Dhdds T206A and Dhdds K42E knock-in mouse models of retinitis pigmentosa 59 are phenotypically similar
Year: 2025
Type: article
Abstract: Dehydrodolichyl diphosphate synthase complex subunit (DHDDS) is required for protein glycosylation in eukaryotes, and variants. Surprisingly, three variant alleles (K42E/K42E, T206A/K42E and R98W/K42E) have been reported to cause retinitis pigmentosa 59 (RP59). Because T206A only has been reported to occur heterozygously with K42E, we generated homozygous and hererozygous mutants - i.e. T206A/T206A and T206A/K42E, respectively - in mice to assess the effect of the T206A allele. By postnatal age of 12 month (PN 12-mo), T206A/T206A and T206A/K42E mice exhibited reduction of inner nuclear layer thickness as observed in K42E/K42E mice. Electroretinography (ERG) revealed a reduction in b-waves, but spared reduction in a-wave amplitudes. By PN 3-mo, ERG c- and d-waves were significantly attenuated in all phenotypes. Consistent with a reduction in inner nuclear layer thickness as seen by using optical coherence tomography (OCT), cell loss observed by histology, as well as bipolar and amacrine cell densities were reduced in all Dhdds mutant phenotypes compared to those of PN 8-12 mo age-matched controls. These results indicated that the DHDDS T206A allele, like the K42E allele, causes retinal disease, probably through a common pathobiological mechanism. We propose that the physiological basis of retinal dysfunction in RP59 involves defective photoreceptor to bipolar cell synaptic transmission with concomitant bipolar/amacrine cell degeneration.
Source: Disease Models & Mechanisms
DOI: 10.1242/dmm.052243
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,750
Funders: U.S. Department of Health and Human Services, U.S. Department of Veterans Affairs, Biomedical Laboratory Research and Development, VA Office of Research and Development, University of Alabama at Birmingham, University of Alabama, National Institutes of Health, University at Buffalo, VA Western New York Healthcare System, National Eye Institute, National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Center for Advancing Translational Sciences
Awards: G1442900148, G1509645712, G1619675495, G2457495176, G2684445025, G2733069588, G283777812, Center for Clinical and Translational Science, G2919543814, G309175821, G3282182166, G3579185629, G362742471, G406260681, UAB Diabetes Research and Training Center, G5173842171, G6551168429, G6860983262, G8608632838, G8855347160, G9000004278, G9000009152, G9000021492, G9000033697, G9000040708, G9000059066, G9000102579, G9000169993, G9000177686, G9000264968, G9000333407
OpenAlex ID: W4411709284