A gene mutated in nephronophthisis and retinitis pigmentosa encodes a novel protein, nephroretinin, conserved in evolution

Am J Hum Genet. 2002 Nov;71(5):1161-7. doi: 10.1086/344395. Epub 2002 Aug 29.

Abstract

Nephronophthisis (NPHP) comprises a group of autosomal recessive cystic kidney diseases, which constitute the most frequent genetic cause for end-stage renal failure in children and young adults. The most prominent histologic feature of NPHP consists of development of renal fibrosis, which, in chronic renal failure of any origin, represents the pathogenic event correlated most strongly to loss of renal function. Four gene loci for NPHP have been mapped to chromosomes 2q13 (NPHP1), 9q22 (NPHP2), 3q22 (NPHP3), and 1p36 (NPHP4). At all four loci, linkage has also been demonstrated in families with the association of NPHP and retinitis pigmentosa, known as "Senior-Løken syndrome" (SLS). Identification of the gene for NPHP type 1 had revealed nephrocystin as a novel docking protein, providing new insights into mechanisms of cell-cell and cell-matrix signaling. We here report identification of the gene (NPHP4) causing NPHP type 4, by use of high-resolution haplotype analysis and by demonstration of nine likely loss-of-function mutations in six affected families. NPHP4 encodes a novel protein, nephroretinin, that is conserved in evolution--for example, in the nematode Caenorhabditis elegans. In addition, we demonstrate two loss-of-function mutations of NPHP4 in patients from two families with SLS. Thus, we have identified a novel gene with critical roles in renal tissue architecture and ophthalmic function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins / genetics*
  • Haplotypes
  • Humans
  • Kidney Diseases, Cystic / genetics*
  • Membrane Proteins
  • Molecular Sequence Data
  • Organ Specificity
  • Proteins*
  • Retinitis Pigmentosa / genetics*
  • Sequence Analysis, DNA

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Membrane Proteins
  • NPHP1 protein, human
  • NPHP4 protein, human
  • Proteins

Associated data

  • GENBANK/Z81579
  • OMIM/256100
  • OMIM/266900
  • OMIM/602088
  • OMIM/604387
  • OMIM/606966
  • SWISSPROT/P33964