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Review
. 2022 Nov 1;23(21):13324.
doi: 10.3390/ijms232113324.

Vertebrate Animal Models of RP59: Current Status and Future Prospects

Steven J Fliesler  1   2 , Sriganesh Ramachandra Rao  1   2 , Mai N Nguyen  3 , Mahmoud Tawfik KhalafAllah  3 , Steven J Pittler  3
Affiliations
Review

Vertebrate Animal Models of RP59: Current Status and Future Prospects

Steven J Fliesler et al. Int J Mol Sci. .

Abstract

Retinitis pigmentosa-59 (RP59) is a rare, recessive form of RP, caused by mutations in the gene encoding DHDDS (dehydrodolichyl diphosphate synthase). DHDDS forms a heterotetrameric complex with Nogo-B receptor (NgBR; gene NUS1) to form a cis-prenyltransferase (CPT) enzyme complex, which is required for the synthesis of dolichol, which in turn is required for protein N-glycosylation as well as other glycosylation reactions in eukaryotic cells. Herein, we review the published phenotypic characteristics of RP59 models extant, with an emphasis on their ocular phenotypes, based primarily upon knock-in of known RP59-associated DHDDS mutations as well as cell type- and tissue-specific knockout of DHDDS alleles in mice. We also briefly review findings in RP59 patients with retinal disease and other patients with DHDDS mutations causing epilepsy and other neurologic disease. We discuss these findings in the context of addressing "knowledge gaps" in our current understanding of the underlying pathobiology mechanism of RP59, as well as their potential utility for developing therapeutic interventions to block the onset or to dampen the severity or progression of RP59.

Keywords: DHDDS; RP59; cis-prenyltransferase; dolichol; nogo-B receptor; retinal degeneration.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Immunofluorescence confocal microscopy images of (A) WT control and (B) DhddsK42E/K42E mouse retinas (age: PN 2 months). Binding of antibodies against GFAP (red) and rod opsin (green) is shown, with DAPI (blue) counterstain. Abbreviations: OS, outer segment layer; IS, inner segment layer; ONL, outer nuclear layer; OPL, outer plexiform layer; INL, inner nuclear layer; IPL, inner plexiform layer; GCL, ganglion cell layer. Scale bar (both panels): 20 μm. (Reproduced (open access) from Ramachandra Rao S et al., Cells, 2020, 9, 896 [52]).
Figure 2
Figure 2
Binding of fluor-labeled Con-A (green) to retinas from (A,B) WT control and (C,D) DhddsK42E/K42E mice, with (B,D) or without (A,C) pretreatment with PNGase-F (age: PN 6 months). Binging of fluor-labeled peanut agglutinin (PNA; magenta) also shown; DAPI (blue) counterstain. Abbreviations: See legend, Figure 1. Scale bar (all panels): 20 μm. (Reproduced (open access) from Ramachandra Rao S et al., Cells, 2020, 9, 896 [52]).
Figure 3
Figure 3
(Left panel) SD-OCT images of retinas from rod-specific Dhdds knockout (Dhddsflx/flx iCre+) mice, compared to age-matched controls (Dhddsflx/flx iCre−), between PN 4 and 6 weeks (color key included in panel). The ONL is demarcated by yellow dotted lines. (Right panel) Corresponding graph of ONL thickness measurements (in mm; n = 4 per genotype/age). * p < 0.05, ** p < 0.01; Welch’s (unpaired) t-test. Abbreviations as in legend, Figure 1; ONH, optic nerve head. (Reproduced, with permission, from Ramachandra Rao S et al., iScience, 2020, 23, 101198 [56]).
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