Alternative titles; symbols
HGNC Approved Gene Symbol: RDH12
Cytogenetic location: 14q24.1 Genomic coordinates (GRCh38) : 14:67,701,886-67,734,451 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q24.1 | Leber congenital amaurosis 13 | 612712 | Autosomal dominant; Autosomal recessive | 3 |
Retinoids are indispensable light-sensitive elements of vision and also serve as essential modulators of cellular differentiation and proliferation in diverse cell types. RDH12 belongs to a family of dual-specificity retinol dehydrogenases that metabolize both all-trans- and cis-retinols (Haeseleer et al., 2002).
By searching databases for sequences similar to RDH11 (607849), followed by PCR of a retina cDNA library, Haeseleer et al. (2002) cloned RDH12. The deduced 316-amino acid RDH12 protein has a calculated molecular mass of about 35 kD and shares 79% similarity with RDH11. RDH12 contains 2 motifs highly conserved among short chain alcohol dehydrogenases/reductases, the cofactor-binding site and catalytic residues. EST database analysis indicated that RDH12 is expressed predominantly in eye and also in kidney, brain, skeletal muscle, and stomach. In situ hybridization to monkey and mouse retina indicated Rdh12 is expressed at the base of photoreceptor inner segments.
Haeseleer et al. (2002) determined that the RDH12 gene contains 7 exons and spans about 13 kb.
By genomic sequence analysis, Haeseleer et al. (2002) mapped the RDH12 gene to chromosome 14q23.3, where it lies about 30 kb from the RDH11 gene and within the locus for the recessive blinding disease Leber congenital amaurosis-13 (LCA13; 612712).
Haeseleer et al. (2002) determined that recombinant RDH12 was expressed in insect cells as a membrane protein with enzymatic properties similar to those of RDH11. Both enzymes catalyzed the reduction of all-trans-retinal and its 9-cis-, 11-cis-, and 13-cis-retinal isomers in the presence of NADPH. Analysis of the reactions suggested that these enzymes catalyze the reaction in both directions (NADPH/retinals--NADP/retinols), with equal utilization of 11-cis-retinal and all trans-retinal. No steroid dehydrogenase activity was detected for RDH12. RDH12 activity was potently inhibited by retinoic acids, recombinant CRBP1 (180260), and CRALBP (180090).
Janecke et al. (2004) described 3 consanguineous kindreds with LCA13 (612712) in which relatedness seemed likely because of geographic proximity and similar disease phenotype, although genealogic studies could not link the families. A whole-genome scan by microarray analysis of SNPs identified a founder haplotype and defined a critical interval of 1.53 cM on 14q23.3-q24.1 that contained the RDH12 gene, encoding a retinol dehydrogenase thought to function in the visual cycle (Haeseleer et al., 2002). All affected family members studied from the 3 kindreds, as well as 2 Austrian individuals with sporadic LCA, were found to be homozygous for a tyr226-to-cys mutation in the RDH12 gene (Y226C; 608830.0001). Janecke et al. (2004) identified additional mutations in RDH12 in 3 of 89 non-Austrian individuals with LCA13: 806delCCCTG (608830.0002) and gln189 to ter (Q189X; 608830.0003), each in homozygous state, and thr49 to met (T49M; 608830.0004) and arg62 to ter (R62X; 608830.0005) in compound heterozygosity. The severe visual impairment of individuals with mutations in RDH12 was in marked contrast to the mild visual deficiency in individuals with fundus albipunctatus (136880) caused by mutations in RDH5 (601617), encoding another retinol dehydrogenase.
