Abstract
Leber congenital amaurosis (LCA, MIM 204000) accounts for at least 5% of all inherited retinal disease1 and is the most severe inherited retinopathy with the earliest age of onset2. Individuals affected with LCA are diagnosed at birth or in the first few months of life with severely impaired vision or blindness, nystagmus and an abnormal or flat electroretinogram (ERG). Mutations in GUCY2D (ref. 3), RPE65 (ref. 4) and CRX (ref. 5) are known to cause LCA, but one study identified disease-causing GUCY2D mutations in only 8 of 15 families whose LCA locus maps to 17p13.1 (ref. 3), suggesting another LCA locus might be located on 17p13.1. Confirming this prediction, the LCA in one Pakistani family mapped to 17p13.1, between D17S849 and D17S960—a region that excludes GUCY2D. The LCA in this family has been designated LCA4 (ref. 6). We describe here a new photoreceptor/pineal-expressed gene, AIPL1 (encoding aryl-hydrocarbon interacting protein-like 1), that maps within the LCA4 candidate region and whose protein contains three tetratricopeptide (TPR) motifs, consistent with nuclear transport or chaperone activity. A homozygous nonsense mutation at codon 278 is present in all affected members of the original LCA4 family. AIPL1 mutations may cause approximately 20% of recessive LCA, as disease-causing mutations were identified in 3 of 14 LCA families not tested previously for linkage.
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Acknowledgements
We thank the LCA families for participation; O.L. June, C. Inglehearn, J. McHale and D. Hughbanks-Wheaton for expert assistance; and R. McInnes and D. Ing for providing the retinal northern blot. Supported by grants from the Foundation Fighting Blindness and the George Gund Foundation, the William Stamps Farish Fund, the M.D. Anderson Foundation, the John S. Dunn Research Foundation and by grant EY07142 from the National Eye Institute-National Institutes of Health (M.M.S., S.J.B., L.S.S. and S.P.D.) S.S.B. acknowledges support of the Medical Research Council (grant ref: G9301094) and the Wellcome Trust (grant ref: 049571/Z/96sol;Z) for research funding.
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Sohocki, M., Bowne, S., Sullivan, L. et al. Mutations in a new photoreceptor-pineal gene on 17p cause Leber congenital amaurosis. Nat Genet 24, 79–83 (2000). https://doi.org/10.1038/71732
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DOI: https://doi.org/10.1038/71732
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