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E. M. Stone, A. V. Cideciyan, T. S. Aleman, T. E. Scheetz, M. A. Ehlinger, G. A. Fishman, E. I. Traboulsi, B. L. Lam, A. B. Fulton, S. G. Jacobson; Variations in NPHP5 Cause Nonsyndromic Leber Congenital Amaurosis (LCA). Invest. Ophthalmol. Vis. Sci. 2010;51(13):6354.
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To investigate the possibility that variations in NPHP5 cause LCA in the absence of overt renal disease.
DNA samples from 276 patients with the clinical diagnosis of nonsyndromic LCA were screened for variations in the coding sequence and proximal promoter of the NPHP5 gene (also known as IQCB1) using a combination of Sanger and pyrophosphate sequencing. Each of these individuals had been previously screened for mutations in 8 known LCA genes (AIPL1, CRB1, CRX, GUCY2D, RHD12, RPE65, RPGRIP1, and CEP290) without identifying a plausible disease-causing genotype. 276 ethnically matched control individuals were also screened for NPHP5 variations. High resolution optical coherence tomography and near-infrared autofluorescence imaging were performed on a subset of these LCA probands.
Nine of the 276 LCA probands (3.2%) were each found to harbor two plausible disease-causing mutations in NPHP5. Seven different alleles were observed, four of which have been previously reported in patients affected with Senior-Loken syndrome (F141del, R461X, R489X and H506del) and three of which are novel (A111del, E346X, and R455X). One patient inherited both of his disease alleles from his mother (uniparental isodisomy). Ocular examinations revealed reduced visual acuity in all patients (ranging from 20/80 to light perception), hyperopia, severely limited visual fields, nystagmus, and non-detectable ERGs. Imaging studies showed a retained photoreceptor nuclear layer and RPE integrity mainly in the cone-rich central retina. None of the 9 patients had manifestations of renal disease in early childhood but 2 were diagnosed with nephronophthisis in the second decade of life.
Mutations in NPHP5 appear to cause a small fraction of nonsyndromic LCA. The retinal phenotype associated with these mutations has strong similarities to that seen in NPHP6 disease, consistent with the similar intracellular localization and molecular interaction of the two proteins. The persistence of a recognizable photoreceptor layer in these patients is encouraging for future therapeutic interventions. Of immediate clinical significance, nonsyndromic LCA patients with variations in NPHP5 should be periodically monitored for renal disease which can be slow to manifest.
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