Materiały źródłowe

• #1 Pathophysiology of childhood polycystic kidney diseases: new insights into disease-specific therapy | Pediatric Research

  https://www.nature.com/articles/pr2013191

  Autosomal recessive polycystic kidney disease (ARPKD) is a dual-organ hepatorenal disease with an incidence of 1:20,000 to 1:40,000 and a heterozygote carrier rate of 1 in 70. […] ARPKD occurs as a result of mutations in a single gene, polycystic kidney and hepatic disease 1 (PKHD1). […] Mutation analysis of the PKHD1 gene has shown that ARPKD may present in individuals older than age 20, a finding that has significantly broadened the clinical spectrum of the disease. […] ARPKD belongs to a group of congenital hepatorenal fibrocystic syndromes and is a cause of significant renal and liver-related morbidity and mortality in children. […] Nearly 50% of affected individuals surviving the neonatal period progress to end-stage renal disease within the first decade of life. […] The carrier status is estimated at 1 in 70.

• #2 Autosomal Recessive Polycystic Kidney Disease – NIDDK

  https://www.niddk.nih.gov/health-information/kidney-disease/polycystic-kidney-disease/autosomal-recessive-pkd

  Autosomal recessive polycystic kidney disease (ARPKD) is a rare genetic disorder that affects 1 in 20,000 children. […] Autosomal recessive means that for a child to have this disorder, both parents must have and pass along the gene mutation. […] How quickly ARPKD progresses to kidney failure is different for each child. […] Children born with ARPKD often develop kidney failure before reaching adulthood. […] Liver scarring occurs in all cases of ARPKD and is usually present at birth. […] Most children with ARPKD have high blood pressure.

• #3 Autosomal Recessive Polycystic Kidney Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK537137/

  Autosomal recessive polycystic kidney disease (ARPKD) is a rare genetic disorder primarily affecting the kidneys and liver. ARPKD most commonly results from mutations in PKHD1, causing renal cysts and congenital hepatic fibrosis early in life. More than 90% of ARPKD cases are caused by mutations in the PKHD1 gene on chromosome 6p12. Its function is to regulate the production of fibrocystin (polyductin), which is involved in cellular adhesion, ciliary function, and cell proliferation in the kidney and liver. A critical amount of full-length protein secreted by this gene is responsible for the normal function of tubular epithelium. More recently, DAZ-interacting zinc finger protein 1-like (DZIP1L) has been implicated in some cases of ARPKD, but it is extremely rare. Defects of PKHD1 also cause embryologic ductal plate malformations, leading to congenital hepatic fibrosis. The gene responsible for most ARPKD cases is Polycystic Kidney and Hepatic Disease 1 (PHKD1). The protein encoded by PKHD1 is fibrocystin (polyductin), a membrane protein found mainly in the distal tubules of the kidneys and biliary ducts of the liver.

• #4 Pediatric Polycystic Kidney Disease: Background, Etiology, Epidemiology

  https://emedicine.medscape.com/article/983281-overview

  ARPKD is primarily caused by variants in the PKHD1 gene, located on chromosome 6p21. This gene encodes fibrocystin (also known as polyductin), a large integral membrane protein. To date, over 750 PKHD1 variants have been identified. Most individuals with ARPKD are compound heterozygotes, meaning they inherit two different mutant alleles. […] In 1994, the ARPKD gene (PKDHD1) was localized to the short arm of chromosome 6. Fibrocystin/polyductin, a protein encoded by PKDHD1, is expressed on the cilia of renal and bile duct epithelial cells and is thought to be crucial in maintaining the normal tubular architecture of renal tubules and bile ducts. However, the precise function of this protein has yet to be completely studied or understood. The protein strengthens the theory that the primary defect in ARPKD is linked to ciliary dysfunction. […] A study that included 304 patients with ARPKD found that biallelic null variants in PKHD1 are associated with severe disease and a poor prognosis. For example, variants that affect amino acids 2625-4074 of fibrocystin are linked to worse hepatic outcomes.

• #5 Autosomal Recessive Polycystic Kidney Disease | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/19424

  Defects of PKHD1 also cause embryologic ductal plate malformations, leading to congenital hepatic fibrosis. Eventually, this results in variable dilatation in the intrahepatic and extrahepatic bile ducts (Caroli disease). […] The pathogenesis of ARPKD is characterized by circumferential proliferation of epithelial cells, which predominantly affects the collecting ducts in renal tubules. The primary pathology involves abnormal epithelial cell proliferation, which forms cysts that detach from the tubule once they reach a certain size. […] Defects of the PKHD1 gene also cause embryologic ductal plate malformation, leading to congenital hepatic fibrosis. Eventually, this results in variable dilatation in the intrahepatic and extrahepatic bile ducts (Caroli disease). Associated clinical manifestations are primarily portal hypertension, splenomegaly, hepatic fibrosis, and cholangitis.

