 Androgen Insensitivity Syndrome – StatPearls – NCBI Bookshelf

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

  Androgen insensitivity syndrome (AIS) is a common etiology of sexual developmental disorders and results in varying phenotypes. […] 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. […] Androgen insensitivity syndrome is the result of profound resistance of the androgen receptor towards the action of androgen. Various studies done in women established the androgen receptor (AR) dysfunction with no detectable androgen receptor binding, leading to resistance to the virilization effect of the exogenous androgen. […] The diagnosis of CAIS and PAIS includes assessing clinical and biochemical features, 46 XY karyotype, and exclusion of defects in testosterone synthesis.

• #1 Pathogenesis and clinical features of disorders of androgen action – UpToDate

  https://www.uptodate.com/contents/pathogenesis-and-clinical-features-of-disorders-of-androgen-action

  Loss-of-function mutations of the gene that encodes the androgen receptor (AR) result in androgen insensitivity syndrome (AIS) in 46,XY individuals with functional testes and unhindered testosterone formation. AIS encompasses a clinical continuum of decreased to absent androgen effects, varying from a completely female phenotype to a male phenotype with undervirilization or infertility. […] Specific mutations of the AR gene have been identified in many patients with androgen insensitivity syndromes (AIS). Most mutations today have been localized in the hormone-binding domain and, to a lesser extent, in the DNA-binding domain and the transactivation domain. […] The androgen receptor (AR) gene has a coding region of eight exons and is located on chromosome Xq11-12. It encodes a protein of approximately 920 amino acids, which compose the typical three major functional domains of the nuclear receptor superfamily. Over 1000 mutations, as well as some larger structural alterations, have been identified in patients with all forms of androgen insensitivity syndrome, and these mutations can be spread out over the whole coding region. […] Furthermore, a distinct class of AR mutation-negative patients with AIS have been described, in whom the AR-responsive target gene apolipoprotein D (APOD) is diminished in genital skin fibroblasts. The exact molecular defect in these patients has not been identified yet.

• #1 Androgen insensitivity syndrome pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Androgen_insensitivity_syndrome_pathophysiology

  Androgen insensitivity syndrome is due to hormone resistance which may be due to defective androgen receptor (AR) function by either abnormal androgen receptor (AR) binding, decreased receptor binding, or impaired androgen receptor (AR) binding. AIS is an X linked disorder. The development of androgen insensitivity syndrome is a result of genetic mutations of the androgen receptor (AR) gene located on the chromosome Xq11-12. […] Androgen resistance may develop during fetal development and after birth. […] The hormone resistance may be due to defective androgen receptor (AR) function by either abnormal androgen receptor (AR) binding, decreased receptor binding, or impaired androgen receptor (AR) binding. […] A spectrum of phenotypes may be caused due to missense mutations in the androgen receptor (AR) protein. The two important domains of the receptor protein namely DBD and LDB domains are the ones wherein the most frequent missense mutations are found.

• #1 Androgen insensitivity syndrome – Wikipedia

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

  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. […] Exactly which steps a particular mutation will impair can be predicted, to some extent, by identifying the area of the AR in which the mutation resides. […] For example, mutations in the steroid binding domain have been known to affect androgen binding affinity or retention, mutations in the hinge region have been known to affect nuclear translocation, mutations in the DNA-binding domain have been known to affect dimerization and binding to target DNA, and mutations in the transactivation domain have been known to affect target gene transcription regulation. […] Some mutations can adversely impact more than one functional domain.

• #1 Clinical, hormonal and genetic characteristics of androgen insensitivity syndrome in 39 Chinese patients | Reproductive Biology and Endocrinology | Full Text

  https://rbej.biomedcentral.com/articles/10.1186/s12958-020-00593-0

  Abnormal androgen receptor (AR) genes can cause androgen insensitivity syndrome (AIS), and AIS can be classified into complete androgen insensitivity syndrome (CAIS), partial androgen insensitivity syndrome (PAIS) and mild AIS. […] We identified 21 reported pathogenic AR mutations and 9 novel AR mutations that led to different types of AIS. Missense mutations were the major cause of AIS and mostly occurred in exon 7 of the AR gene. […] Mutations in the AR gene can lead to AIS, and AIS requires genetic diagnosis with or without a family history of AIS because the rate of spontaneous mutation is 30%. […] Common mutations of the AR gene include missense mutations, insertions and deletions. Most of these mutations are relevant to AIS, and few are related to gonadal tumours. […] The most common mutations identified in this study were missense mutations, and exon 7 was the exon that was most prone to mutation.

• #1 Androgen insensitivity syndrome – Wikipedia

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

  A single mutation can affect all downstream functional domains if a premature stop codon or framing error results; such a mutation can result in a completely unusable (or unsynthesizable) androgen receptor protein. […] The steroid binding domain is particularly vulnerable to the effects of a premature stop codon or framing error, since it occurs at the end of the gene, and its information is thus more likely to be truncated or misinterpreted than other functional domains.

