title: Mutational analysis in 119 families with nephronophthisis.
abstract: Nephronophthisis (NPHP) is the most common genetic cause of end-stage renal disease (ESRD) in the first three decades of life. Six genes, NPHP1-6, have been reported, which when mutated result in NPHP. Our aim was to examine 119 families with NPHP and absence of homozygous NPHP1 deletions for mutations in NPHP2-6 and the two candidate genes BCL2 and CYS1. The 119 individuals affected with NPHP were selected from unrelated families, in which homozygous NPHP1 deletions were excluded. A combination of CEL-1 endonuclease digestion and direct sequencing was used for focused mutational analysis in this cohort. All individuals were examined for homozygous deletions in NPHP1 and directly sequenced for BCL2 and CYS1. As selected by appropriate phenotype, 9%, 38%, 97%, 20% and 20% of individuals were examined for mutations in NPHP2, 3, 4, 5, and 6 respectively. No mutations in known NPHP genes or in the candidate genes, BCL2 and CYS1, were found sufficient to explain NPHP in affected individuals. These findings demonstrate the need to evaluate additional candidate genes as the cause of NPHP.
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109-0676, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: O'Toole
authors.forename: Edgar A
authors.initials: EA
authors.lastname: Otto
authors.forename: Julia
authors.initials: J
authors.lastname: Hoefele
authors.forename: Juliana
authors.initials: J
authors.lastname: Helou
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D017668:Age of Onset; D003598:Cytoskeletal Proteins; D004252:DNA Mutational Analysis; D019254:Genes, bcl-2 / Q000235:genetics; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007674:Kidney Diseases / Q000150:complications / Q000235:genetics*; D007676:Kidney Failure, Chronic / Q000209:etiology / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D009154:Mutation; D011506:Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C482294:CYS1 protein, human; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; C108725:NPHP1 protein, human; D011506:Proteins