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

详细信息    查看全文

• 作者：Edgar Otto ; Julia Hoefele ; Rainer Ruf ; Adelheid M. Mueller ; Karl S. Hiller ; Matthias T.F. Wolf ; Maria J. Schuermann ; Achim Becker ; Ralf Birkenhä ; ger ; Ralf Sudbrak ; Hans C. Hennies ; Peter Nü ; rnberg ; Friedhelm Hildebr ; t
• 刊名：The American Journal of Human Genetics
• 出版年：2002
• 出版时间：November 2002
• 年：2002
• 卷：71
• 期：5
• 页码：1161-1167
• 全文大小：925 K

文摘

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.