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. 2024 Jan 13;25(2):1004.
doi: 10.3390/ijms25021004.

Inherited Retinal Degeneration Caused by Dehydrodolichyl Diphosphate Synthase Mutation-Effect of an ALG6 Modifier Variant

Elisha Monson  1 , Artur V Cideciyan  2 , Alejandro J Roman  2 , Alexander Sumaroka  2 , Malgorzata Swider  2 , Vivian Wu  2 , Iryna Viarbitskaya  2 , Samuel G Jacobson  2 , Steven J Fliesler  3   4 , Steven J Pittler  1   5
Affiliations

Inherited Retinal Degeneration Caused by Dehydrodolichyl Diphosphate Synthase Mutation-Effect of an ALG6 Modifier Variant

Elisha Monson et al. Int J Mol Sci. .

Abstract

Modern advances in disease genetics have uncovered numerous modifier genes that play a role in the severity of disease expression. One such class of genetic conditions is known as inherited retinal degenerations (IRDs), a collection of retinal degenerative disorders caused by mutations in over 300 genes. A single missense mutation (K42E) in the gene encoding the enzyme dehydrodolichyl diphosphate synthase (DHDDS), which is required for protein N-glycosylation in all cells and tissues, causes DHDDS-IRD (retinitis pigmentosa type 59 (RP59; OMIM #613861)). Apart from a retinal phenotype, however, DHDDS-IRD is surprisingly non-syndromic (i.e., without any systemic manifestations). To explore disease pathology, we selected five glycosylation-related genes for analysis that are suggested to have disease modifier variants. These genes encode glycosyltransferases (ALG6, ALG8), an ER resident protein (DDOST), a high-mannose oligosaccharyl transferase (MPDU1), and a protein N-glycosylation regulatory protein (TNKS). DNA samples from 11 confirmed DHDDS (K42E)-IRD patients were sequenced at the site of each candidate genetic modifier. Quantitative measures of retinal structure and function were performed across five decades of life by evaluating foveal photoreceptor thickness, visual acuity, foveal sensitivity, macular and extramacular rod sensitivity, and kinetic visual field extent. The ALG6 variant, (F304S), was correlated with greater macular cone disease severity and less peripheral rod disease severity. Thus, modifier gene polymorphisms may account for a significant portion of phenotypic variation observed in human genetic disease. However, the consequences of the polymorphisms may be counterintuitively complex in terms of rod and cone populations affected in different regions of the retina.

Keywords: DHDDS; genetic modifier; glycosylation; retinitis pigmentosa.

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Conflict of interest statement

The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
Representative chromatograms for each potential modifier gene. DNA from each patient sample was PCR-amplified at all five modifier sites and purified prior to DNA sequence analysis. Single nucleotide changes are marked with a black rectangle and enlarged for visibility below each rectangle. (A) ALG6 (B) ALG8 (C) DDOST (D) MPDU1 (E) TNKS (F) DHDDS. Only the T→C variant in ALG6 was found in some patient samples.
Figure 2
Figure 2
Phenotypes of two DHDDS patients showing two distinct distributions of retinal disease. (A) En face reduced-illuminance autofluorescence imaging (RAFI) with short-wavelength (SW) or near-infrared (NIR) excitation to evaluate disease distribution based on lipofuscin- or melanin-related pigments, respectively, across the RPE. (B) Cross-section imaging with optical coherence tomography (OCT) along the horizontal meridian crossing the fovea. The outer nuclear layer (ONL) is highlighted blue and the optic nerve head is hashed. (C) Sensitivity profiles sampled across the horizontal meridian crossing fixation using dark-adapted 500 nm (DA 500) stimuli mediated by rods and light-adapted 600 nm (LA 600) stimuli mediated by cones. Gray regions are normal limits and physiological blind spot is whited out.
Figure 3
Figure 3
ALG6 variant and retinal disease severity in DHDDS patients. (A) Best corrected visual acuity. (B) Foveal cone sensitivity loss (CSL). (C) Foveal outer nuclear layer (ONL) thickness. (D) Least rod-mediated sensitivity loss (RSL) representing best rod function within the confines of the macula. (E) The extent of the kinetic visual field (as a percent of mean normal) to a Goldman V-4e test target. All data originating from the macula are censored such that results represent the extramacular visual function. (F) Peak rod-mediated sensitivity (least RSL) representing best rod function outside the macula. In all panels, patients with ALG6 wildtype are shown with green up triangles, and ALG6 variant are shown with pink circles. Serial data obtained from the same eye are connected by lines. In panels (A,E), results reported in the literature [50] are digitized and plotted (gray squares) for reference. Kinetic visual field extent published in the literature uses a different target (III-4e) which was normalized using 183 cm2 as the mean normal value to plot on the same ordinate.
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