Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA.
Casey Eye Institute, Oregon Health and Science University, Portland, OR, USA.
Commun Biol. 2023 Aug 29;6(1):890. doi: 10.1038/s42003-023-05268-1.
Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is a fatty acid oxidation disorder (FAOD) caused by a pathogenic variant, c.1528 G > C, in HADHA encoding the alpha subunit of trifunctional protein (TFPα). Individuals with LCHADD develop chorioretinopathy and peripheral neuropathy not observed in other FAODs in addition to the more ubiquitous symptoms of hypoketotic hypoglycemia, rhabdomyolysis and cardiomyopathy. We report a CRISPR/Cas9 generated knock-in murine model of G1528C in Hadha that recapitulates aspects of the human LCHADD phenotype. Homozygous pups are less numerous than expected from Mendelian probability, but survivors exhibit similar viability with wildtype (WT) littermates. Tissues of LCHADD homozygotes express TFPα protein, but LCHADD mice oxidize less fat and accumulate plasma 3-hydroxyacylcarnitines compared to WT mice. LCHADD mice exhibit lower ketones with fasting, exhaust earlier during treadmill exercise and develop a dilated cardiomyopathy compared to WT mice. In addition, LCHADD mice exhibit decreased visual performance, decreased cone function, and disruption of retinal pigment epithelium. Neurological function is affected, with impaired motor function during wire hang test and reduced open field activity. The G1528C knock-in mouse exhibits a phenotype similar to that observed in human patients; this model will be useful to explore pathophysiology and treatments for LCHADD in the future.
长链 3-羟酰基辅酶 A 脱氢酶缺乏症（LCHADD）是一种脂肪酸氧化障碍（FAOD），由 HADHA 编码的三功能蛋白（TFPα）α亚基中的致病性变异 c.1528G>C 引起。除了常见的低酮性低血糖、横纹肌溶解和心肌病等症状外，LCHADD 患者还会出现其他 FAOD 中未见的脉络膜视网膜病变和周围神经病。我们报告了 HADHA 中 G1528C 的 CRISPR/Cas9 产生的敲入鼠模型，该模型重现了人类 LCHADD 表型的某些方面。纯合子幼鼠的数量少于孟德尔概率所预期的数量，但存活下来的幼鼠与野生型（WT）同窝仔鼠的存活能力相似。LCHADD 纯合子组织表达 TFPα 蛋白，但与 WT 小鼠相比，LCHADD 小鼠氧化的脂肪较少，血浆 3-羟酰基肉碱积累较多。与 WT 小鼠相比，LCHADD 小鼠在禁食时酮体水平较低，在跑步机运动中更早疲劳，并发展为扩张型心肌病。此外，LCHADD 小鼠的视觉表现下降，视锥功能下降，视网膜色素上皮层破坏。神经功能受到影响，在悬线测试中运动功能受损，在开阔场地活动中活动减少。G1528C 敲入鼠表现出与人类患者观察到的表型相似；该模型将有助于未来探索 LCHADD 的病理生理学和治疗方法。