• #6 Genetics – CORE Kidney | UCLA Health

  https://www.uclahealth.org/programs/core-kidney/conditions-treated/adpkd/pkd-information/genetics

  Mutation of the PKHD1 gene Autosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in the PKHD1 gene located on chromosome 6, which encodes fibrocystin (also referred to as polyductin), a large protein. […] The largest database for PKHD1 mutations contains more than 750 different mutations. Most patients with ARPKD are compound heterozygotes, who carry two different mutant alleles.

• #7

  https://link.springer.com/article/10.1007/s00467-021-04970-8

  Autosomal recessive polycystic kidney disease (ARPKD) is a rare but highly relevant disorder in pediatric nephrology. This genetic disease is mainly caused by variants in the PKHD1 gene and is characterized by fibrocystic hepatorenal phenotypes with major clinical variability. […] The disease is in most cases caused by variants in the gene Polycystic Kidney and Hepatic Disease 1 (PKHD1) on chromosome 6. […] Homozygous or compound heterozygous variants in PKHD1 are found in approximately 80-90% of ARPKD patients. […] The most frequent variant resulting in the T36M change of the protein affects approximately 10% of the screened alleles. […] It is widely accepted that patients with two truncating variants show a more severe phenotype with more frequent peri- or neonatal demise. […] Given the mentioned differential diagnosis with partly overlapping phenotypes that may be clinically hard to differentiate from each other, the establishment of a genetic diagnosis in patients with an early-onset ARPKD phenotype may be helpful for counseling of families, e.g., on the risk of recurrence and, in some cases, on risks of disease progression.

• #8 Autosomal Recessive (Infantile) Polycystic Kidney Disease | Radiology Key

  https://radiologykey.com/autosomal-recessive-infantile-polycystic-kidney-disease/

  Autosomal recessive polycystic kidney disease, also called infantile polycystic kidney disease, is a chronic, progressive condition that causes cystic dilatation of the renal collecting ducts and congenital hepatic fibrosis. […] ARPKD is caused by mutations of a large, complex gene, PKHD1, and it has an unusually wide spectrum of phenotypic variability. […] ARPKD is caused by mutations of the PKHD1 gene, which is located on the short arm of chromosome 6. PKHD1 is one of the largest human genes, possessing a complex splicing pattern that results in multiple transcripts, the largest of which is fibrocystin/polyductin. […] Molecular genetic testing is available for affected families. PKHD1 mutation screening using denaturing high-performance liquid chromatography has identified mutations in more than 75% of cases, including 85% of patients with perinatal or neonatal demise. […] In general, inheritance of two truncating mutations is more strongly associated with perinatal mortality, whereas those with missense mutations tend to display a milder phenotype.

• #9 Autosomal recessive polycystic kidney disease in children – UpToDate

  https://www.uptodate.com/contents/autosomal-recessive-polycystic-kidney-disease-in-children

  Autosomal recessive polycystic kidney disease (ARPKD, MIM #263200), previously called infantile polycystic kidney disease, is a recessively inherited disorder characterized by cystic dilations of the renal collecting ducts and developmental defects of hepatobiliary ductal plate remodeling, which result in varying degrees of congenital hepatic fibrosis. […] Most cases of ARPKD are caused by variants in PKHD1 (polycystic kidney and hepatic disease 1 gene) located on chromosome 6p21, which encodes fibrocystin (also referred to as polyductin), a large integral membrane protein. […] The DZIP1L gene is a second locus for ARPKD, although it is much less common than PKHD1. Variants in the DZIP1L gene were reported in seven patients with an atypical form of ARPKD from four unrelated consanguineous families.

• #10 Orphanet: Autosomal recessive polycystic kidney disease

  https://www.orpha.net/en/disease/detail/731

  PKHD1 (6p12.2-3) is the most frequently identified causative gene, and encodes the ciliary protein fibrocystin. Mutations in a cilia-related gene, DZIP1L (3q22.3), encoding a zinc finger protein, has also been identified. […] The pattern of inheritance is autosomal recessive. The risk of recurrence in siblings of an affected child is 25%.

