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ID: 272860.0, MPI für molekulare Genetik / Sequencing Group
Mutational analysis of the NPHP4 gene in 250 patients with nephronophthisis
Authors:Hoefele, Julia; Sudbrak, Ralf; Reinhardt, Richard; Lehrack, Silvia; Hennig, Steffen; Imm, Anita; Muerb, Ulla; Utsch, Boris; Attanasio, Massimo; O'Toole, John F.; Otto, Edgar; Hildebrandt, Friedhelm
Date of Publication (YYYY-MM-DD):2005-03-17
Title of Journal:Human Mutation
Journal Abbrev.:Hum Mutat
Issue / Number:4
Start Page:411
End Page:411
Copyright:© 2005 Wiley-Liss, Inc.
Review Status:not specified
Audience:Experts Only
Abstract / Description:Nephronophthisis (NPH), a recessive cystic kidney disease, is the most frequent genetic cause for end-stage renal disease in the first two decades of life. Mutations in three genes (NPHP1, 2, and 3) were identified as causative. Extrarenal manifestations are known, such as retinitis pigmentosa (Senior-Løken syndrome, SLS) and ocular motor apraxia type Cogan. Recently, we identified a novel gene (NPHP4) as mutated in NPH. To date, a total of only 13 different NPHP4 mutations have been described. To determine the frequency of NPHP4 mutations, we performed mutational analysis by direct sequencing of all 30 NPHP4 exons in 250 different patients with isolated NPH, SLS, or Cogan syndrome ascertained worldwide over 14 years. We identified 23 novel NPHP4 sequence variants in 26/250 different patients (10%). Interestingly, we detected homozygous or compound heterozygous mutations of NPHP4 in only 6/250 different patients (2.4%), but only one heterozygous NPHP4 sequence variant in 20/250 different patients (8%). In the six patients with two NPHP4 mutations, 5/8 mutations (63%) were likely loss-of-function mutations, whereas in the 20 patients with only one sequence variant, only 1/20 (5%) was a likely loss-of-function (i.e., truncating) mutation. We conclude that: i) two recessive mutations in NPHP4 are a rare cause of nephronophthisis; ii) single heterozygous NPHP4 sequence variants are three times more prevalent than two recessive mutations; iii) there is no genotype/phenotype correlation; iv) there must exist further genes causing nephronophthisis, since in 224/250 (90%) patients, no sequence variants in either of the four NPH genes were detected.
Free Keywords:nephronophthisis; NPHP4; Senior-Løken syndrome; Cogan syndrome; mutational analysis
Comment of the Author/Creator:Email: Friedhelm Hildebrandt (fhilde@umich.edu)
External Publication Status:published
Document Type:Article
Communicated by:Richard Reinhardt
Affiliations:MPI für molekulare Genetik
External Affiliations:Department of Pediatrics, Human Genetics, University of Michigan, Ann Arbor, Michigan;
University Children's Hospital, Department of Pediatric Surgery, University of Munich, Munich, Germany;
Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany;
University Children's Hospital Freiburg, Freiburg, Germany;
Department of Human Genetics, University of Michigan, Ann Arbor, Michigan
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