Abstract
We identified three consanguineous Austrian kindreds with 15 members affected by autosomal recessive childhood-onset severe retinal dystrophy, a genetically heterogeneous group of disorders characterized by degeneration of the photoreceptor cells1. A whole-genome scan by microarray analysis of single-nucleotide polymorphisms (ref. 2) identified a founder haplotype and defined a critical interval of 1.53 cM on chromosome 14q23.3–q24.1 that contains the gene associated with this form of retinal dystrophy. RDH12 maps in this region and encodes a retinol dehydrogenase proposed to function in the visual cycle3. A homozygous 677A→G transition (resulting in Y226C) in RDH12 was present in all affected family members studied, as well as in two Austrian individuals with sporadic retinal dystrophy. We identified additional mutations in RDH12 in 3 of 89 non-Austrian individuals with retinal dystrophy: a 5-nucleotide deletion (806delCCCTG) and the transition 565C→T (resulting in Q189X), each in the homozygous state, and 146C→T (resulting in T49M) and 184C→T (resulting in R62X) in compound heterozygosity. When expressed in COS-7 cells, Cys226 and Met49 variants had diminished and aberrant activity, respectively, in interconverting isomers of retinol and retinal. The severe visual impairment of individuals with mutations in RDH12 is in marked contrast to the mild visual deficiency in individuals with fundus albipunctatus caused by mutations in RDH5, encoding another retinal dehydrogenase4. Our studies show that RDH12 is associated with retinal dystrophy and encodes an enzyme with a unique, nonredundant role in the photoreceptor cells.
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Acknowledgements
We thank G. Huber and J. Oversier for technical assistance and W. Göttinger for discussions. This work was supported by grants from Tiroler Medizinischer Forschungsfond, Fond zur Förderung der Wissenschaftlichen Forschung in Österreich, the German Federal Ministry of Science and Education through the National Genome Research Network, EVI-GENORET, the Deutsche Forschungsgemeinschaft, the Forschungsforderungsfonds FM, UKE, the National Institutes of Health, the Foundation Fighting Blindness and Research to Prevent Blindness.
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Janecke, A., Thompson, D., Utermann, G. et al. Mutations in RDH12 encoding a photoreceptor cell retinol dehydrogenase cause childhood-onset severe retinal dystrophy. Nat Genet 36, 850–854 (2004). https://doi.org/10.1038/ng1394
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DOI: https://doi.org/10.1038/ng1394
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