• #1 Mechanism of mutagenesis and phenotype implications of small indels in the Androgen Receptor gene in Androgen Insensitivity Syndrome | ESPE2023 | 61st Annual ESPE (ESPE 2023) | ESPE Abstracts

  https://abstracts.eurospe.org/hrp/0097/hrp0097p1-176

  Mechanism of mutagenesis and phenotype implications of small indels in the Androgen Receptor gene in Androgen Insensitivity Syndrome […] To explore the contribution of indels in a monogenic disorder, we analyzed all indels already described in the AR gene, including three novel indels found in our cohort. […] We present 82 different indels in the AR gene reported in individuals with AIS. […] Most short indels in the AR gene among AIS are frameshift indels (n=64; 79%). […] Most indels are short (10 bp; n=81 = 98.8%), with an average of 2.4 nucleotides by indel. […] In summary, indels represent a significant portion of the variants identified in the AR gene in patients with AIS. […] However, small NFS indels at small triplet runs can slightly compromise AR function leading to the mild phenotype. […] These results increase the molecular understanding of the androgen receptor disruption and the underlined mechanisms of indel mutagenesis in exonic regions and their implication on phenotype.

• #1

  https://journals.lww.com/10.4103/aja.aja_32_17

  To date, over 1000 AIS-causing variants in the AR gene have been identified. Among these variants, missense mutations are the most common anomalies, while splicing mutations are rare. […] Here, we identified a novel mutation (c.2450-6CG; RefSeqNM_000044.4) in the polypyrimidine tract of the AR gene in a CAIS patient, which led to an aberrant splicing product. […] The polypyrimidine tract mutation (c.2450-6 CG) in intron 6 of the AR gene in the patient formed a new conserved dinucleotide (AG) upstream of the original splice site at the 3 terminus. […] This alternative splicing pathway generated an aberrant splicing product. Our report provides the first evidence of this type of mutation in the AR gene. […] Use of the newly created alternative splice acceptor site results in an aberrant transcript that includes five nucleotides (ATCAG) inserted between exons 6 and 7. This insertion leads to a frameshift with a premature stop codon in exon 7 (p.Ile817AsnfsX8; RefProtNP_000035.2), which could induce a truncated AR protein lacking the last 107 amino acids of the LBD.

• #1 Pathogenesis and clinical features of disorders of androgen action – UpToDate

  https://www.uptodate.com/contents/pathogenesis-and-clinical-features-of-disorders-of-androgen-action/print

  Loss-of-function mutations of the gene that encodes the androgen receptor (AR) result in androgen insensitivity syndrome (AIS) in 46,XY individuals with functional testes and unhindered testosterone formation. AIS encompasses a clinical continuum of decreased to absent androgen effects, varying from a completely female phenotype to a male phenotype with undervirilization or infertility. […] Specific mutations of the AR gene have been identified in many patients with androgen insensitivity syndromes (AIS). Most mutations today have been localized in the hormone-binding domain and, to a lesser extent, in the DNA-binding domain and the transactivation domain. […] Mutations in the 5′ untranslated region of the AR gene have also been described, which impair AR function by reducing AR protein levels.

• #1 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. […] We show that a deep intronic pseudoexon-activating mutation in the intron between exons 6 and 7 of AR, detected in two siblings with CAIS with normal AR coding region and conserved splice sites, leads to aberrant splicing of the AR mRNA and insufficient AR protein production. […] In our knowledge, although several splicing mutations of AR have already been reported in AIS patients, most are situated in the conserved splice sites close to the exon-intron junctions. […] Here, we show that the deep intronic mutation identified in this study severely disrupts the normal splicing through pseudoexon activation, a mechanism that is increasingly being recognized as a cause of human disorders, but, in our knowledge, has not been earlier demonstrated in AIS.

• #1 Androgen insensitivity syndrome (AIS) | Britannica

  https://www.britannica.com/science/androgen-insensitivity-syndrome

  androgen insensitivity syndrome (AIS), rare genetic disorder in which a genetically male individual fails to respond naturally to the effects of male hormones (also known as androgens). Androgen insensitivity syndrome (AIS) is an X-chromosome-linked recessive disorder, being caused by a mutation that is inherited on a single X chromosome. Inherited androgen resistance results in diminished virilization of the male external genitalia. […] The degree to which the male external genitalia are feminized depends on the functionality of the androgen receptor. Deletion of the receptor gene results in complete AIS (CAIS), in which the individuals external genitalia appear female. Reduction in androgen receptor functionality results in partial AIS (PAIS). PAIS is graded on the extent of feminization of external genitalia, which can be ambiguous at birth.

• #1 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. These mutations can cause a variety of functional defects, ranging from a complete loss of receptors on the cell surface because of incomplete protein synthesis to alterations in substrate binding affinity. Altered substrate binding affinity causes a signal transmission loss, despite normal cell surface receptor numbers.

• #1 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). It is organized in eight exons located on the X chromosome. Hundreds of genetic variants in the AR gene have been reported in CAIS. […] According to some AR mutation databases, hundreds of pathogenetic mutations related to CAIS are known. 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. […] In the absence of any mutation in the AR gene, but in the presence of the phenotype as well as biochemical data suggesting AIS, an altered signaling pathway due to the impairment of some coactivators or some postligand binding factor has been suggested. However, mutations in cofactor genes have not been found in the large majority of such cases; if so, this hypothesis will require more investigations.

• #1 Androgen insensitivity syndrome Information | Mount Sinai – New York

  https://www.mountsinai.org/health-library/diseases-conditions/androgen-insensitivity-syndrome

  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. […] Treatment and gender assignment can be a very complex issue and must be targeted to each individual person. Treatment guidelines are still evolving.

