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MN Preising, S Rita, U Kellner, T Rosenberg, B Lorenz; Screening of three genes for Lebers Congenital Amaurosis - Novel mutations in AIPL1 . Invest. Ophthalmol. Vis. Sci. 2002;43(13):1201.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: To identify disease causing mutations in the AIPL1 gene underlying Leber Congenital Amaurosis (LCA). Methods: Index cases with LCA (n=56) and early onset retinal degenerations/RP (n=46) examined by the authors (n=82) and by collaborating local ophthalmologists (n=20) were screened for mutations in the RPE65, RetGC1, and AIPL1 genes by SSCP and direct sequencing. Results: 12 index cases were identified to carry disease causing mutations in the RPE65 (n=8) and RetGC1 genes (n=4). 4 LCA index cases were found to carry mutations in the AIPL1 gene. Case 1 is a German girl aged 5 from the North-East compound heterozygous for the D90H and a novel R53W mutation. The RPE showed pigment defects progressing from the periphery to the center. ERGs were extinct. R53W was inherited from her mother and her father is homozygous for D90H. Both parents show a severe form of early onset retinal degeneration. Case 2 is a Danish male aged 24 compound heterozygous for the D90H and a novel H82I mutation. His affected sister shares the same genotype. Both showed heavy eye rubbing from childhood on. Their ERGs were extinct. The D90H mutation was inherited from the unaffected mother and the H82I mutation from the unaffected father. Case 3 is a Danish patient aged 6. We could identify a novel V96I mutation heterozygously in the unaffected mother. Case 4 is a Turkish boy from a consanguineous marriage carrying a novel homozygous C89R mutation. At 9 months of age heavy eye rubbing and nystagmus were noticed. Flash-VEP was extinct. Photophobia was not present. The fundus was unremarkable. Conclusion: The D90H mutation of AIPL1 was reported previously as a benign variant. Our results in two independent families may indicate some pathogeneity. However, control DNAs of 50 unaffected probands from the general population revealed 2 homozygous and 6 single heterozygous individuals. If at all D90H predisposes to LCA a mutation in a second gene has to be expected. The other 4 AIPL1 mutations affect conserved residues in primates and have not been found in the control DNAs. Additionally Cys89 is conserved in several mammals. Therefore, we consider these to be pathogenic. Mutation analysis continues in cases 1 - 3.
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