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G. Kumaramanickavel, V. L. Ramprasad, N. Soumittra, D. Nancarrow, P. Sen, M. McKibbin, G. A. Williams, T. Arokiasamy, L. Praveena, C. F. Inglehearn; Homozygosity Mapping in Consanguineous Retinal Dystrophy Families: Identification of a Novel c.955G>A Splice Site Mutation in the Lebercilin Gene in Leber Congential Amaurosis. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2979. doi: https://doi.org/.
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Reinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are, respectively, the commonest and the most severe retinal dystrophies. Over 40 genes in RP and 13 genes in LCA, have been implicated. Three non-syndromic LCA, caused by mutations in RPGRIP1, CEP290 and Lebercilin, are ciliopathy-related, as are Joubert and Senior-Loken syndromes which include LCA. Two consanguineous families, one with LCA and another with RP, were studied to identify the disease causing genes.
A thorough ophthalmic examination was carried out on family members and homozygosity mapping was performed using the Affymetrix 10K Xba1 GeneChip and ExcludeAR program. The coding exons of the lebercilin and CERKL genes were sequenced to screen for mutations co-segregating with the phenotype.
The LCA family had two affected children, but the second child aged 11 months died due to asphyxia. In a 24.5cM homozygous region at 6q12- q16.3, both the affecteds had a homozygous novel c.955G>A missense lebercilin mutation in the last base of exon 6, causing disruption of the splice donor site. This mutation ablates the correct splice donor site, leading to mis-splicing at an alternative donor site 5bp into the adjacent intron, which results in a 5bp insert in the transcript. This in turn leads to a frameshift and premature truncation of the lebercilinprotein. The RP family also with two affecteds had a 55.5cM homozygous region identified at 2q24-2q33, overlapping the RP26 locus. The gene implicated in RP26-RP, CERKL, did not show any mutation.
Homozygosity mapping is a simple, rapid method to locate genes underlying recessively inherited disease in consanguineous families. In this way a novel lebercilin mutation was identified in an LCA family. The respiratory related pathology in the deceased child could be the result of a defect in the primary cilia. Given that the libercilin gene is expressed in nasopharynx, trachea and lungs and was originally identified in the proteome of bronchial epithelium ciliary axonemes, this may imply that libercilin mutations can in fact cause a wider spectrum of phenotypes including respiratory disease.
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