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M.N. Preising, R.S. Sitorus, T. Rosenberg, U. Kellner, B. Lorenz; Screening of NUB1 in Patients With Leber Congenital Amaurosis . Invest. Ophthalmol. Vis. Sci. 2003;44(13):2317.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: To identify disease causing mutations in the NUB1 gene underlying Leber Congenital Amaurosis (LCA). NUB1 has been reported as a interaction protein of AIPL1 recently. We tested the hypothesis that mutations in NUB1 cause an LCA phenotype. A first focus was set on patients carrying missense mutations of AIPL1 previously reported as non-pathogenic. Methods: Index cases with LCA (n=67) examined by the authors (n=50) and by collaborating local ophthalmologists (n=17) were screened for mutations in the AIPL1 and NUB1 genes by SSCP and direct sequencing. Results: 8 index cases were identified to carry missense mutations in the AIPL1 gene. Among these mutations the D90H polymorphism has been identified in 5 of 16 alleles. The other mutations included R53W, H82Y, C89Y, C89R, V96I, and I206N. All of these were present in the single heterozygous state or with D90H as compound allele. The NUB1 gene was screened in these 8 index cases carrying AIPL1 missense mutations. Three polymorphisms were identified. All were frequent SNPs (A597A, Y280Y, IVS6+6a/g ) useful for linkage studies. Using these SNPs the NUB1 gene as disease causing gene was excluded in 4 additional familial index cases. No other disease causing mutations were identified up to now in the patients carrying AIPL1 missense mutations. The screening was extended to 30 index cases from our set of LCA patients without identification of any disease related sequence change. Conclusions: We screened the AIPL1-interacting protein NUB1 which shares features of ubiquitin in 8 LCA patients carrying AIPL1 missense mutations of unknown pathogeneity. No NUB1 mutation was found in these LCA index cases arguing against digenic inheritance involving NUB1 and AIPL1 in LCA. A further set of 34 LCA index cases were screened without identification of mutations in AIPL1 and failed to show NUB1 mutations. Our results indicate that if at all NUB1 is a very rare cause of LCA. We currently extend our NUB1 screen on early onset RP cases. These data will also be presented.
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