Autosomal recessive polycystic kidney disease and congenital hepatic fibrosis: Summary statement of a first National Institutes of Health/Office of Rare Diseases Conference

George Washington University, Washington, Washington, D.C., United States
Journal of Pediatrics (Impact Factor: 3.79). 09/2006; 149(2):159-64. DOI: 10.1016/j.jpeds.2006.03.014
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Available from: Gregory J Pazour
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    • "6p12.2 and contains a 16.2 kb coding sequence divided into 66 exons, separated by introns varying in size up to 472 kb [12], [13]. It encodes fibrocystin/polyductin (FPC), a type of membrane-associated receptor-like protein [14], [15] that is predominantly expressed in the apical domain of renal tubule epithelial cells, and may play an important role in collecting duct and biliary differentiation [16]. Recently, advances in next generation sequencing technologies have enabled whole exome sequencing (WES) to become a technically feasible and powerful tool for identifying pathogenic mutations in various Mendelian disorders [17], including rare diseases [18], [19]. "
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    ABSTRACT: Mutations in PKHD1 cause autosomal recessive Caroli disease, which is a rare congenital disorder involving cystic dilatation of the intrahepatic bile ducts. However, the mutational spectrum of PKHD1 and the phenotype-genotype correlations have not yet been fully established. Whole exome sequencing (WES) was performed on one twin sample with Caroli disease from a Chinese family from Shandong province. Routine Sanger sequencing was used to validate the WES and to carry out segregation studies. We also described the PKHD1 mutation associated with the genotype-phenotype of this twin. A combination of WES and Sanger sequencing revealed the genetic defect to be a novel compound heterozygous genotype in PKHD1, including the missense mutation c.2507 T>C, predicted to cause a valine to alanine substitution at codon 836 (c.2507T>C, p.Val836Ala), and the nonsense mutation c.2341C>T, which is predicted to result in an arginine to stop codon at codon 781 (c.2341C>T, p.Arg781*). This compound heterozygous genotype co-segregates with the Caroli disease-affected pedigree members, but is absent in 200 normal chromosomes. Our findings indicate exome sequencing can be useful in the diagnosis of Caroli disease patients and associate a compound heterozygous genotype in PKHD1 with Caroli disease, which further increases our understanding of the mutation spectrum of PKHD1 in association with Caroli disease.
    Full-text · Article · Apr 2014 · PLoS ONE
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    • "Severe hypertension is shown to be the prominent factor causing deterioration of renal function. Most ARPKD patients have enlarged livers with ductal plate malformation, dilated intrahepatic bile ducts with abnormal branching of the intrahepatic portal veins, and progressive fibrosis of the portal tracts, resulting in CHF/Caroli’s syndrome (CS) and the occurrence of significant portal hypertension [4], [5], [6]. Systemic and portal hypertension is a well-recognized complication of ARPKD. "
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    ABSTRACT: Human autosomal recessive polycystic kidney disease (ARPKD) produces kidneys which are massively enlarged due to multiple cysts, hypertension, and congenital hepatic fibrosis characterized by dilated bile ducts and portal hypertension. The PCK rat is an orthologous model of human ARPKD with numerous fluid-filled cysts caused by stimulated cellular proliferation in the renal tubules and hepatic bile duct epithelia, with interstitial fibrosis developed in the liver. We previously reported that a peroxisome proliferator activated receptor (PPAR)-γ full agonist ameliorated kidney and liver disease in PCK rats. Telmisartan is an angiotensin receptor blocker (ARB) used widely as an antihypertensive drug and shows partial PPAR-γ agonist activity. It also has nephroprotective activity in diabetes and renal injury and prevents the effects of drug-induced hepatotoxicity and hepatic fibrosis. In the present study, we determined whether telmisartan ameliorates progression of polycystic kidney and fibrocystic liver disease in PCK rats. Five male and 5 female PCK and normal control (+/+) rats were orally administered 3 mg/kg telmisartan or vehicle every day from 4 to 20 weeks of age. Treatment with telmisartan decreased blood pressure in both PCK and +/+ rats. Blood levels of aspartate amino transferase, alanine amino transferase and urea nitrogen were unaffected by telmisartan treatment. There was no effect on kidney disease progression, but liver weight relative to body weight, liver cystic area, hepatic fibrosis index, expression levels of Ki67 and TGF-β, and the number of Ki67- and TGF-β-positive interstitial cells in the liver were significantly decreased in telmisartan-treated PCK rats. Therefore, telmisartan ameliorates congenital hepatic fibrosis in ARPKD, possibly through the inhibition of signaling cascades responsible for cellular proliferation and interstitial fibrosis in PCK rats. The present results support the potential therapeutic use of ARBs for the treatment of fibrocystic liver disease in ARPKD patients.
    Full-text · Article · Dec 2013 · PLoS ONE
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    ABSTRACT: The cystic diseases of the liver are mostly autosomal recessive disorders with variable intrahepatic biliary dilatation and increased hepatic fibrosis either as part of the underlying defect or as a result of liver damage from recurrent episodes of ascending cholangitis. Caroli disease (CD) denotes congenital saccular intrahepatic dilatation of the biliary tree. Caroli syndrome (CS) is a more common disorder in which the bile duct dilatation is associated with congenital hepatic fibrosis (CHF). The clinical manifestations of CS are related to the biliary abnormalities and portal hypertension. Recurrent bacterial cholangitis, liver abscesses, intra- and extrahepatic stones, and increased risk of cholangiocarcinoma are the main complications of CD and CS. Treatment is supportive and directed toward treating the biliary tract infections and the complications of portal hypertension. Surgical treatment consists of liver resection or liver transplantation. The prognosis of CD and CS is variable depending on the severity of the disease, the presence of portal hypertension, and the presence of coexisting renal disease. CHF is a hereditary developmental malformation that belongs to the family of hepatic ductal plate malformation (DPM), which resulted from persistence of excess embryonic bile duct structures in the portal tracts. It may be associated with other liver malformations such as in CS and it is usually associated with autosomal recessive polycystic kidney disease (ARPKD). The identification of the gene for ARPKD, PKHD1 (polycystic kidney and hepatic disease 1) had shown that most cases of ARPKD with CHF are genetically homogeneous. Clinically, symptoms vary and different manifestations of CHF have been described such as portal hypertensive CHF, cholangitic CHF, combined portal hypertensive and cholangitic CHF, and latent forms of CHF. Therapy of CHF depends on the clinical manifestation of the disease. Treatment is largely supportive and it is directed toward treating biliary tract infection and the complications of portal hypertension. Liver transplantation is indicated in patients with recurrent uncontrolled cholangitis and in patients with end-stage liver disease.
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