title: Retinal degeneration associated with RDH12 mutations results from decreased 11-cis retinal synthesis due to disruption of the visual cycle.
abstract: Retinoid dehydrogenases/reductases catalyze key oxidation-reduction reactions in the visual cycle that converts vitamin A to 11-cis retinal, the chromophore of the rod and cone photoreceptors. It has recently been shown that mutations in RDH12, encoding a retinol dehydrogenase, result in severe and early-onset autosomal recessive retinal dystrophy (arRD). In a cohort of 1011 individuals diagnosed with arRD, we have now identified 20 different disease-associated RDH12 mutations, of which 16 are novel, in a total of 22 individuals (2.2%). Haplotype analysis suggested a founder mutation for each of the three common mutations: p.L99I, p.T155I and c.806_810delCCCTG. 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 in our study 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. For the p.T49M variant, differing activity profiles were associated with each of the alleles of the common p.R161Q RDH12 polymorphism, suggesting that genetic background may act as a modifier of mutation effect. A locus (LCA3) for Leber congenital amaurosis, a severe, early-onset form of arRD, maps close to RDH12 on chromosome 14q24. Haplotype analysis in the family in which LCA3 was mapped excluded RDH12 as the LCA3 gene and thus suggests the presence of a novel arRD gene in this region.
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Michigan Medical School, Ann Arbor 48105, USA, and Unidad de Genética Médica y Diagnóstico Prenatal, Hospitales Universitarios Virgen del Rocío, Seville, Spain. dathom@umich.edu
authors.forename: Debra A
authors.initials: DA
authors.lastname: Thompson
authors.forename: Andreas R
authors.initials: AR
authors.lastname: Janecke
authors.forename: Jessica
authors.initials: J
authors.lastname: Lange
authors.forename: Kecia L
authors.initials: KL
authors.lastname: Feathers
authors.forename: Christian A
authors.initials: CA
authors.lastname: Hübner
authors.forename: Christina L
authors.initials: CL
authors.lastname: McHenry
authors.forename: David W
authors.initials: DW
authors.lastname: Stockton
authors.forename: Gabriele
authors.initials: G
authors.lastname: Rammesmayer
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.forename: Guillermo
authors.initials: G
authors.lastname: Antinolo
authors.forename: Carmen
authors.initials: C
authors.lastname: Ayuso
authors.forename: Montserrat
authors.initials: M
authors.lastname: Baiget
authors.forename: Peter
authors.initials: P
authors.lastname: Gouras
authors.forename: John R
authors.initials: JR
authors.lastname: Heckenlively
authors.forename: Anneke
authors.initials: A
authors.lastname: den Hollander
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Jacobson
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lewis
authors.forename: Paul A
authors.initials: PA
authors.lastname: Sieving
authors.forename: Bernd
authors.initials: B
authors.lastname: Wissinger
authors.forename: Suzanne
authors.initials: S
authors.lastname: Yzer
authors.forename: Eberhart
authors.initials: E
authors.lastname: Zrenner
authors.forename: Gerd
authors.initials: G
authors.lastname: Utermann
authors.forename: Andreas
authors.initials: A
authors.lastname: Gal
mesh_terms: D000429:Alcohol Oxidoreductases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001766:Blindness / Q000235:genetics; D019556:COS Cells; D002522:Chlorocebus aethiops; D005260:Female; D005808:Genes, Recessive; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D029242:Optic Atrophy, Hereditary, Leber / Q000235:genetics; D010375:Pedigree; D011110:Polymorphism, Genetic; D012162:Retinal Degeneration / Q000235:genetics*; D012172:Retinaldehyde / Q000096:biosynthesis* / Q000378:metabolism
chemical_list: D000429:Alcohol Oxidoreductases; C489649:RDH12 protein, human; D012172:Retinaldehyde