Perrault et al. (2004) studied a series of 110 unrelated patients with LCA; in 4.1% of the patients, they identified mutations in the RDH12 gene: 1 splice site (608830.0013), 1 frameshift deletion (608830.0002), 2 nonsense mutations (608830.0005, 608830.0006), and 7 missense mutations (608830.0001, 608830.0007-608830.0012). All patients harboring RDH12 mutations had a severe yet progressive rod-cone dystrophy with severe macular atrophy but no or mild hyperopia; Perrault et al. (2004) noted that this phenotype may represent the upper extreme of the spectrum of retinitis pigmentosa (RP; see 268000). No RDH12 mutations were identified in patients presenting with congenital stationary cone-rod dystrophy.
In a cohort of 1,011 individuals diagnosed with autosomal recessive retinal dystrophy, Thompson et al. (2005) identified 20 different disease-associated RDH12 mutations in a total of 22 individuals. Haplotype analysis suggested a founder mutation for each of the 3 common mutations: L99I (608830.0010), T155I (608830.0014), and 806_810delCCCTG (608830.0002). Patients typically presented with early disease that affected the function of both rods and cones and progressed to legal blindness in early adulthood. Eleven of the missense variants identified exhibited profound loss of catalytic activity when expressed in transiently transfected COS-7 cells and assayed for ability to convert all-trans retinal to all-trans retinol. Loss of function appeared to result from decreased protein stability, as expression levels were significantly reduced.
In a large 6-generation family segregating autosomal dominant retinitis pigmentosa mapping to chromosome 14q (RP53; see 612712), Fingert et al. (2008) sequenced the candidate gene RDH12 and identified heterozygosity for a 1-bp deletion (608830.0015) in 19 affected individuals that was not found in unaffected family members or in 158 controls.
In a large, highly consanguineous pedigree segregating autosomal recessive early-onset retinitis pigmentosa, Benayoun et al. (2009) identified a homozygous missense mutation (A126V; 608830.0016) that segregated with disease in 8 sibships.
In affected members of 3 consanguineous Austrian kindreds with Leber congenital amaurosis-13 (LCA13; 612712), Janecke et al. (2004) identified homozygosity for a 677A-G transition in exon 6 of the RDH12 gene, resulting in a tyr226-to-cys (Y226C) substitution. The same mutation was identified in 2 Austrian individuals with sporadic LCA13. Janecke et al. (2004) demonstrated that, when expressed in COS-7 cells, the cys226 variant had diminished activity in interconverting isomers of retinol and retinal.
In affected members of a French family with LCA, Perrault et al. (2004) identified the Y226C mutation in compound heterozygous state with a 523T-C transition in exon 5 of the RDH12 gene, resulting in a ser175-to-pro substitution (S175P; 608830.0011).
In a 19-year-old individual with Leber congenital amaurosis-13 (LCA13; 612712), Janecke et al. (2004) identified a homozygous 5-bp deletion in exon 6 of the RDH12 gene, 806delCCCTG, resulting in a frameshift and a premature stop codon at position 269. Visual acuity was reduced to light reception in the right eye and 0.05 in the left eye. ERGs were extinguished, and the fundi showed heavy hyperpigmentation with bone spicule-like pattern.
In affected members of 4 unrelated French families with LCA13, Perrault et al. (2004) identified the 806delCCCTG mutation. The mutation was present in homozygous state in 1 family; in the other 3 families it was present in compound heterozygous state with either a 451C-A transversion in exon 5, resulting in a his151-to-asn mutation (H151N; 608830.0007), a 687C-G transversion in exon 6, resulting in a pro230-to-ala substitution (P230A; 608830.0008), or a 658+1G-A (608830.0013) splice site mutation.
In a male patient of Turkish origin with Leber congenital amaurosis-13 (LCA13; 612712), the offspring of consanguineous parents, Janecke et al. (2004) identified a homozygous 565C-T transition in exon 5 of the RDH12 gene, resulting in a gln189-to-ter (Q189X) substitution. The patient's sister was also diagnosed with LCA13.
