title: A missense mutation in DHDDS, encoding dehydrodolichyl diphosphate synthase, is associated with autosomal-recessive retinitis pigmentosa in Ashkenazi Jews.
abstract: Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal degenerations caused by mutations in at least 50 genes. Using homozygosity mapping in Ashkenazi Jewish (AJ) patients with autosomal-recessive RP (arRP), we identified a shared 1.7 Mb homozygous region on chromosome 1p36.11. Sequence analysis revealed a founder homozygous missense mutation, c.124A>G (p.Lys42Glu), in the dehydrodolichyl diphosphate synthase gene (DHDDS) in 20 AJ patients with RP of 15 unrelated families. The mutation was not identified in an additional set of 109 AJ patients with RP, in 20 AJ patients with other inherited retinal diseases, or in 70 patients with retinal degeneration of other ethnic origins. The mutation was found heterozygously in 1 out of 322 ethnically matched normal control individuals. RT-PCR analysis in 21 human tissues revealed ubiquitous expression of DHDDS. Immunohistochemical analysis of the human retina with anti-DHDDS antibodies revealed intense labeling of the cone and rod photoreceptor inner segments. Clinical manifestations of patients who are homozygous for the c.124A>G mutation were within the spectrum associated with arRP. Most patients had symptoms of night and peripheral vision loss, nondetectable electroretinographic responses, constriction of visual fields, and funduscopic hallmarks of retinal degeneration. DHDDS is a key enzyme in the pathway of dolichol, which plays an important role in N-glycosylation of many glycoproteins, including rhodopsin. Our results support a pivotal role of DHDDS in retinal function and may allow for new therapeutic interventions for RP.
authors.affiliation: Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Lina
authors.initials: L
authors.lastname: Zelinger
authors.forename: Eyal
authors.initials: E
authors.lastname: Banin
authors.forename: Alexey
authors.initials: A
authors.lastname: Obolensky
authors.forename: Liliana
authors.initials: L
authors.lastname: Mizrahi-Meissonnier
authors.forename: Avigail
authors.initials: A
authors.lastname: Beryozkin
authors.forename: Dikla
authors.initials: D
authors.lastname: Bandah-Rozenfeld
authors.forename: Shahar
authors.initials: S
authors.lastname: Frenkel
authors.forename: Tamar
authors.initials: T
authors.lastname: Ben-Yosef
authors.forename: Saul
authors.initials: S
authors.lastname: Merin
authors.forename: Sharon B
authors.initials: SB
authors.lastname: Schwartz
authors.forename: Artur V
authors.initials: AV
authors.lastname: Cideciyan
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Jacobson
authors.forename: Dror
authors.initials: D
authors.lastname: Sharon
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000235:genetics*; D000595:Amino Acid Sequence; D002874:Chromosome Mapping; D005260:Female; D005808:Genes, Recessive / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007585:Jews / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D012174:Retinitis Pigmentosa / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid
chemical_list: D019883:Alkyl and Aryl Transferases; C051389:dehydrodolichyl diphosphate synthetase