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A. Estrada Cuzcano, R. K. Koenekoop, S. Kohl, K. Rohrschneider, I. H. Maumenee, S. G. Jacobson, C. B. Hoyng, E. Zrenner, F. P. M. Cremers, A. I. den Hollander; Nphp5 Mutations in Patients With Leber Congenital Amaurosis. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2578.
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Leber congenital amaurosis (LCA) is genetically heterogeneous with 15 genes identified thusfar, accounting for ~70% of LCA patients. The aim of the current study was to identify new genetic causes of LCA.
Homozygosity mapping in >150 LCA patients of worldwide origin was performed with high-density SNP microarrays (Affymetrix 250K) to identify new disease-causing genes.
In one isolated LCA patient we identified a large 17-Mb homozygous region on chromosome 3 encompassing NPHP5. Mutations in NPHP5 have previously been detected in patients with Senior-Loken syndrome (SLSN), characterized by nephronophthisis and retinal degeneration, prompting us to hypothesize that NPHP5 represents a new gene mutated in LCA without kidney disease. Our mutation analysis of NPHP5 in a cohort of 225 strictly defined LCA patients identified frameshift and nonsense mutations in 11 patients. Upon re-inspection of the patient’s disease status, four were found to have developed SLSN, while seven maintained the diagnosis of LCA as the kidney function remained normal. In one LCA patient we identified one heterozygous frameshift mutation in NPHP5 and one heterozygous mutation in CEP290, suggesting a digenic inheritance mechanism.
Our results show that NPHP5 mutations are found in 3% of LCA patients without nephronophthisis. Although some patients may develop kidney disease later in life, a significant number of patients did not experience any signs of renal failure even at an advanced age (up to age 55). The presence or absence of nephronophthisis in patients carrying NPHP5 mutations might therefore depend on modifier alleles that remain to be identified. We recommend that all LCA patients be screened for NPHP5 mutations, in order to follow them more closely for kidney disease. NPHP5 represents a new gene for LCA and adds to the growing list of ciliary proteins involved in its pathogenesis.
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