Abstract
Nine affected individuals with isolated anophthalmia/microphthalmia from a large Muslim-inbred kindred were investigated. Assuming autosomal-recessive mode of inheritance, whole-genome linkage analysis, on DNA samples from four affected individuals, was undertaken. Homozygosity mapping techniques were employed and a 1.5-Mbp region, homozygous in all affected individuals, was delineated. The region contained nine genes, one of which, aldehyde dehydrogenase 1 (ALDH1A3), was a clear candidate. This gene seems to encode a key enzyme in the formation of a retinoic-acid gradient along the dorsoventral axis during an early eye development and the development of the olfactory system. Sanger sequence analysis revealed a missense mutation, causing a substitution of valine (Val) to methionine (Met) at position 71. Analyzing the p.Val71Met missense mutation using standard open access software (MutationTaster online, PolyPhen, SIFT/PROVEAN) predicts this variant to be damaging. Enzymatic activity, studied in vitro, showed no changes between the mutated and the wild-type ALDH1A3 protein.
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Acknowledgements
We are grateful to all family members for their participation in this study. We thank Gregg Duester who provided the ALDH1A3 cDNA clone. Affymetrix GeneChip Human Mapping 250K Nsp microarray was carried out in the Biological Services Unit at the Weizmann Institute. This work was supported in part by the Spanish Ministerio de Economía y Competitividad (BFU2011-24176) and Generalitat de Catalunya (2009 SGR 795).
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Mory, A., Ruiz, F., Dagan, E. et al. A missense mutation in ALDH1A3 causes isolated microphthalmia/anophthalmia in nine individuals from an inbred Muslim kindred. Eur J Hum Genet 22, 419–422 (2014). https://doi.org/10.1038/ejhg.2013.157
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DOI: https://doi.org/10.1038/ejhg.2013.157
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