• #1

  https://step1.medbullets.com/evidence/20301602

  Androgen insensitivity syndrome (AIS) is typically characterized by evidence of feminization (i.e., undermasculinization) of the external genitalia at birth, abnormal secondary sexual development in puberty, and infertility in individuals with a 46,XY karyotype. AIS represents a spectrum of defects in androgen action and can be subdivided into three broad phenotypes: Complete androgen insensitivity syndrome (CAIS), with typical female external genitalia. Partial androgen insensitivity syndrome (PAIS) with predominantly female, predominantly male, or ambiguous external genitalia. Mild androgen insensitivity syndrome (MAIS) with typical male external genitalia. […] 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. […] AIS is inherited in an X-linked manner. Affected 46,XY individuals are almost always infertile.

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

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

  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.

• #1 Androgen insensitivity syndrome pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Androgen_insensitivity_syndrome_pathophysiology

  The phenotypic variability impacts and translates the degree to which ligand-binding and receptor functions are disrupted by different substitutions. […] The genetic background has an influence on the resulting phenotype as a result of the same mutation which may lead to different forms of AIS within a family. […] Mutations in the androgen receptor (AR) gene helps as a trusted tool for the diagnosis and molecular subclassification of AIS. The resulting phenotype is affected by the kind of amino acid substitution occurring due to mutation. […] Information regarding the mutation in the androgen receptor (AR) and its functional consequences helps in determining the genotype-phenotype correlation, to improve and better manage the cases of male pseudohermaphroditism pertaining to surgery of the genitalia, gonadectomy and gender assignment.

• #1 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. It can manifest as complete AIS, partial AIS and mild AIS. […] 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. […] 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. Genetic sequencing identified the same missense hemizygous variant (NM_000044.3:c.2263TC;p.Phe755Leu) of AR gene in all affected individuals. […] Our study first identified the same AR variant (c.2263TC;p.Phe755Leu) in four affected patients displaying highly diverse phenotypes of AIS and fertility outcomes, thereby significantly expanding the phenotypic spectrum of AIS. Notably, we presented a clear insight into different fertility outcomes of AIS patients with identical AR (c.2263TC;p.Phe755Leu) variant, which provided reliable evidence that males harboring this variant may obtain biological offspring naturally or in combination with assisted reproductive technology.

• #1

  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 AR gene is located in the Xq11-13 region of the X chromosome and contains 8 exons that encode the androgen receptor. The AR is a large polypeptide (containing 920 amino acids) that belongs to the steroid hormone receptor family and it presents 4 functional domains. […] 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. This protein (TDF) is responsible for activation of two other proteins, SOX9 and SF1 (steroid genetic factor 1), which promote differentiation of the bipotent cells of the embryonic gonads into Sertoli cells, therefore leading to the appearance of the primordial testes. These two proteins (SOX9 and SF1) regulate the Sertoli cells production of anti-Mullerian hormone (AMH), which suppresses the development of the uterus and fallopian tubes from the Mullerian ducts, favouring instead the development of the Wolffian ducts. Leydig cells maturation is promoted by the Desert Hedgehog protein (DHH), which is produced by Sertoli cells. It has been reported that anomalies of this protein can be responsible for 46XY gonadal abnormal development.

• #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. In people with androgen insensitivity syndrome, the body’s cells and tissues are unable to respond to certain male sex hormones (called androgens) that are important for normal male 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. […] 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.

• #1 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. […] This unresponsiveness can impair or prevent the development of male genitals, as well as impairing or preventing the development of male secondary sexual characteristics at puberty. […] 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). […] 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.

• #1 Molecular mechanism of androgen receptor mutation in multigenerational mild androgen insensitivity syndrome in: Endocrine Connections Volume 14 Issue 1 (2025)

  https://ec.bioscientifica.com/view/journals/ec/14/1/EC-24-0567.xml

  Androgen insensitivity syndrome (AIS) due to androgen receptor (AR) mutations creates a spectrum of clinical presentations based on residual AR function with the mildest impairment creating mild AIS (MAIS) whose undefined molecular mechanism and subtle clinical features leave it less understood and underdiagnosed. […] The missense AR exon 8 mutation (nucleotide aga gga, p.R872G arginine to glycine), known to cause an increased ligand dissociation rate in mutant AR in binding assays, was analyzed. Modeling shows that the mutation weakens the closure energy of the lid of the ligand-binding pocket, allowing easier ligand dissociation from the binding site but with unimpaired in vitro androgen bioactivity. […] The novel molecular mechanism of an AR ligand-binding domain mutation in MAIS may be present in other cases of MAIS.

• #1 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20230327/Discovery-enables-a-clear-diagnosis-for-more-patients-with-androgen-insensitivity-syndrome.aspx

  The new research findings show that filamentous actin, a component of the cytoskeleton, interacts with the androgen receptor directly in the cell nucleus and strengthens its effect. […] The researchers became aware of the previously unknown connection between actin and steroid hormones while studying the cells of patients with a so-called androgen insensitivity syndrome (AIS). […] This is often due to a change in the androgen receptor, which means that male sex hormones can no longer take effect. […] The discovery also provides a basis for further research on the development of sexual characteristics and enables a clear diagnosis for more patients with AIS: „Previously, patients with androgen insensitivity but without a modification in the androgen receptor did not receive a clear diagnosis despite having clear symptoms,” says Hornig. „Now we can make a clear diagnosis for those in whom DAAM2 is altered.”