• #11 Molecular Pathophysiology of Autosomal Recessive Polycystic Kidney Disease

  https://www.mdpi.com/1422-0067/22/12/6523

  Autosomal recessive polycystic kidney disease (ARPKD) is a rare disorder and one of the most severe forms of polycystic kidney disease, leading to end-stage renal disease (ESRD) in childhood. PKHD1 is the gene that is responsible for the vast majority of ARPKD. However, some cases have been related to a new gene that was recently identified (DZIP1L gene), as well as several ciliary genes that can mimic a ARPKD-like phenotypic spectrum. […] The ARPKD phenotype is not only caused by mutations in PKHD1. This makes diagnosis and management, including care during the perinatal period, a difficult task. A number of other recessive and dominant genes need to be considered. […] A moderate manifestation of ARPKD has been described in patients with DZIP1L mutations. […] The most common mutation, c.107C>T (T36M), only explains about 20% of mutant alleles, but no others are described as a cluster; in fact, many variants are unique to single lineages. […] As we mentioned earlier, ARPKD is caused by mutations in PKHD1 and, the recently discovered, DZIP1L.

• #12 POLYCYSTIC KIDNEY DISEASE, AUTOSOMAL RECESSIVE (ARPKD)

  https://medicover-genetics.com/product/polycystic-kidney-disease-autosomal-recessive-arpkd/

  Autosomal recessive polycystic kidney disease (ARPKD) is a rare form of polycystic kidney disease that originates primarily from the collecting duct. It occurs in about 1:20,000 live births. […] The most frequent molecular cause is pathogenic variants in the PKHD1 gene. […] In rare cases, causal changes in the DZIP1L gene can be found. Variants in numerous other genes, often from the group of ciliopathies, can also cause an ARPKD-like genotype.

• #13

  https://www.nhs.uk/conditions/autosomal-recessive-polycystic-kidney-disease-arpkd/

  ARPKD is caused by a genetic fault that disrupts normal development of the kidneys and liver. […] ARPKD is caused by a genetic alteration in the gene PKHD1, which in most cases is passed on to a child by their parents. […] If both parents carry a faulty version of this gene, there’s a 1 in 4 chance of each child they have developing ARPKD.

• #14 ARPKD basics

  https://pkdcharity.org.uk/arpkd/what-is-arpkd/arpkd-basics

  ARPKD is a genetic condition caused by a fault often called a mutation – in a gene called PKHD1. […] ARPKD occurs when a child is conceived from parents who both pass on a faulty copy of the PKHD1 gene. […] Parents of children with ARPKD dont have the disease themselves because they have one normal copy of the gene and one faulty copy. […] About one in every 70 people in the general public is an ARPKD carrier. […] If both parents are carriers, the chance of a child inheriting the faulty gene from both parents (and therefore having ARPKD) is one in four (25%). […] This pattern of inheritance is called autosomal recessive.

• #15 What causes ARPKD? – Polycystic kidney disease | PKD treatment research | PKD Foundation

  https://pkdcure.org/about-the-disease/arpkd/what-causes-arpkd/

  Autosomal recessive polycystic kidney disease (ARPKD) is caused by a mutation of the chromosome that carries the PKHD1 gene. […] ARPKD is a recessive disorder, meaning a child must inherit a copy of the PKHD1 gene from each parent to be diagnosed. […] To inherit two PKHD1 genes, both parents must be carriers. […] A carrier isnt diagnosed with ARPKD, but they do carry the PKHD1 gene. […] As illustrated in the diagram, parents carrying the mutated PKHD1 gene have a 25% chance that their child will have ARPKD. […] There is also a 50% chance each child will not have ARPKD but will be carriers of the disease. […] If one parent is a carrier while the other parent has ARPKD, there is a 100% chance of their children being carriers and a 50% chance of their children having the disease.

• #16

  https://www.nhs.uk/conditions/autosomal-recessive-polycystic-kidney-disease-arpkd/complications/

  Autosomal recessive polycystic kidney disease (ARPKD) is an inherited condition, which means it’s passed on to a child from their parents. […] ARPKD is caused by a DNA mutation (abnormality) in a gene called PKHD1, which produces a protein called fibrocystin that gives the kidney its structure. […] The faulty PKHD1 gene is responsible for small fluid-filled sacs (cysts) and scarring developing in the kidneys. […] The genetic fault responsible for ARPKD is usually passed on to a child by their parents. […] The mutation that causes ARPKD is known as an autosomal recessive mutation. […] This means that a baby needs to receive 2 copies of the mutated gene to develop the condition: 1 from their mother and 1 from their father. […] If a baby only receives 1 copy of the mutated gene from 1 of their parents, he or she will not develop ARPKD, but will carry the mutated gene.

