TY - JOUR
T1 - Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis, tapeto-retinal degeneration and hepatic fibrosis
AU - Olbrich, Heike
AU - Fliegauf, Manfred
AU - Hoefele, Julia
AU - Kispert, Andreas
AU - Otto, Edgar
AU - Volz, Andreas
AU - Wolf, Matthias T.
AU - Sasmaz, Gürsel
AU - Trauer, Ute
AU - Reinhardt, Richard
AU - Sudbrak, Ralf
AU - Antignac, Corinne
AU - Gretz, Norbert
AU - Walz, Gerd
AU - Schermer, Bernhard
AU - Benzing, Thomas
AU - Hildebrandt, Friedhelm
AU - Omran, Heymut
N1 - Funding Information:
We thank the affected individuals and their families for their participation in this study, R. Melkaoui and M. Petry for technical assistance and B. Kränzlin for microscopic photographs. This work was supported by the Italian Association for Leber’s Congenital Amaurosis and by grants from the German Research Foundation (H.O. and A.K.), Zentrum für klinische Forschung Freiburg (H.O.) and the F.G. L. Huetwell fund (F.H.).
PY - 2003/8/1
Y1 - 2003/8/1
N2 - Nephronophthisis (NPHP), a group of autosomal recessive cystic kidney disorders, is the most common genetic cause of progressive renal failure in children and young adults. NPHP may be associated with Leber congenital amaurosis, tapetoretinal degeneration, cerebellar ataxia, cone-shaped epiphyses, congenital oculomotor apraxia and hepatic fibrosis. Loci associated with an infantile type of NPHP on 9q22-q31 (NPHP2), juvenile types of NPHP on chromosomes 2q12-q13 (NPHP1) and 1 p36 (NPHP4) and an adolescent type of NPHP on 3q21-q22 (NPHP3) have been mapped. NPHP1 and NPHP4 have been identified, and interaction of the respective encoded proteins nephrocystin and nephrocystin-4 has been shown. Here we report the identification of NPHP3, encoding a novel 1,330-amino acid protein that interacts with nephrocystin. We describe mutations in NPHP3 in families with isolated NPHP and in families with NPHP with associated hepatic fibrosis or tapeto-retinal degeneration. We show that the mouse ortholog Nphp3 is expressed in the node, kidney tubules, retina, respiratory epithelium, liver, biliary tract and neural tissues. In addition, we show that a homozygous missense mutation in Nphp3 is probably responsible for the polycystic kidney disease (pcy) mouse phenotype. Interventional studies in the pcy mouse have shown beneficial effects by modification of protein intake and administration of methylprednisolone, suggesting therapeutic strategies for treating individuals with NPHP3.
AB - Nephronophthisis (NPHP), a group of autosomal recessive cystic kidney disorders, is the most common genetic cause of progressive renal failure in children and young adults. NPHP may be associated with Leber congenital amaurosis, tapetoretinal degeneration, cerebellar ataxia, cone-shaped epiphyses, congenital oculomotor apraxia and hepatic fibrosis. Loci associated with an infantile type of NPHP on 9q22-q31 (NPHP2), juvenile types of NPHP on chromosomes 2q12-q13 (NPHP1) and 1 p36 (NPHP4) and an adolescent type of NPHP on 3q21-q22 (NPHP3) have been mapped. NPHP1 and NPHP4 have been identified, and interaction of the respective encoded proteins nephrocystin and nephrocystin-4 has been shown. Here we report the identification of NPHP3, encoding a novel 1,330-amino acid protein that interacts with nephrocystin. We describe mutations in NPHP3 in families with isolated NPHP and in families with NPHP with associated hepatic fibrosis or tapeto-retinal degeneration. We show that the mouse ortholog Nphp3 is expressed in the node, kidney tubules, retina, respiratory epithelium, liver, biliary tract and neural tissues. In addition, we show that a homozygous missense mutation in Nphp3 is probably responsible for the polycystic kidney disease (pcy) mouse phenotype. Interventional studies in the pcy mouse have shown beneficial effects by modification of protein intake and administration of methylprednisolone, suggesting therapeutic strategies for treating individuals with NPHP3.
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U2 - 10.1038/ng1216
DO - 10.1038/ng1216
M3 - Article
C2 - 12872122
AN - SCOPUS:0042093746
SN - 1061-4036
VL - 34
SP - 455
EP - 459
JO - Nature genetics
JF - Nature genetics
IS - 4
ER -