In a woman with Leber congenital amaurosis-13 (LCA13; 612712), the offspring of nonconsanguineous parents, Janecke et al. (2004) identified compound heterozygosity for mutations in exon 2 of the RDH12 gene: a 146C-T transition, resulting in a thr49-to-met (T49M) substitution, and a 184C-T transition, resulting in an arg62-to-ter (R62X; 608830.0005) substitution. Janecke et al. (2004) demonstrated that, when expressed in COS-7 cells, the met49 variant had aberrant activity in interconverting isomers of retinol and retinal.
Thompson et al. (2005) found differing activity profiles for the T49M variant associated with each of the alleles of the R161Q RDH12 polymorphism, suggesting that genetic background may act as a modifier of mutation effect.
For discussion of the arg62-to-ter (R62X) mutation in the RDH12 gene that was found in compound heterozygous state in a patient with Leber congenital amaurosis-13 (LCA13; 612712) by Janecke et al. (2004), see 608830.0004.
In affected members of a French family with LCA13, Perrault et al. (2004) identified compound heterozygosity for mutations in the RDH12 gene: the arg62-to-ter (R62X) substitution and a 152T-A transversion in exon 2, resulting in an ile51-to-asn (I51N; 608830.0012) substitution.
In affected members of a French family with Leber congenital amaurosis-13 (LCA13; 612712), Perrault et al. (2004) identified compound heterozygosity for mutations in the RDH12 gene: a 379G-T transversion in exon 4, resulting in a gly127-to-ter (G127X) substitution, and a 295C-A transversion in exon 3, resulting in a leu99-to-ile (L99I; 608830.0010) substitution.
For discussion of the his151-to-asn (H151N) mutation in the RDH12 gene that was found in compound heterozygous state in patients with Leber congenital amaurosis-13 (LCA13; 612712) by Perrault et al. (2004), see 608830.0002.
For discussion of the pro230-to-ala (P230A) mutation in the RDH12 gene that was found in compound heterozygous state in patients with Leber congenital amaurosis-13 (LCA13; 612712) by Perrault et al. (2004), see 608830.0002.
In affected members of a French family with Leber congenital amaurosis-13 (LCA13; 612712), Perrault et al. (2004) identified homozygosity for a 451C-G transversion in exon 5 of the RDH12 gene, resulting in a his151-to-asp (H151D) substitution.
For discussion of the leu99-to-ile (L99I) mutation in the RDH12 gene that was found in compound heterozygous state in patients with Leber congenital amaurosis-13 (LCA13; 612712) by Perrault et al. (2004), see 608830.0006.
For discussion of the ser175-to-pro (S175P) mutation in the RDH12 gene that was found in compound heterozygous state in patients with Leber congenital amaurosis-13 (LCA13; 612712) by Perrault et al. (2004), see 608830.0001.
For discussion of the ile51-to-asn (I51N) mutation in the RDH12 gene that was found in compound heterozygous state in patients with Leber congenital amaurosis-13 (LCA13; 612712) by Perrault et al. (2004), see 608830.0005.
For discussion of the splice site mutation in the RDH12 gene (658+1G-A) that was found in compound heterozygous state in patients with Leber congenital amaurosis-13 (LCA13; 612712) by Perrault et al. (2004), see 608830.0002.
In 3 patients with Leber congenital amaurosis-13 (LCA13; 612712), Thompson et al. (2005) identified a 464C-T transition in exon 5 of the RDH12 gene that resulted in a thr155-to-ile substitution (T155I). The mutation was homozygous in 2 patients and carried heterozygously on the maternal allele in the third; the paternal allele carried an H151D mutation (608830.0009). Haplotype analysis indicated that the T115I substitution is a founder mutation.
In affected members of a large 6-generation family segregating autosomal dominant retinitis pigmentosa (RP53; see 612712), Fingert et al. (2008) identified heterozygosity for a 1-bp deletion (776delG) in the RDH12 gene, resulting in a premature termination codon predicted to eliminate the highly conserved 57 terminal amino acids of RDH12. The mutation was not found in unaffected family members or in 158 controls.