• #17 A rare deep intronic mutation of PKHD1 gene, c.8798-459 C > A, causes autosomal recessive polycystic kidney disease by pseudoexon activation | Journal of Human Genetics

  https://www.nature.com/articles/s10038-018-0550-8

  Autosomal recessive polycystic kidney disease (ARPKD), is a rare hepatorenal fibrocystic disorder primarily associated with progressive growth of multiple cysts in the kidneys causing progressive loss of renal function. The disease is linked to mutations in the PKHD1 gene. […] ARPKD is primarily caused by mutations in the PKHD1 gene, which is located on chromosome 6p12.2. […] To date, more than 500 different pathogenic mutations have been identified in the PKHD1 gene. […] In this study, we identified a rare deep intron mutation of the PKHD1 gene in a family with the clinical diagnosis of ARPKD and explored its functional characteristics. […] We identified a rare deep intron mutation (c.8798-459CA) in the PKHD1 gene of a family with ARPKD. This novel mutation was associated with a cryptic splicing pattern, leading to an aberrant splicing product.

• #17 A rare deep intronic mutation of PKHD1 gene, c.8798-459 C > A, causes autosomal recessive polycystic kidney disease by pseudoexon activation | Journal of Human Genetics

  https://www.nature.com/articles/s10038-018-0550-8

  The result of the in vitro experiment identified the same insertion (c.8797-8798ins111) as found in the patient, which demonstrated that this mutation causes dysfunction by abnormal transcription. This mutation activates a downstream pseudoexon, leading to an aberrant splicing product with a 111-bp insertion. […] This report is the first discovery of another mechanism, which activates pseudoexon in PKHD1 gene.

• #18 Pathophysiology of childhood polycystic kidney diseases: new insights into disease-specific therapy | Pediatric Research

  https://www.nature.com/articles/pr2013191

  The 15-y survival of patients surviving the first year of life is projected to be 85%. […] Despite improved survival, morbidity of this dual-organ disease is significant due to the following reasons: (i) renal collecting duct ectatic cysts and marked renal enlargement, leading to hypertension and progressive renal failure and (ii) biliary dysgenesis, leading to abnormal bile duct formation with progressive periportal congenital hepatic fibrosis. […] The gene product of PKHD1 encodes a 67-exon mRNA and is predicted to encode a protein of 4,074 amino acids called fibrocystin or polyductin. […] The lack of functional PC1, PC2, or fibrocystin is embryonically lethal, indicating that these proteins are essential and that PKD begins in utero. […] Studies from multiple laboratories and multiple models demonstrate that ADPKD and ARPKD share common phenotypic abnormalities and intersecting signaling pathways whose disruption leads to cyst formation.

• #19 Polycystic kidney disease – Wikipedia

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

  PKD is caused by abnormal genes that produce a specific abnormal protein; this protein has an adverse effect on tubule development. […] Autosomal recessive polycystic kidney disease (ARPKD) (OMIM #263200) is the less common of the two types of PKD, with an incidence of 1:20,000 live births and is typically identified in the first few weeks after birth. […] PKHD1 is involved. […] Both autosomal dominant and autosomal recessive polycystic kidney disease cyst formation are tied to abnormal cilia-mediated signaling. […] The disease is characterized by a 'second hit’ phenomenon, in which a mutated dominant allele is inherited from a parent, with cyst formation occurring only after the normal, wild-type gene sustains a subsequent second genetic 'hit’, resulting in renal tubular cyst formation and disease progression. […] PKD results from defects in the primary cilium, an immotile, hair-like cellular organelle present on the surface of most cells in the body, anchored in the cell body by the basal body.

• #20 Autosomal Recessive Polycystic Kidney Disease: ERKNet for Patients

  https://www.erknet.org/patients/your-kidney-disease/arpkd/disease-information

  Autosomal recessive polycystic kidney disease (ARPKD) is a rare genetic disorder that primarily affects the kidneys and the liver and is characterized with formation and uncontrolled growth of fluid-filled cysts in the kidney, the spread of which eventually leads to the loss of kidney function. […] The primary cause of ARPKD is mutations in the PKHD1 gene encoding the fibrocystin. […] ARPKD is inherited in an autosomal recessive manner, which means that both parents must carry a mutated copy of the responsible gene for their child to develop the condition. […] Kidney Cysts are a hallmark of ARPKD. These cysts can cause the kidneys to become enlarged and dysfunctional. […] Cysts form in the kidneys, causing them to enlarge and lose function over time. […] The progressive loss of kidney function can lead to kidney failure, which may require dialysis or kidney transplantation, before reaching adulthood.

• #21 Autosomal recessive polycystic kidney disease – Wikipedia

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

  Mutations in the PKHD1 gene cause ARPKD. […] The cause of ARPKD is linked to mutations in the PKHD1 gene. […] PKHD1 is the only gene that is found to be responsible for the disease presentation of ARPKD.

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