TY - JOUR
T1 - A missense mutation in DHDDS, encoding dehydrodolichyl diphosphate synthase, is associated with autosomal-recessive retinitis pigmentosa in ashkenazi jews
AU - Zelinger, Lina
AU - Banin, Eyal
AU - Obolensky, Alexey
AU - Mizrahi-Meissonnier, Liliana
AU - Beryozkin, Avigail
AU - Bandah-Rozenfeld, Dikla
AU - Frenkel, Shahar
AU - Ben-Yosef, Tamar
AU - Merin, Saul
AU - Schwartz, Sharon B.
AU - Cideciyan, Artur V.
AU - Jacobson, Samuel G.
AU - Sharon, Dror
N1 - Funding Information: This study was financially supported by the Foundation Fighting Blindness USA (BR-GE-0510-0490-HUJ to D.S.; C-CL-07-0411,0412 to A.V.C. and S.G.J.), by the Legacy Heritage Biomedical Program of the Israeli Science Foundation (grant 612/09 to T.B.-Y. and D.S.), Hope for Vision (to A.V.C. and S.G.J.), and the Yedidut 1 research grant (to E.B.). We thank the patients and their families for their participation in the study. The authors thank Michal Ben-Hur, Rob W. Collin, Sandro Banfi, Robert K. Koenekoop, Israel Barzel, Alejandro Roman, Malgorzata Swider, Alexander Sumaroka, Yelena Piontek, and Michael Kogan for excellent and generous assistance. The authors would also like to thank Steven J. Fliesler for helpful discussions.
PY - 2011/2/11
Y1 - 2011/2/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79851508986&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.ajhg.2011.01.002
DO - https://doi.org/10.1016/j.ajhg.2011.01.002
M3 - مقالة
SN - 0002-9297
VL - 88
SP - 207
EP - 215
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 2
ER -