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R. K. Koenekoop, G. A. Fishman, L. Bou-Khzam, F. Al-Wadaani, M. Musarella, I. Maumenee, R. Roepman, I. Lopez, A. den Hollander; Leber Congenital Amaurosis (LCA) Patients With Possible Mutations in Two Ciliary Genes: CEP290 and RPGRIP1. Does Oligogenic Inheritance Exist in LCA?. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1686.
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To assess the possibility of oligogenic inheritance in Leber congenital amaurosis (LCA). LCA is the most common cause of hereditary retinal childhood blindness and is characterized by visual loss, nystagmus, an absent ERG, and autosomal recessive inheritance. LCA is currently thought to be a monogenic disorder with surprising genetic heterogeneity (14 genes). An emerging group of LCA proteins are involved in ciliary transport and four LCA genetic subtypes appear to be "ciliopathies" (CEP290, LCA5, RPGRIP1 and TULP1). In Bardet-Biedl syndrome (BBs) and nephronophtisis, oligogenic inheritance has been described, which involves mutations in more than one gene modifying the severity of the phenotype.
We tested the hypothesis that mutations in RPGRIP1 and CEP290 coexist in LCA patients and modify the phenotype. We screened 300 LCA patients for RPGRIP1 mutations and found heterozygous changes in 22 patients. These were then screened for CEP290 mutations. We performed co-segregation studies of the mutations, and are performing RT-PCR and cDNA sequencing of both genes.
In a non-consanguineous LCA family, we found a heterozygous (htz) c. 3402-3404 delGTC, p. M1134I /del S1135 mutation in RPGRIP1 and a htz p. Cys998X mutation in CEP290. We found no-light perception vision, pale optic discs and diffuse mid-peripheral white retinal spots in the proband. We are continuing to search for LCA families carrying mutations in both RPGRIP1 and CEP290.
There is increasing evidence that oligogenic inheritance occurs (e.g. BBs, NPHP). We do not have evidence yet for oligogenic inheritance in LCA, although we found presumed mutations in both RPGRIP1 and CEP290 in an LCA patient with a phenotype not typically associated with RPGRIP1 or CEP290 mutations alone. We also found both mutations in the mother, necessitating a third mutation to explain the affected status. The RPGRIP1 mutation is in the RPGR binding domain (RID), while the CEP290 mutation leads to a stop. Both CEP290 and RPGRIP1 proteins belong to the same protein complex as RPGR and all co-localize to the photoreceptor cilium. Further genetic and functional studies are in progress.
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