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*Institute of Human Genetics, Aachen University, Aachen, Germany; Medicine and Genetics, Yale University, New Haven, Connecticut; Medicine and Genetics, Johns Hopkins University, Baltimore, Maryland; Medicine, University of Sao Paulo, Sao Paulo, Brazil; ¶Institute of Pathology, University of Bonn, Germany; #Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania; ||Medicine and Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama; &Max-Planck-Institute for Biochemistry, Martinsried, Germany.
Correspondence to Dr. Carsten Bergmann, Institute of Human Genetics, Aachen University, Pauwelsstra
e 30, D-52074 Aachen, Germany. Phone: +49-241-8080178; Fax: +49-241-8082580;
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. E-mail: cbergmann@ukaachen.de
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