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

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

  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. This results in the phenotype of prenatal undervirilization of external genitalia, absence of pubic and axillary hair, lack of acne, and absence of voice changes at puberty.

• #1 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. […] 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. […] Wolffian structures (the epididymides, vasa deferentia, and seminal vesicles) are typically absent, but will develop at least partially in approximately 30% of cases, depending on which mutation is causing the CAIS.

• #1 Complete androgen insensitivity syndrome – Wikipedia

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

  However, luteinizing hormone (LH) levels are elevated while sex hormone-binding globulin (SHBG) levels are more consistent with those of females. […] The production rates of testosterone, estradiol, and estrone have been reported to be higher in gonadally intact with CAIS than in men. […] CAIS is associated with a decreased bone mineral density. […] Some have hypothesized that the decreased bone mineral density observed in women with CAIS is related to the timing of gonadectomy and inadequate estrogen supplementation. […] However, recent studies show that bone mineral density is similar whether gonadectomy occurs before or after puberty, and is decreased despite estrogen supplementation, leading some to hypothesize that the deficiency is directly attributable to the role of androgens in bone mineralization. […] CAIS is also associated with an increased risk for gonadal tumors (e.g. germ cell malignancy) in adulthood if gonadectomy is not performed. […] The risk of malignant germ cell tumors in women with CAIS increases with age and has been estimated to be 3.6% at 25 years and 33% at 50 years.

• #1 Orphanet: Complete androgen insensitivity syndrome

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

  The diagnosis is based on clinical and biochemical findings in a female with a 46,XY karyotype. The typical hormone profile is increased basal luteinizing hormone (LH) and testosterone levels in adults, and increased testosterone levels in infants following human chorionic gonadotropin (hCG) stimulation. […] Mutation analysis of the AR gene confirms the diagnosis.

• #1 Androgen insensitivity syndrome pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Androgen_insensitivity_syndrome_pathophysiology

  As a result of the defective androgen receptor (AR) due to imperfect feedback mechanism of testosterone at the pituitary and hypothalamus there are elevated levels of serum testosterone, FSH and LH observed. […] Testosterone biosynthetic defects are ruled out by the normal serum 17 hydroxyprogesterone, DHEA and androstenedione levels. […] Sufficient peripheral conversion of testosterone is indicative of normal estradiol level.

• #1

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

  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. During the intrauterine life, the normal virilisation process usually takes place between the 8th and the 14th week. This process depends on androgen production and AR capability to bind the androgens. Therefore, the existence of a mutation that affects the androgen production or the androgen receptor will impair the normal virilisation process in 46XY embryos. Due to the insensitivity of androgen receptors to testosterone and dihydrotestosterone, AIS embryos will develop different phenotypes according to AR sensitivity to androgens, this varying from a complete feminine phenotype (in complete androgen insensitivity) to a male phenotype, but with altered spermatogenesis (mild androgen insensitivity). There is an intermediate form, characterized by partial androgen insensitivity, which leads to a male phenotype (usually these patients have associated malformations such as micropenis, hypospadias, bifid scrotum) or to ambiguous genitalia.

• #1

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

  In patients with CAIS, prostate development and masculinization are inhibited by the impaired androgen receptor function, the prostate remaining practically undeveloped. In PAIS patients, prostate is significantly smaller compared to normal male patients, often being impalpable, whereas MAIS patients usually present a quasi-normally developed prostate. Therefore, the risk of prostate cancer and benign prostatic hyperplasia in patients with CAIS is virtually absent, whereas in patients with partial and mild androgen resistance syndrome this risk can be increased by the exogenous androgen supplementation with testosterone and dihydrotestosterone, as well as by the type of androgen receptor mutation. […] In conclusion, androgen insensitivity syndrome is a frequent 46XY disorder of sex development, the mechanism involved being an AR mutation. The clinical presentation of AIS depends on the AR sensitivity to testosterone and dihydrotestosterone stimulation, varying from male phenotype and infertility to female phenotype with a 46XY karyotype. The diagnosis in patients with mild AIS is made usually during adulthood due to infertility or during puberty due to the development of gynecomastia, whereas in patients with complete androgen insensitivity the diagnosis can be made during pregnancy, at birth, during childhood or adulthood. For cases with PAIS, the diagnosis is made in most cases at birth due to the presence of ambiguous genitalia. The treatment in CAIS patients implies bilateral orchiectomy to prevent malignant degeneration of the testes and hormonal therapy to maintain the normal female phenotype, despite the 46XY karyotype. The timing of gonadectomy has been debated by many authors, but current guidelines recommend postponing it until after puberty, to achieve complete natural feminization and due to the fact that the risk of testicular tumours in CAIS patients is low before adulthood. Compared with CAIS patients, PAIS patients present a higher risk of developing testicular tumours. Establishing the correct sex assignment may be very difficult in PAIS patients, because they present ambiguous genitalia. The management of AIS requires a multidisciplinary team of paediatricians, endocrinologists, gynaecologists, urologists, plastic surgeons and psychiatrists. Psychological counselling should be recommended for these patients and their parents.

