Retinal degeneration associated with RDH12 mutations results from decreased 11-cis retinal synthesis due to disruption of the visual cycle.
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.
Thompson
Debra A
DA
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
Janecke
Andreas R
AR
Lange
Jessica
J
Feathers
Kecia L
KL
Hübner
Christian A
CA
McHenry
Christina L
CL
Stockton
David W
DW
Rammesmayer
Gabriele
G
Lupski
James R
JR
Antinolo
Guillermo
G
Ayuso
Carmen
C
Baiget
Montserrat
M
Gouras
Peter
P
Heckenlively
John R
JR
den Hollander
Anneke
A
Jacobson
Samuel G
SG
Lewis
Richard A
RA
Sieving
Paul A
PA
Wissinger
Bernd
B
Yzer
Suzanne
S
Zrenner
Eberhart
E
Utermann
Gerd
G
Gal
Andreas
A
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
D000429:Alcohol Oxidoreductases; C489649:RDH12 protein, human; D012172:Retinaldehyde