A Gene Mutated in Nephronophthisis and Retinitis Pigmentosa Encodes a Novel Protein, Nephroretinin, Conserved in Evolution

• Published in: American journal of human genetics Vol. 71; no. 5; pp. 1161 - 1167
• Main Authors: Otto, Edgar, Hoefele, Julia, Ruf, Rainer, Mueller, Adelheid M., Hiller, Karl S., Wolf, Matthias T.F., Schuermann, Maria J., Becker, Achim, Birkenhäger, Ralf, Sudbrak, Ralf, Hennies, Hans C., Nürnberg, Peter, Hildebrandt, Friedhelm
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01.11.2002; University of Chicago Press; The American Society of Human Genetics
• Subjects: Adaptor Proteins, Signal Transducing; Biological and medical sciences; Carrier Proteins - genetics; Haplotypes; Humans; Kidney Diseases, Cystic - genetics; Medical sciences; Membrane Proteins; Molecular Sequence Data; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Organ Specificity; Proteins; Retinitis Pigmentosa - genetics; Sequence Analysis, DNA; Tubulopathies; Human; Kidney disease; High resolution; Urinary system disease; Retinopathy; Linkage; Family study; Pathogenesis; Gene product; Retinitis pigmentosa; Clinical form; Juvenile nephronophtisis; Genetic determinism; Biological activity; Genetic disease; Eye disease; Gene; Degenerative disease; Mutation; Child; Haplotype
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/344395

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.