Retinopathy-associated inosine monophosphate dehydrogenase 1 mutations cause metabolic and filament defects in cones.

IF 3.3 3区 医学 Q2 CELL BIOLOGY
Disease Models & Mechanisms Pub Date : 2025-10-01 Epub Date: 2025-09-17 DOI:10.1242/dmm.052389
Kaitlyn M Rutter, Michelle M Giarmarco, Vivian Truong, Yekai Wang, Mark Eminhizer, Yinxiao Xiang, Whitney M Cleghorn, Gardenia Sanchez, Anika L Burrell, Justin M Kollman, Jianhai Du, Susan E Brockerhoff
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引用次数: 0

Abstract

Dominant variants in inosine monophosphate dehydrogenase 1 (IMPDH1), a key enzyme in the de novo synthesis of purine bases, cause progressive photoreceptor death, leading to blindness. To investigate the cause of degeneration, we generated the first mutant IMPDH1 animal models and expressed mutant forms of impdh1a in zebrafish cone photoreceptors. Unlike cones expressing exogenous normal impdh1a, cones containing impdh1a with the K238E mutation degenerated. Cones expressing impdh1a with the D226N mutation did not show significant cone loss by 2 years. Steady-state and flux metabolomics in zebrafish retinas revealed no differences in glucose shunting to the pentose phosphate pathway, no change in AMP or GMP due to D226N expression, but reduced AMP/IMP and GMP/IMP in K238E-expressing cones. cGMP levels were normal in both mutant retinas. Further, pde6cw59; impdh1asa23234 double mutant cones were not rescued from degeneration. Both K238E and D226N mutant-containing proteins formed abnormally large mislocalized filaments, which could disrupt normal dynamic protein-protein interactions. Our work disproves the model of a hyperactive enzyme leading to elevated cGMP causing cell death and reveals new defects associated with IMPDH1 mutant expression.

视网膜病变相关的肌苷单磷酸脱氢酶1突变导致锥体代谢和纤维缺陷。
肌苷单磷酸脱氢酶I (IMPDH1)是嘌呤碱基重新合成的关键酶,其显性突变可导致进行性光感受器死亡,导致失明。为了研究退化的原因,我们建立了第一个突变体IMPDH1动物模型,并在斑马鱼视锥细胞中表达了突变体impdh1a。与表达外源性正常impdh1a的锥体不同,含有K238E突变的impdh1a的锥体退化。表达D226N突变的球果在2年后没有表现出明显的球果损失。稳态代谢组学和通量代谢组学显示,斑马鱼视网膜中葡萄糖向戊糖磷酸通路的分流没有差异,D226N的表达没有改变AMP或GMP,但表达K238E的锥体中AMP/IMP和GMP/IMP降低。两个突变视网膜的cGMP水平均正常。进一步pde6cw59;Impdh1asa23234双突变体锥体未从变性中恢复。含有蛋白质的K238E和D226N突变体都形成了异常大的错定位细丝,这可能会破坏正常的动态蛋白质相互作用。我们的研究推翻了一种过度活跃的酶导致cGMP升高导致细胞死亡的模型,并揭示了与IMPDH1突变体表达相关的新缺陷。
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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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