Spectrum of Mutations in the Gene for Autosomal Recessive Polycystic Kidney Disease (ARPKD/PKHD1)

Abstract

Abstract. Autosomal recessive polycystic kidney disease (ARPKD/PKHD1) is an important cause of renal-related and liver-related morbidity and mortality in childhood. Recently mutations in the PKHD1 gene on chromosome 6p21.1-p12 have been identified as the molecular cause of ARPKD. The longest continuous open reading frame (ORF) is encoded by a 67-exon transcript and predicted to yield a 4074 -amino acid protein ("polyductin") of thus far unknown function. By now, a total of 29 different PKHD1 mutations have been described. This study reports mutation screening in 90 ARPKD patients and identifies mutations in 110 alleles making up a detection rate of 61%. Thirty-four of the detected mutations have not been reported previously. Two underlying mutations in 40 patients and one mutation in 30 cases are disclosed, and no mutation was detected on the remaining chromosomes. Mutations were found to be scattered throughout the gene without evidence of clustering at specific sites. About 45% of the changes were predicted to truncate the protein. All missense mutations were nonconservative, with the affected amino acid residues found to be conserved in the murine polyductin orthologue. One recurrent missense mutation (T36M) likely represents a mutational hotspot and occurs in a variety of populations. Two founder mutations (R496X and V3471G) make up about 60% of PKHD1 mutations in the Finnish population. Preliminary genotype-phenotype correlations could be established for the type of mutation rather than for the site of the individual mutation. All patients carrying two truncating mutations displayed a severe phenotype with perinatal or neonatal demise. PKHD1 mutation analysis is a powerful tool to establish the molecular cause of ARPKD in a given family. Direct identification of mutations allows an unequivocal diagnosis and accurate genetic counseling even in families displaying diagnostic challenges. cbergmann@ukaachen.de

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

“…Consistently, our previous analysis of mutations in a large cohort of ARPKD patients showed that patients with 2 truncating mutations displayed a severe phenotype with perinatal or neonatal demise. 18 However, in the absence of data concerning functional relevance of different PKHD1 protein motifs, it is impossible to precisely interpret the frequent missense mutations. In this respect, our study provides further evidence that the precise phenotype of hepatic and kidney disease in ARPKD patients correlates with the genotype.…”

“…For reverse transcription, 1 g total RNA was primed with 1 g oligo d(T) [12][13][14][15][16][17][18] , and transcription was performed by Superscript II RT following the manufacturer's description (Invitrogen). PCR was run with 35 cycles (1 minute at 94°C, 45 seconds at 53°C to 55°C, and 1 to 2 minutes at 72°C).…”

Transcriptional Complexity in Autosomal Recessive Polycystic Kidney Disease

“…Patients were chosen for analysis if they showed typical clinical and/or histologic features of ARPKD as previously described in detail (2,5,8). We performed PKHD1 mutation analysis in a large cohort of .500 patients with polycystic kidney disease phenotypes using conventional Sanger sequencing or a targeted next-generation sequencing approach.…”

“…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).…”

Autosomal Recessive Polycystic Kidney Disease

“…[1] The causative factor is the mutations in the PKHD1 (chromosomal locus 6p12.2). [2] The disease has a wide clinical variation from stillbirth and neonatal demise to survival into adulthood; the carrier frequency for a PKHD1 mutation is estimated to be about 1:70 in general population. The majority of cases present in the neonatal period though the diagnosis may be suspected on prenatal ultrasound.…”