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          Institute: MPI für Biochemie     Collection: Molecular Medicine (R. Fässler)     Display Documents



  history
ID: 35334.0, MPI für Biochemie / Molecular Medicine (R. Fässler)
Spectrum of mutations in the gene for autosomal recessive polycystic kidney disease (ARPKD/PKHD1)
Authors:Bergmann, C.; Senderek, J.; Sedlacek, B.; Pegiazoglou, I.; Puglia, P.; Eggermann, T.; Rudnik-Schoneborn, S.; Furu, L.; Onuchic, L. F.; De Baca, M.; Germino, G. G.; Guay-Woodford, L.; Somlo, S.; Moser, M.; Buttner, R.; Zerres, K.
Language:English
Date of Publication (YYYY-MM-DD):2003-01
Title of Journal:Journal of the American Society of Nephrology
Journal Abbrev.:J. Am. Soc. Nephrol.
Volume:14
Issue / Number:1
Start Page:76
End Page:89
Review Status:Peer-review
Audience:Not Specified
Abstract / Description: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.
Comment of the Author/Creator:Date: 2003, JAN
External Publication Status:published
Document Type:Article
Communicated by:N.N.
Affiliations:MPI für Biochemie/Molecular Medicine (R. Fässler)/Research Group Moser
External Affiliations:Univ Aachen, Inst Human Genet, Pauwelsstr 30, D-52074 Aachen,; Germany; Univ Aachen, Inst Human Genet, D-52074 Aachen, Germany; Yale Univ, New Haven, CT USA; Johns Hopkins Univ, Baltimore, MD USA; Univ Sao Paulo, Sao Paulo, Brazil; Univ Bonn, Inst Pathol, D-5300 Bonn, Germany; Thomas Jefferson Univ, Dept Pathol, Philadelphia, PA 19107 USA; Univ Alabama, Birmingham, AL USA
Identifiers:ISI:000180072800009 [ID No:1]
ISSN:1046-6673 [ID No:2]
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