• #1 Androgen insensitivity syndrome pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Androgen_insensitivity_syndrome_pathophysiology

  The lack of virilization of external genitalia is due to the failure of genital folds to fuse and to form scrotum and penis. […] The agenesis of the fallopian tubes, uterus, cervix and proximal vagina is due to the simultaneous testicular production of mullerian inhibiting factor which regresses the mullerian structures. […] In CAIS (complete androgen insensitivity syndrome), the development of the wolffian duct and the differentiation of male external genitalia do not occur correctly, and the Mullerian ducts regress due to the presence of anti-Mullerian hormone (AMH) produced by the sertoli cells of normally developed gonads. The residual Mullerian structures exist in approximately one third of patients. […] The female phenotype along with breast development is a result of the peripheral aromatization of testosterone into estrogen.

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

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

  Androgen insensitivity syndrome (AIS) is typically characterized by evidence of feminization (i.e., undermasculinization) of the external genitalia at birth, abnormal secondary sexual development in puberty, and infertility in individuals with a 46,XY karyotype. AIS represents a spectrum of defects in androgen action and can be subdivided into three broad phenotypes: […] 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.

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

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

  AIS is inherited in an X-linked manner. Affected 46,XY individuals are almost always infertile. Each offspring of a female known to carry an AR pathogenic variant (heterozygote) is at a 25% risk for each of the following: […] The diagnosis of AIS is established in a 46,XY proband with: 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 LH production by the pituitary gland; AND/OR a hemizygous pathogenic (or likely pathogenic) variant in AR identified by molecular genetic testing. […] More than 550 single-nucleotide variants in AR have been found to cause AIS. The great majority are missense variants that impair DNA or androgen binding and cause CAIS or PAIS; a small number have been proven to cause MAIS.

• #1 Pathogenesis and clinical features of disorders of androgen action – UpToDate

  https://www.uptodate.com/contents/pathogenesis-and-clinical-features-of-disorders-of-androgen-action/print

  Androgen action via the AR leads to long-term programming effects by implementing stable functional and structural androgen-dependent traits. These occur during defined androgen-sensitive time windows of individual ontogenesis. Therefore, the AR acts in concert with many other co-factors to induce individual effects within each cell and organ, including the brain. […] The androgen receptor (AR) gene has a coding region of eight exons and is located on chromosome Xq11-12. It encodes a protein of approximately 920 amino acids, which compose the typical three major functional domains of the nuclear receptor superfamily. Over 1000 mutations, as well as some larger structural alterations, have been identified in patients with all forms of androgen insensitivity syndrome, and these mutations can be spread out over the whole coding region. […] Furthermore, a distinct class of AR mutation-negative patients with AIS have been described, in whom the AR-responsive target gene apolipoprotein D (APOD) is diminished in genital skin fibroblasts. The exact molecular defect in these patients has not been identified yet.

• #1 Androgen Insensitivity Syndrome – StatPearls – NCBI Bookshelf

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

  Management of androgen insensitivity syndrome involves a holistic approach toward the psychological, physiological, and social well-being of the individual suffering from this disorder. […] Androgen insensitivity syndrome and individuals with cryptorchid testes have an increased risk of tumorigenesis. […] Studies have suggested an increased tumor risk of greater than 30% in late adulthood if a gonadectomy is not done. […] Untreated or inadequately managed AIS may result in severe psychological distress in patients as they go through puberty into adulthood and their families at the same time.

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

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

  In patients with CAIS the real need of gonadectomy is still debated: in fact on one hand the syndrome is associated with an increased risk of testicular germ cell tumour (TGCT), so gonads should be removed in order to prevent testicular cancer; on the other hand, the postponement of gonadectomy until at least puberty allows spontaneous pubertal development thanks to oestradiol deriving from the peripheral aromatization of testosterone produced by the retained testes. […] The CAIS condition has been related to a higher incidence of TGCT than in the general population. […] 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. The majority of tumoral lesions detected are non-invasive ones, with a low rate of progression into aggressive forms.

• #1 Androgen Insensitivity syndrome | Contact

  https://contact.org.uk/conditions/androgen-insensitivity-syndrome/

  This condition is caused by a genetic defect in the androgen (male hormone) receptor, which enables the male hormone, testosterone, to have its affect. […] The most important part of the management of AIS is the explanation and counselling given to the parents as to what and how to tell the child. This should involve an expert psychologist. […] In partial androgen insensitivity, the genetic abnormality in the androgen receptor produces an incomplete block of male hormone action.

• #1 Pacific Center for Sex and Society – Androgen Insensitivity Syndrome and Klinefelter’s Syndrome

  http://www.hawaii.edu/PCSS/biblio/articles/2000to2004/2004-ais-and-klinefelters.html

  The value of androgens for those who have AIS probably is related to the exact nature of the mutation that is involved because it helps a few people but not most. In large dosages, testosterone was successful in producing significant phallic growth and enhancing male living. DHT was helpful in restoring male genital development in an infant who had PAIS.

• #2 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. These mutations can cause a variety of functional defects, ranging from a complete loss of receptors on the cell surface because of incomplete protein synthesis to alterations in substrate binding affinity. Altered substrate binding affinity causes a signal transmission loss, despite normal cell surface receptor numbers.

