The gene mutated in juvenile nephronophthisis type 4 encodes a novel protein that interacts with nephrocystin


Mollet G., Salomon R., Gribouval O., Silbermann F., Bacq D., Landthaler G., ...Daha Fazla

NATURE GENETICS, cilt.32, sa.2, ss.300-305, 2002 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 32 Sayı: 2
  • Basım Tarihi: 2002
  • Doi Numarası: 10.1038/ng996
  • Dergi Adı: NATURE GENETICS
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Sayfa Sayıları: ss.300-305
  • İstanbul Üniversitesi Adresli: Hayır

Özet

Nephronophthisis, the most common genetic cause of chronic renal failure in children, is a progressive tubulo-interstitial kidney disorder that is inherited as an autosomal recessive trait. The disease is characterized by polyuria, growth retardation and deterioration of renal function during childhood or adolescence. The most prominent histological features are modifications of the tubules with thickening of the basement membrane, interstitial fibrosis and, in the advanced stages, medullary cysts(1). Nephronophthisis can also be associated with conditions affecting extrarenal organs, such as retinitis pigmentosa (Senior-Loken syndrome) (2,3) and ocular motor apraxia (Cogan syndrome)(4). Three loci are associated with the juvenile, infantile and adolescent forms, on chromosomes 2q13 (NPHP1; refs 5,6), 9q22 (NPHP2; ref. 7) and 3q21 (NPHP3; ref. 8), respectively. NPHP1, the only gene identified so far, encodes nephrocystin(9,10), which contains a Src homology 3 (SH3) domain and interacts with intracytoplasmic proteins involved in cell adhesion (11-13). Recently, a second locus associated with the juvenile form of the disease, NPHP4, was mapped to chromosome 1p36 (ref. 14). We carried out haplotype analysis of families affected with nephronophthisis that were not linked to the NPHP1, NPHP2 or NPHP3 loci, using markers covering this region. This allowed us to reduce the NPHP4 interval to a one centimorgan interval between D1S2795 and D1S2870, which contains six genes. We identified five different mutations in one of these genes, designated NPHP4, in unrelated individuals with nephronophthisis. The NPHP4 gene encodes a 1,250-amino acid protein of unknown function that we named nephrocystin-4. We demonstrated the interaction of nephrocystin-4 with nephrocystin suggesting that these two proteins participate in a common signaling pathway.