DHDDS – Retinitis Pigmentosa

Dehydrodolichyl diphosphate synthase (DHDDS) catalyzes dolichol chain elongation required for N-glycosylation. Biallelic pathogenic variants in DHDDS underlie autosomal-recessive retinitis pigmentosa (Retinitis Pigmentosa).

In 2011, a shared homozygous missense variant c.124A>G (p.Lys42Glu) was identified in 20 unrelated Ashkenazi Jewish patients from 15 families, all presenting with classic RP features including nyctalopia and visual field constriction (PMID:21295282).

A subsequent cohort of 230 Ashkenazi Jewish RP families found c.124A>G in 33% (76/230) of probands, establishing a founder effect, and independent screening of 275 RP patients detected homozygous p.Lys42Glu in 8.6% of Jewish cases (∼3/35) (PMID:29276052; PMID:25255364).

The variant spectrum in RP59 is dominated by the founder p.Lys42Glu missense allele; a secondary missense c.292C>T (p.Arg98Trp) has been reported in a small number of families, while truncating or splice variants are notably absent, supporting a hypomorphic mechanism (PMID:29276052).

Functional assays demonstrate that zebrafish embryos expressing Lys42Glu exhibit rhodopsin mislocalization and photoreceptor degeneration (PMID:21295283), and RPE-specific Dhdds knockout mice develop retinal thinning and severely reduced ERG responses (PMID:32245241).

Conversely, Dhdds K42E knock-in mice show pronounced retinal gliosis without overt photoreceptor loss or glycosylation defects, indicating possible species differences or compensatory pathways (PMID:32272552).

Collectively, robust segregation in >100 unrelated probands across multiple families, the strong founder effect, and concordant in vivo functional data establish a definitive gene-disease relationship. Screening for DHDDS c.124A>G (p.Lys42Glu) is clinically valuable for early diagnosis in Ashkenazi Jewish individuals. Key take-home: recurrent homozygous p.Lys42Glu and rare p.Arg98Trp alleles in DHDDS cause autosomal-recessive RP59, supporting inclusion in diagnostic panels.

References

• American journal of human genetics • 2011 • A missense mutation in DHDDS, encoding dehydrodolichyl diphosphate synthase, is associated with autosomal-recessive retinitis pigmentosa in Ashkenazi Jews. PMID:21295282
• American journal of human genetics • 2011 • Whole-exome sequencing links a variant in DHDDS to retinitis pigmentosa. PMID:21295283
• Genetics in medicine • 2015 • Two specific mutations are prevalent causes of recessive retinitis pigmentosa in North American patients of Jewish ancestry. PMID:25255364
• Ophthalmology • 2018 • Nonsyndromic Retinitis Pigmentosa in the Ashkenazi Jewish Population: Genetic and Clinical Aspects. PMID:29276052
• Ophthalmology. Retina • 2018 • Ultra-Widefield Fundus Autofluorescence Imaging of Patients with Retinitis Pigmentosa: A Standardized Grading System in Different Genotypes. PMID:31047384
• Protein expression and purification • 2017 • Purification and characterization of human dehydrodolichil diphosphate synthase (DHDDS) overexpressed in E. coli. PMID:28167250
• Cells • 2020 • Selective Ablation of Dehydrodolichyl Diphosphate Synthase in Murine Retinal Pigment Epithelium (RPE) Causes RPE Atrophy and Retinal Degeneration. PMID:32245241
• Cells • 2020 • Lack of Overt Retinal Degeneration in a K42E Dhdds Knock-In Mouse Model of RP59. PMID:32272552
• Cell death & disease • 2023 • A Dhdds K42E knock-in RP59 mouse model shows inner retina pathology and defective synaptic transmission. PMID:37443173

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