Lina Zelinger, Eyal Banin, Alexey Obolensky, Liliana Mizrahi-Meissonnier, Avigail Beryozkin, Dikla Bandah-Rozenfeld, Shahar Frenkel, Tamar Ben-Yosef, Saul Merin, Sharon B. Schwartz, Artur V. Cideciyan, Samuel G. Jacobson, Dror Sharon | American Society of Human Genetics (AJHG) | 2011 Feb 11 | 88(2) | 207–215 |
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.
Main Text
Retinitis pigmentosa (RP; MIM 268000) is the most common inherited retinal degeneration, with an estimated worldwide prevalence of 1:4000.1–3 The disease is highly heterogeneous and has several patterns of inheritance. At present, 35 genetic loci have been implicated in nonsyndromic autosomal-recessive RP (arRP), most of which account for a few percent of RP cases each.
Although many of the early identified arRP genes were excellent candidates for the disease when mutated, mainly because of the function of the encoded protein (e.g., PDE6A4 [MIM 180071] and PDE6B5 [MIM 180072]), a large proportion of the recently identified genes were not a priori considered as candidates and were identified through whole-genome linkage or homozygosity mapping followed by mutation screening of a large number of genes in the linked intervals (e.g., EYS6 [MIM 612424] and SPATA77 [MIM 609868]). Through those studies, a new class of genes encoding proteins with housekeeping-like function (e.g., IDH3B [MIM 604526] for arRP8 and splicing factors for autosomal-dominant RP9,10) have been identified and provided new insight into processes that result in retinal degeneration. The reason for the retina-specific phenotype caused by mutations in these genes is still unclear.
The Ashkenazi Jewish (AJ) population was established by Jews who originated in the Middle East and migrated to Europe, initially settling in Germany (the “Ashkenaz” region) at or before the 4th century. The AJ lived in closed communities in European countries and developed a unique culture and language (named Yiddish, which is based on a few different languages, including German, Hebrew, and Aramaic). After the Holocaust, the population size dropped from about 8.8 million individuals to only 2.8 million, and AJ immigrated out of Europe, mainly to the United States and the emerging state of Israel. AJ currently constitute the largest Jewish ethnic group in both countries. A large amount of effort was directed to study the genetic structure of the AJ population, in the context of other Jewish ethnic groups and Middle Eastern populations, at the Y chromosome,11,12 mitochondrial,13 and genomic14,15 levels. Although consanguineous marriages are relatively uncommon among AJ (1.5% and rapidly declining),16,17 most individuals who are affected by a rare AR disease in this ethnic group are homozygous for the disease-causing mutation, mainly because of a high rate of intracommunity marriages.17 Therefore, genetic analysis of hereditary diseases in the AJ population, via homozygosity mapping, can be highly efficient.
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