title: A novel gene that encodes a protein with a putative src homology 3 domain is a candidate gene for familial juvenile nephronophthisis.
abstract: Familial juvenile nephronophthisis (NPH) is an autosomal recessive, genetically heterogeneous disorder, representing the most frequent inherited cause of chronic renal failure in children. One of the responsible loci, NPH1 , has been mapped to 2q13. The presence of large homozygous deletions of approximately 250 kb in the majority of affected patients allowed us to define a minimal deletion interval for NPH1 . A BAC contig covering this interval was established. Combination of large scale genomic sequencing, cDNA selection and computer-aided analysis led to the characterization of two transcriptional units. One encodes the already known BENE protein, and the other encodes a novel protein of at least 732 amino acids containing a putative src homology 3 domain. In two patients carrying the large deletion of the NPH1 region on only one allele, two mutations were detected in two independent exons of the novel gene. One consists of a single base deletion, causing a frameshift, and the other is a G-->A substitution in the consensus 5' splice donor site. Both mutations thus potentially generate null mutants. One of these mutations was found to segregate with the disease in the family, and the second appeared to be a de novo mutation. We therefore conclude that this novel gene is a strong candidate for NPH.
authors.affiliation: INSERM U 423, Tour Lavoisier, 6 degrees étage, Hôpital Necker-Enfants Malades, 75743 Paris Cedex 15, France.
authors.forename: S
authors.initials: S
authors.lastname: Saunier
authors.forename: J
authors.initials: J
authors.lastname: Calado
authors.forename: R
authors.initials: R
authors.lastname: Heilig
authors.forename: F
authors.initials: F
authors.lastname: Silbermann
authors.forename: F
authors.initials: F
authors.lastname: Benessy
authors.forename: G
authors.initials: G
authors.lastname: Morin
authors.forename: M
authors.initials: M
authors.lastname: Konrad
authors.forename: M
authors.initials: M
authors.lastname: Broyer
authors.forename: M C
authors.initials: MC
authors.lastname: Gubler
authors.forename: J
authors.initials: J
authors.lastname: Weissenbach
authors.forename: C
authors.initials: C
authors.lastname: Antignac
mesh_terms: D000595:Amino Acid Sequence; D029681:Arabidopsis Proteins; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000235:genetics; D016521:Electrophoresis, Gel, Pulsed-Field; D005091:Exons / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation; D005808:Genes, Recessive; D005838:Genotype; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000235:genetics*; D007679:Kidney Medulla; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D010375:Pedigree; D010750:Phosphoproteins / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases; D012326:RNA Splicing; D017384:Sequence Deletion; D014158:Transcription, Genetic; D018909:src Homology Domains
chemical_list: D029681:Arabidopsis Proteins; D002352:Carrier Proteins; D018076:DNA, Complementary; C110862:MALL protein, human; D008565:Membrane Proteins; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D010750:Phosphoproteins; C103646:NPH1 protein, Arabidopsis; D017346:Protein Serine-Threonine Kinases