A complete mutation screen of PKHD1 in autosomal-recessive polycystic kidney disease (ARPKD) pedigrees

Rossetti, Sandro; Torra, Roser; Coto, Eliécer; Consugar, Mark; Kubly, Vickie; S, Málaga; Navarro, Mercedes; El–Youssef, Mounif; Torres, Vicente E.; Harris, Peter C.

doi:10.1046/j.1523-1755.2003.00111.x

Cited by 118 publications

(97 citation statements)

References 31 publications

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“…Mutation analyses of ARPKD patients included individuals with predominant liver disease manifest as congenital hepatic fibrosis or Caroli's disease and only mild renal involvement. 6,7,10,[12][13][14]40 In such families, the mutations invariably include at least one predicted amino acid substitution that may act in a hypomorphic manner. In the case of the Pkhd1 del4 mouse model, the transcript bears a deletion of 66 amino acids that includes part of exon 4 and all of exon 5.…”

Section: Discussionmentioning

confidence: 99%

“…The location of the mutations in the genes may also affect the severity of the disease, hence the clinical lesion in mice, and this is borne out in human studies in which genotype-phenotype interactions have been reported. [11][12][13][14] Human mutations in the region of the Pkhd1 del4 mutation have resulted in severe loss of function. For example, one mutation, IVS5 ϩ 1G3 T, predicted to result in loss of the exon 5 splice donor site causing aberrant splicing of exon 5 was found in a child with the severe perinatal lethal presentation associated with presumed complete loss-of-function alleles.…”

Section: Discussionmentioning

confidence: 99%

“…Patients with two predicted truncation mutations invariably present with the more severe perinatal lethal phenotype, whereas patients with later-onset disease have at least one missense mutation. [11][12][13][14] The fibrocystin transcript is strongly expressed in the developing kidney, where it is primarily localized to the ureteric bud. In the adult kidney it appears in the collecting ducts and loops of Henle.…”

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confidence: 99%

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Biliary and Pancreatic Dysgenesis in Mice Harboring a Mutation in Pkhd1

Gallagher

Esquivel

Briere

et al. 2008

The American Journal of Pathology

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Autosomal recessive polycystic kidney disease is a hereditary fibrocystic disease that involves the kidneys and the biliary tract. Mutations in the PKHD1 gene are responsible for typical forms of autosomal recessive polycystic kidney disease. We have generated a mouse model with targeted mutation of Pkhd1 by disrupting exon 4, resulting in a mutant transcript with deletion of 66 codons and expression at ϳ30% of wild-type levels. Pkhd1 del4/del4 mice develop intrahepatic bile duct proliferation with progressive cyst formation and associated periportal fibrosis. In addition, these mice exhibit extrahepatic manifestations, including pancreatic cysts, splenomegaly, and common bile duct dilation. The kidneys are unaffected both histologically and functionally. Fibrocystin is expressed in the apical membranes and cilia of bile ducts and distal nephron segments but is absent from the proximal tubule. This pattern is unchanged in orthologous models of autosomal dominant polycystic kidney disease due to mutation in Pkd1 or Pkd2. Mutant fibrocystin in Pkhd1 del4/del4 mice also retains this expression pattern. The hypomorphic Pkhd1 del4/del4 mouse model provides evidence that reduced functional levels of fibrocystin are sufficient for cystogenesis and fibrosis in the liver and pancreas, but not the kidney, and supports the hypothesis of species-dependent differences in susceptibility of tissues to Pkhd1 mutations. (Am J

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Biliary and Pancreatic Dysgenesis in Mice Harboring a Mutation in Pkhd1

Gallagher

Esquivel

Briere

et al. 2008

The American Journal of Pathology

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“…19 We therefore recommend that neonatal patients and children with congenital hepatic fibrosis and CaroliЈs disease should be screened for PKHD1 mutations even in the absence of renal pathology.…”

