Dhdds T206A and Dhdds K42E knock-in mouse models of retinitis pigmentosa 59 are phenotypically similar.

IF 3.3 3区 医学 Q2 CELL BIOLOGY
Disease Models & Mechanisms Pub Date : 2025-07-01 Epub Date: 2025-08-01 DOI:10.1242/dmm.052243
Mai N Nguyen, Dibyendu Chakraborty, Jeffrey Messinger, Timothy W Kraft, David M Sherry, Steven J Fliesler, Steven J Pittler
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引用次数: 0

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.

Dhdds T206A和Dhdds K42E敲入59型视网膜色素变性小鼠模型在表型上相似。
脱氢多酚二磷酸合成酶(DHDDS)是真核生物蛋白糖基化的必需酶。令人惊讶的是,三个突变等位基因(K42E/K42E, T206A/K42E和R98W/K42E)已被报道引起视网膜色素变性(RP59)。由于T206A仅报道与K42E杂合,我们在小鼠中产生T206A/T206A和T206A/K42E,以评估T206A等位基因的影响。经PN 12个月观察,T206A/T206A和T206A/K42E小鼠的内核层厚度与K42E/K42E小鼠相同。视网膜电图(ERG)显示b波减少,但a波振幅未受影响。通过pn3 -mo ERG,所有表型的c-、d波均显著减弱。与OCT观察到的内核层厚度减少和组织学观察到的细胞损失一致,与PN 8-12个月年龄匹配的对照组相比,所有dhdd突变型的双极和无腺细胞密度都降低了。这些结果表明,与K42E等位基因一样,DHDDS T206A等位基因可能通过共同的病理生物学机制导致视网膜疾病。我们提出RP59视网膜功能障碍的生理基础涉及双极细胞突触传递的光感受器缺陷,并伴有双极/无腺细胞变性。
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来源期刊
Disease Models & Mechanisms
Disease Models & Mechanisms 医学-病理学
CiteScore
6.60
自引率
7.00%
发文量
203
审稿时长
6-12 weeks
期刊介绍: Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.
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