Mutations in RDH12 encoding a photoreceptor cell retinol dehydrogenase cause childhood-onset severe retinal dystrophy

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 cells. 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 cycle. 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 dehydrogenase. Our studies show that RDH12 is associated with retinal dystrophy and encodes an enzyme with a unique, nonredundant role in the photoreceptor cells.

Mutations in LCA5 are an uncommon cause of Leber congenital amaurosis (LCA) type II

“…This observation raises the question to know whether non-truncating mutations of this gene could be involved in autosomal recessive retinal dystrophies less severe than LCA. Indeed, LCA-associated mutations are commonly deleterious mutations and mutations in several LCA genes can be responsible for autosomal recessive retinal dystrophies (retinitis pigmentosa or cone-rod dystrophies) [Gu et al, 1997;Freund et al, 1997;Banerjee et al, 1998;Sohocki et al, 1998;Lewis et al, 1999;den Hollander 1999;Lorenz et al, 2000;den Hollander et al, 2001;Sohocki et al, 2001;Thompson et al, 2001Thompson et al, , 2002Hameed et al, 2003;den Hollander et al, 2004;Janecke et al, 2004;Perrault et al, 2004].…”

“…60%) [Perrault et al, 1999;Hanein et al, 2004]. Up to date, 13 LCA genes have been mapped, 10 of which have been identified: GUCY2D/retGC1 [Perrault et al, 1996], RPE65 [Marlhens et al, 1997], CRX [Swaroop et al, 1999], AIPL1 [Sohocki et al, 2000], RPGRIP1 [Dryja et al, 2001;Gerber et al, 2001], CRB1 [den Hollander et al, 2001;Gerber et al, 2002], LRAT [Thompson and Gal, 2003], TULP1 , RDH12 [Janecke et al, 2004;Perrault et al, 2004], CEP290 [den Hollander et al, 2006;Perrault et al, 2007]. Mutations in 3/10of them were shown to account for LCA type I (GUCY2D, RPGRIP1, CEP290) while, although less frequent, LCA type II was hitherto accounted for by mutations in 7/10 genes (RPE65, CRX, AIPL1, CRB1, LRAT TULP12, RDH12) [Perrault et al, 1999;Hanein et al, 2004;Perrault et al, 2004;Perrault et al, 2007].…”

Novel mutations in CRB1 and ABCA4 genes cause Leber congenital amaurosis and Stargardt disease in a Swedish family

“…The following genes are known to be associated with LCA: GUCY2D, RPE65, SPATA7, AIPL1, LCA5, RPGRIP1, CRX, CRB1, CEP290, IMPDH1, RD3, RDH12, KCNJ13, LRAT and TULP1. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] It is difficult to estimate the proportion of patients with mutations in the different genes, as some, such as IMPDH1 (LCA11) is considered to be rare, other, as CEP290 accounts for almost 20%, and for some such as TULP1 and LRAT the number is uncertain. One of the most studied LCA genes is CRB1 at 1q31q32.1, which consists of 12 exons and encodes a protein Crumbs homologue that participates in determination and maintenance of photoreceptor architecture.…”

Using high-throughput SNP technologies to study cancer

“…Numerous disease genes have been localized using SNP-based genome-wide scans including genes implicated in multiple sclerosis (Sawcer et al, 2004(Sawcer et al, , 2005, Pelizaeus-Merzbacher-like disease (Uhlenberg et al, 2004), childhood severe retinal dystrophy (Janecke et al, 2004), neonatal diabetes (Sellick et al, 2003), age-related maculopathy (Jakobsdottir et al, 2005), erythrokeratodermia (Saba et al, 2005), arthrogryposisrenal dysfunction-cholestasis (ARC) syndrome (Gissen et al, 2004), familial glucocorticoid deficiency type 2 (Metherell et al, 2005), bipolar disorder , Charcot-Marie-Tooth disease (Shrimpton et al, 2004) and sudden infant death with dysgenesis of the testes (Puffenberger et al, 2004). Owing to the sporadic nature of cancer development, few linkage studies have been performed using SNP-based approaches.…”