• #2

  https://journals.lww.com/10.4103/aja.aja_32_17

  Androgen insensitivity syndrome (AIS) is a common 46, XY disorder of sex development resulting from androgen resistance. AIS can be subdivided into three phenotypes according to the degree of external genital defects: complete AIS (CAIS), with typical female external genitalia; partial AIS, with predominantly male or ambiguous external genitalia; and mild AIS, with typical male external genitalia. CAIS is the classical manifestation of AIS. Individuals affected by CAIS typically exhibit inguinal swellings during infancy or primary amenorrhea during puberty. AIS is usually caused by mutations in the androgen receptor (AR) gene. […] The AR gene is located on chromosome Xq11-12 and encodes a 920-amino acid residue protein. This protein functions as a steroid-hormone-activated transcription factor and contains three major functional domains: the N-terminal domain, the DNA-binding domain, and the ligand-binding domain (LBD), which is involved in binding to androgens and relevant coactivator proteins.

• #2 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 insensitivity syndrome is the result of profound resistance of the androgen receptor towards the action of androgen. Various studies done in women established the androgen receptor (AR) dysfunction with no detectable androgen receptor binding, leading to resistance to the virilization effect of the exogenous androgen. The androgen receptor nuclear receptor contains a hormone-binding domain and an N-terminal region used for transactivation, and most mutations cause androgen receptor dysfunction to localize specifically in the hormone-binding domain.[5]

• #2 Pathogenesis and clinical features of disorders of androgen action – UpToDate

  https://www.uptodate.com/contents/pathogenesis-and-clinical-features-of-disorders-of-androgen-action/print

  Loss-of-function mutations of the gene that encodes the androgen receptor (AR) result in androgen insensitivity syndrome (AIS) in 46,XY individuals with functional testes and unhindered testosterone formation. AIS encompasses a clinical continuum of decreased to absent androgen effects, varying from a completely female phenotype to a male phenotype with undervirilization or infertility. […] Specific mutations of the AR gene have been identified in many patients with androgen insensitivity syndromes (AIS). Most mutations today have been localized in the hormone-binding domain and, to a lesser extent, in the DNA-binding domain and the transactivation domain. […] Mutations in the 5′ untranslated region of the AR gene have also been described, which impair AR function by reducing AR protein levels.

• #2 Androgen insensitivity syndrome pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Androgen_insensitivity_syndrome_pathophysiology

  Androgen insensitivity syndrome is due to hormone resistance which may be due to defective androgen receptor (AR) function by either abnormal androgen receptor (AR) binding, decreased receptor binding, or impaired androgen receptor (AR) binding. AIS is an X linked disorder. The development of androgen insensitivity syndrome is a result of genetic mutations of the androgen receptor (AR) gene located on the chromosome Xq11-12. […] Androgen resistance may develop during fetal development and after birth. […] The hormone resistance may be due to defective androgen receptor (AR) function by either abnormal androgen receptor (AR) binding, decreased receptor binding, or impaired androgen receptor (AR) binding. […] A spectrum of phenotypes may be caused due to missense mutations in the androgen receptor (AR) protein. The two important domains of the receptor protein namely DBD and LDB domains are the ones wherein the most frequent missense mutations are found.

• #2 Clinical, hormonal and genetic characteristics of androgen insensitivity syndrome in 39 Chinese patients | Reproductive Biology and Endocrinology | Full Text

  https://rbej.biomedcentral.com/articles/10.1186/s12958-020-00593-0

  In this research, we identified 21 reported pathogenic AR gene mutations in 29 patients, and we detected 9 novel mutations, including c.2107TC (p. Ser703Pro), c.2740CG, c.2351AG (p. Gln784Arg), c.2024TA (p. Leu675Gln), c.1684AT (p. Ile562Phe), c.2221TA (p. Ser741Thr) and c.2441TA (p.Phe814Tyr. […] These findings will provide deeper insight into AIS and contribute to its clinical assessment.

• #2 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. […] We show that a deep intronic pseudoexon-activating mutation in the intron between exons 6 and 7 of AR, detected in two siblings with CAIS with normal AR coding region and conserved splice sites, leads to aberrant splicing of the AR mRNA and insufficient AR protein production. […] In our knowledge, although several splicing mutations of AR have already been reported in AIS patients, most are situated in the conserved splice sites close to the exon-intron junctions. […] Here, we show that the deep intronic mutation identified in this study severely disrupts the normal splicing through pseudoexon activation, a mechanism that is increasingly being recognized as a cause of human disorders, but, in our knowledge, has not been earlier demonstrated in AIS.

• #2 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.

• #2 Androgen insensitivity syndrome – Wikipedia

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

  A single mutation can affect all downstream functional domains if a premature stop codon or framing error results; such a mutation can result in a completely unusable (or unsynthesizable) androgen receptor protein. […] The steroid binding domain is particularly vulnerable to the effects of a premature stop codon or framing error, since it occurs at the end of the gene, and its information is thus more likely to be truncated or misinterpreted than other functional domains.