In 14 affected members from 8 sibships of a large, highly consanguineous pedigree segregating autosomal recessive early-onset retinitis pigmentosa (RP53; see 612712), Benayoun et al. (2009) identified homozygosity for a 377C-T transition in exon 4 of the RDH12 gene, resulting in an ala126-to-val (A126V) substitution at a conserved residue within the RDH domain. A 45-year-old male family member who was heterozygous for A126V appeared to have a subclinical phenotype: although he did not describe significant subjective visual difficulties and denied nyctalopia or photosensitivity, his photopic ERG was at the lower limit of the normal range and his scotopic ERG was markedly reduced. In a screen of 159 controls, 1 heterozygous carrier was detected, indicating a carrier frequency of 0.62% in this population.
Benayoun, L., Spiegel, R., Auslender, N., Abbasi, A. H., Rizel, L., Hujeirat, Y., Salama, I., Garzozi, H. J., Allon-Shalev, S., Ben-Yosef, T. Genetic heterogeneity in two consanguineous families segregating early onset retinal degeneration: the pitfalls of homozygosity mapping. Am. J. Med. Genet. 149A: 650-656, 2009. [PubMed: 19140180] [Full Text: https://doi.org/10.1002/ajmg.a.32634]
Fingert, J. H., Oh, K., Chung, M., Scheetz, T. E., Andorf, J. L., Johnson, R. M., Sheffield, V. C., Stone, E. M. Association of a novel mutation in the retinol dehydrogenase 12 (RDH12) gene with autosomal dominant retinitis pigmentosa. Arch. Ophthal. 126: 1301-1307, 2008. [PubMed: 18779497] [Full Text: https://doi.org/10.1001/archopht.126.9.1301]
Haeseleer, F., Jang, G.-F., Imanishi, Y., Driessen, C. A. G. G., Matsumura, M., Nelson, P. S., Palczewski, K. Dual-substrate specificity short chain retinol dehydrogenases from the vertebrate retina. J. Biol. Chem. 277: 45537-45546, 2002. [PubMed: 12226107] [Full Text: https://doi.org/10.1074/jbc.M208882200]
Janecke, A. R., Thompson, D. A., Utermann, G., Becker, C., Hubner, C. A., Schmid, E., McHenry, C. L., Nair, A. R., Ruschendorf, F., Heckenlively, J., Wissinger, B., Nurnberg, P., Gal, A. Mutations in RDH12 encoding a photoreceptor cell retinol dehydrogenase cause childhood-onset severe retinal dystrophy. Nature Genet. 36: 850-854, 2004. Note: Erratum: Nature Genet. 36: 1024 only, 2004. [PubMed: 15258582] [Full Text: https://doi.org/10.1038/ng1394]
Perrault, I., Hanein, S., Gerber, S., Barbet, F., Ducroq, D., Dollfus, H., Hamel, C., Dufier, J.-L., Munnich, A., Kaplan, J., Rozet, J.-M. Retinal dehydrogenase 12 (RDH12) mutations in Leber congenital amaurosis. Am. J. Hum. Genet. 75: 639-646, 2004. [PubMed: 15322982] [Full Text: https://doi.org/10.1086/424889]
Thompson, D. A., Janecke, A. R., Lange, J., Feathers, K. L., Hubner, C. A., McHenry, C. L., Stockton, D. W., Rammesmayer, G., Lupski, J. R., Antinolo, G., Ayuso, C., Baiget, M., and l1 others. Retinal degeneration associated with RDH12 mutations results from decreased 11-cis retinal synthesis due to disruption of the visual cycle. Hum. Molec. Genet. 14: 3865-3875, 2005. Note: Erratum: Hum. Molec. Genet. 15: 1559 only, 2006. [PubMed: 16269441] [Full Text: https://doi.org/10.1093/hmg/ddi411]