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Byron L. Lam, Stephan Züchner, Julia Dallman, Rong Wen, Jeffery M. Vance, Margaret A. Periak-Vance; Dehydrodolichol Diphosphate Synthase (DHDDS) Mutation K42E Causes Retinitis Pigmentosa Phenotype. Invest. Ophthalmol. Vis. Sci. 2011;52(14):6602.
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We have identified a mutation K42E in the DHDDS (dehydrodolichol diphosphate synthase) associated with a non-syndromic recessive retinitis pigmentosa (RP). DHDDS is an enzyme that catalyzes the biosynthesis of dehydrodolichol diphasphate, a lipid carrier in the dolichol pathway for protein glycosylation. Hypo-function of the enzyme results in insufficient amount of dolichol, which would cause the malfunction of N-linked glycosylation.
The members of a family of Ashkenazi Jewish origin were initially examined in 1992. Recent examination included comprehensive ophthalmic and neurologic evaluations, echocardiogram, brain MRI, bone density scan, serum fasting cholesterol and lipid profile, serum thyroid function studies, serum IGF binding protein 1, serum IGF binding protein 2, serum clotting Factors, and antithrombin III. Whole exome sequencing was performed to identify the mutation.
Among the four siblings, three (2 females, 1 male) have early onset retinal degeneration with symptoms of impaired night vision and peripheral vision starting in the teenage years. During initial examination, peripheral retinal degeneration was evident, and only one had detectable electroretinogram (ERG) that showed cone-rod dysfunction. The pigmentary retinal degeneration subsequently progressed rapidly. Extensive systemic testing was negative. Both parents and the unaffected sibling are normal except for one parent with scotopic and photopic ERG responses in the low end of normal range. Whole exome sequencing revealed a single base A>G mutation in the DHDDS gene, which co-segregates with the phenotype. The mutation changes the highly conserved wild-type residue K42 to E.
The K42E mutation in DHDDS causes an early-onset RP/cone-rod dystrophy phenotype with no apparent associated systemic abnormalities. Because the outer segments undergo constant renewal requiring continuous synthesis of large quantity of glycoprotein opsin or rhodopsin, photoreceptors are particularly vulnerable to deficiency in protein glycosylation. Our results indicate that in some patients with glycosylation deficiency, clinical manifestations may be limited to RP.
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