• #2 Two Korean girls with complete androgen insensitivity syndrome diagnosed in infancy

  https://e-apem.org/journal/view.php?number=749

  Mutations in the AR gene cause malfunctions of the AR including loss of function and morphological alterations, many of which are associated with AIS. […] The AR gene that induces AIS is situated on the proximal long arm of the X chromosome, specifically locus Xq11-Xq12. The AR gene encodes four functional domains: the N-terminal domain, which serves as a transcriptional activator, a central DNA-binding domain rich in cysteine residues, a hinge region containing a nuclear-targeting signal and a C-terminal ligand-binding domain (LBD). […] The majority of AR mutations are X-linked recessive, and there are approximately 500 known AR mutations. An AR mutation is found in more than 95% of CAIS patients; therefore, if there is no AR mutation and the patient has a phenotype consistent with CAIS, it is necessary to investigate whether there is an abnormality in AR protein expression.

• #2 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.

• #2

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

  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). […] 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. Most patients are born with incompletely developed and atypical male genitalia, or ambiguous genitalia at birth. Therefore, establishing the correct gender of new-born patients with genital anomalies and development of an appropriate therapeutic protocol require identification of the presence of an androgen receptor mutation for the diagnosis. […] 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. Until now, a small number of androgen receptor mutations that are strictly responsible for MAIS have been reported.

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

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

  Androgen insensitivity syndrome (AIS) is typically characterized by evidence of feminization (i.e., undermasculinization) of the external genitalia at birth, abnormal secondary sexual development in puberty, and infertility in individuals with a 46,XY karyotype. AIS represents a spectrum of defects in androgen action and can be subdivided into three broad phenotypes: […] 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.

• #2 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 nonsynonymous p.Phe755Leu (c.2265 CA) mutant of AR protein was first reported in PAIS by Hiort et al. in 1994. […] These studies indicated that the phenotypic heterogeneity can be partially attributed to the different types of mutation occurring at codon 755, resulting in various degrees of reduction in androgen binding capacity and/or transcriptional activation. […] 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. […] Androgens concentration may play an important role in the phenotypic diversity of AIS, and deserve further investigation.

• #2 Pathogenesis and clinical features of disorders of androgen action – UpToDate

  https://www.uptodate.com/contents/pathogenesis-and-clinical-features-of-disorders-of-androgen-action

  Loss-of-function mutations of the gene that encodes the androgen receptor (AR) result in androgen insensitivity syndrome (AIS) in 46,XY individuals with functional testes and unhindered testosterone formation. AIS encompasses a clinical continuum of decreased to absent androgen effects, varying from a completely female phenotype to a male phenotype with undervirilization or infertility. […] Specific mutations of the AR gene have been identified in many patients with androgen insensitivity syndromes (AIS). Most mutations today have been localized in the hormone-binding domain and, to a lesser extent, in the DNA-binding domain and the transactivation domain. […] The androgen receptor (AR) gene has a coding region of eight exons and is located on chromosome Xq11-12. It encodes a protein of approximately 920 amino acids, which compose the typical three major functional domains of the nuclear receptor superfamily. Over 1000 mutations, as well as some larger structural alterations, have been identified in patients with all forms of androgen insensitivity syndrome, and these mutations can be spread out over the whole coding region. […] Furthermore, a distinct class of AR mutation-negative patients with AIS have been described, in whom the AR-responsive target gene apolipoprotein D (APOD) is diminished in genital skin fibroblasts. The exact molecular defect in these patients has not been identified yet.

• #2 Molecular mechanism of androgen receptor mutation in multigenerational mild androgen insensitivity syndrome in: Endocrine Connections Volume 14 Issue 1 (2025)

  https://ec.bioscientifica.com/view/journals/ec/14/1/EC-24-0567.xml

  Based on identifying the exon 8 point mutation in the AR ligand-binding domain (LBD) with functional AR-binding studies showing rapid dissociation of the ligand from the mutant compared with the WT AR, it is identified that the mutation loosens the binding strength of the lid that closes the ligand-binding pocket. Nevertheless, the androgen bioactivity in a well-characterized in vitro androgen bioassay was not different from the WT AR. […] The present dynamic structural molecular modeling suggests that the arginine at position 872 in the LBD of the AR (mutated in this family) plays a major role in promoting the correct folding of the LBD, notably stabilizing the helix forming the lid of the binding pocket, which effectively locks in the ligand to the binding site. The looser locking of the binding site lid in the mutant AR provides a plausible explanation of its previously demonstrated faster ligand dissociation rate.

• #2

  https://journals.lww.com/10.4103/aja.aja_32_17

  The mutation in the present case may interfere with receptor homodimerization, resulting in CAIS. […] In conclusion, a rare and novel polypyrimidine tract mutation in the AR gene resulting in a rare abnormal splicing mechanism was identified in a patient with CAIS. Our study expands the spectrum of AR gene mutations and may increase the current understanding of the molecular mechanisms involved in splicing defects and may provide relevant information for genetic and reproductive counseling for families with androgen insensitivity syndrome.

• #2 Androgen insensitivity syndrome pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Androgen_insensitivity_syndrome_pathophysiology

  As a result of the defective androgen receptor (AR) due to imperfect feedback mechanism of testosterone at the pituitary and hypothalamus there are elevated levels of serum testosterone, FSH and LH observed. […] Testosterone biosynthetic defects are ruled out by the normal serum 17 hydroxyprogesterone, DHEA and androstenedione levels. […] Sufficient peripheral conversion of testosterone is indicative of normal estradiol level.

