A gene mutated in nephronophthisis and retinitis pigmentosa encodes a novel protein, nephroretinin, conserved in evolution.
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.
Otto
Edgar
E
Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA.
Hoefele
Julia
J
Ruf
Rainer
R
Mueller
Adelheid M
AM
Hiller
Karl S
KS
Wolf
Matthias T F
MT
Schuermann
Maria J
MJ
Becker
Achim
A
Birkenhäger
Ralf
R
Sudbrak
Ralf
R
Hennies
Hans C
HC
Nürnberg
Peter
P
Hildebrandt
Friedhelm
F
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins / Q000235:genetics*; D003598:Cytoskeletal Proteins; D006239:Haplotypes; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000235:genetics*; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D009928:Organ Specificity; D011506:Proteins; D012174:Retinitis Pigmentosa / Q000235:genetics*; D017422:Sequence Analysis, DNA
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; C108725:NPHP1 protein, human; C491578:NPHP4 protein, human; D011506:Proteins