Section: Discussionmentioning

confidence: 99%

A mouse model for cystic biliary dysgenesis in autosomal recessive polycystic kidney disease (ARPKD)†

et al. 2005

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Autosomal recessive polycystic kidney disease (ARPKD) is an important cause of liver-and renal-related morbidity and mortality in childhood. Recently, PKHD1, the gene encoding the transmembrane protein polyductin, was shown to be mutated in ARPKD patients. We here describe the first mouse strain, generated by targeted mutation of Pkhd1. Due to exon skipping, Pkhd1ex40 mice express a modified Pkhd1 transcript and develop severe malformations of intrahepatic bile ducts. Cholangiocytes maintain a proliferative phenotype and continuously synthesize TGF-␤1. Subsequently, mesenchymal cells within the hepatic portal tracts continue to synthesize collagen, resulting in progressive portal fibrosis and portal hypertension. Fibrosis did not involve the hepatic lobules, and we did not observe any pathological changes in morphology or function of hepatocytes. Surprisingly and in contrast to human ARPKD individuals, Pkhd1ex40 mice develop morphologically and functionally normal kidneys. In conclusion, our data indicate that subsequent to formation of the embryonic ductal plate, dysgenesis of terminally differentiated bile ducts occurs in response to the Pkhd1ex40 mutation.

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“…To date, .700 different PKHD1 mutations are known (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). The longest open reading frame of PKHD1 comprises 66 exons and encodes a single-transmembrane protein, called polyductin/fibrocystin, which is mainly expressed in the kidney and liver/cholangiocytes (6,7,19).…”

Section: Introductionmentioning

confidence: 99%

Transcriptional Complexity in Autosomal Recessive Polycystic Kidney Disease

Frank¹,

Zerres

Bergmann

2014

Clinical Journal of the American Society of Nephrology

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Background and objectives Autosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in the PKHD1 gene. The longest open reading frame comprises 66 exons encoding polyductin or fibrocystin, a type I transmembrane protein with 4074 amino acids. Functional investigations are considerably hampered by its large size and lack of expression in tissues that are usually available for analysis such as lymphocytes or fibroblasts.Design, setting, participants, & measurements Allegedly strong and clear-cut genotype-phenotype correlations for the type of PKHD1 mutation could be established. Thus far, practically all patients with two truncating mutations showed perinatal or neonatal demise and at least one hypomorphic missense mutation is thought to be indispensable for survival. Mutation analysis of .500 ARPKD families was performed by conventional and nextgeneration sequencing techniques.Results This study presents four unrelated patients with ARPKD with a nonlethal, moderate clinical course despite the burden of two PKHD1 mutations expected to lead to premature termination of translation. In line with parental consanguinity, all mutations occurred in the homozygous state and segregated with the disorder in these families. To try to unravel the mechanisms that underlie this obvious contradiction, these patients were further analyzed in detail by utilizing different methods. In all cases, complex transcriptional alterations were detected. Alternative splicing patterns might disrupt a critical stoichiometric and temporal balance between different protein products and may play a crucial role in defining the phenotype of these patients.Conclusions Although these findings represent rare events, they are of importance for genetic counseling and illustrate that some caution is warranted in the interpretation of mutations and their clinical significance. The authors hypothesize that expression of a minimal amount of functional protein is needed for survival of the neonatal period in ARPKD.

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A complete mutation screen of PKHD1 in autosomal-recessive polycystic kidney disease (ARPKD) pedigrees

Cited by 118 publications

References 31 publications

Biliary and Pancreatic Dysgenesis in Mice Harboring a Mutation in Pkhd1

Biliary and Pancreatic Dysgenesis in Mice Harboring a Mutation in Pkhd1

A mouse model for cystic biliary dysgenesis in autosomal recessive polycystic kidney disease (ARPKD)†

Transcriptional Complexity in Autosomal Recessive Polycystic Kidney Disease

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