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

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

  AIS is inherited in an X-linked manner. Affected 46,XY individuals are almost always infertile. Each offspring of a female known to carry an AR pathogenic variant (heterozygote) is at a 25% risk for each of the following: […] The diagnosis of AIS is established in a 46,XY proband with: 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 LH production by the pituitary gland; AND/OR a hemizygous pathogenic (or likely pathogenic) variant in AR identified by molecular genetic testing. […] More than 550 single-nucleotide variants in AR have been found to cause AIS. The great majority are missense variants that impair DNA or androgen binding and cause CAIS or PAIS; a small number have been proven to cause MAIS.

• #3 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 insensitivity syndrome is the result of profound resistance of the androgen receptor towards the action of androgen. Various studies done in women established the androgen receptor (AR) dysfunction with no detectable androgen receptor binding, leading to resistance to the virilization effect of the exogenous androgen. The androgen receptor nuclear receptor contains a hormone-binding domain and an N-terminal region used for transactivation, and most mutations cause androgen receptor dysfunction to localize specifically in the hormone-binding domain.[5]

• #3 Pathogenesis and clinical features of disorders of androgen action – UpToDate

  https://www.uptodate.com/contents/pathogenesis-and-clinical-features-of-disorders-of-androgen-action/print

  Androgen action via the AR leads to long-term programming effects by implementing stable functional and structural androgen-dependent traits. These occur during defined androgen-sensitive time windows of individual ontogenesis. Therefore, the AR acts in concert with many other co-factors to induce individual effects within each cell and organ, including the brain. […] The androgen receptor (AR) gene has a coding region of eight exons and is located on chromosome Xq11-12. It encodes a protein of approximately 920 amino acids, which compose the typical three major functional domains of the nuclear receptor superfamily. Over 1000 mutations, as well as some larger structural alterations, have been identified in patients with all forms of androgen insensitivity syndrome, and these mutations can be spread out over the whole coding region. […] Furthermore, a distinct class of AR mutation-negative patients with AIS have been described, in whom the AR-responsive target gene apolipoprotein D (APOD) is diminished in genital skin fibroblasts. The exact molecular defect in these patients has not been identified yet.

• #3

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

  Androgen insensitivity syndrome (AIS) is an X-linked recessive genetic syndrome that occurs as result of an androgen receptor mutation; it affects the normal masculinization process in chromosomal male patients. More than 900 androgen receptor mutations that can lead to AIS have been identified. The complete androgen insensitivity is characterized by a total lack of response to androgens, usually in patients with 46XY karyotype but with feminine phenotype. Primary amenorrhoea and inguinal swellings in female patients are the main signs that could raise suspicion for this syndrome. Patients with partial androgen insensitivity have ambiguous genitalia at birth and gynecomastia during puberty, whereas those with mild androgen insensitivity present a normal male phenotype but altered spermatogenesis during adulthood and pubertal gynecomastia. The diagnosis of AIS often proves to be a challenge; its management is complex and requires a multidisciplinary approach to meet decision-making challenges in sex assignment, fertility and timing of gonadectomy, psychological outcomes and genetic counselling.

• #3

  https://journals.lww.com/10.4103/aja.aja_32_17

  To date, over 1000 AIS-causing variants in the AR gene have been identified. Among these variants, missense mutations are the most common anomalies, while splicing mutations are rare. […] Here, we identified a novel mutation (c.2450-6CG; RefSeqNM_000044.4) in the polypyrimidine tract of the AR gene in a CAIS patient, which led to an aberrant splicing product. […] The polypyrimidine tract mutation (c.2450-6 CG) in intron 6 of the AR gene in the patient formed a new conserved dinucleotide (AG) upstream of the original splice site at the 3 terminus. […] This alternative splicing pathway generated an aberrant splicing product. Our report provides the first evidence of this type of mutation in the AR gene. […] Use of the newly created alternative splice acceptor site results in an aberrant transcript that includes five nucleotides (ATCAG) inserted between exons 6 and 7. This insertion leads to a frameshift with a premature stop codon in exon 7 (p.Ile817AsnfsX8; RefProtNP_000035.2), which could induce a truncated AR protein lacking the last 107 amino acids of the LBD.

• #3 Complete Androgen Insensitivity Syndrome: A Rare Case with 47, XXY/46, XY Mosaic Karyotype and Literature Review

  https://clinmedjournals.org/articles/ogcr/obstetrics-and-gynaecology-cases-reviews-ogcr-9-227.php

  The karyotype, gonad (testis) and androgen secretion of CAIS patients are all normal, but AR function is defective, the biological effect of androgen is lost, and androgen is converted into estrogen by aromatase in peripheral tissue, which combinedly promote the external genitalia develop towards females in embryonic stage. […] It is reported that 70% of CAIS were caused by genetic factors, which were passed on to offspring through female carriers, and another 30% were gene de novo mutations. […] At present, the research on AIS has advanced to molecular and gene levels, but its clinical diagnosis still needs to be established on the combination with clinical manifestations, sex hormone determination, gonadal pathological examination and family genetic history. […] For patients with CAIS, the key to clinical treatment lies in timely orchiectomy and estrogen supplementation.

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