Division of Medical Genetics and Genomics, The Children's Hospital, Zhejiang University School of Medicine and National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China.
Institute of Genetics and Department of Human Genetics, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Hum Mol Genet. 2023 Jan 6;32(2):231-243. doi: 10.1093/hmg/ddac190.
Leber's hereditary optic neuropathy (LHON) is a maternally inherited eye disease that results from degeneration of retinal ganglion cells (RGC). Mitochondrial ND4 11778G > A mutation, which affects structural components of complex I, is the most prevalent LHON-associated mitochondrial DNA (mtDNA) mutation worldwide. The m.11778G > A mutation is the primary contributor underlying the development of LHON and X-linked PRICKLE3 allele (c.157C > T, p.Arg53Trp) linked to biogenesis of ATPase interacts with m.11778G > A mutation to cause LHON. However, the lack of appropriate cell and animal models of LHON has been significant obstacles for deep elucidation of disease pathophysiology, specifically the tissue-specific effects. Using RGC-like cells differentiated from induced pluripotent stem cells (iPSCs) from members of one Chinese family (asymptomatic subjects carrying only m.11778G > A mutation or PRICKLE3 p.Arg53Trp mutation, symptomatic individuals bearing both m.11778G > A and PRICKLE3 p.Arg53Trp mutations and control lacking these mutations), we demonstrated the deleterious effects of mitochondrial dysfunctions on the morphology and functions of RGCs. Notably, iPSCs bearing only m.11778G > A or p.Arg53Trp mutation exhibited mild defects in differentiation to RGC-like cells. The RGC-like cells carrying only m.11778G > A or p.Arg53Trp mutation displayed mild defects in RGC morphology, including the area of soma and numbers of neurites, electrophysiological properties, ATP contents and apoptosis. Strikingly, those RGC-like cells derived from symptomatic individuals harboring both m.11778G > A and p.Arg53Trp mutations displayed greater defects in the development, morphology and functions than those in cells bearing single mutation. These findings provide new insights into pathophysiology of LHON arising from RGC deficiencies caused by synergy between m.11778G > A and PRICKLE3 p.Arg53Trp mutation.
Leber 遗传性视神经病变（LHON）是一种母系遗传眼病，由视网膜神经节细胞（RGC）变性引起。线粒体 ND4 11778G>A 突变，影响复合体 I 的结构成分，是全球最常见的 LHON 相关线粒体 DNA（mtDNA）突变。m.11778G>A 突变是导致 LHON 的主要原因，与 ATP 酶生物发生相关的 X 连锁 PRICKLE3 等位基因（c.157C>T，p.Arg53Trp）与 m.11778G>A 突变相互作用导致 LHON。然而，缺乏适当的 LHON 细胞和动物模型一直是深入阐明疾病病理生理学的重大障碍，特别是组织特异性效应。我们使用来自一个中国家族成员的诱导多能干细胞（iPSC）分化的 RGC 样细胞（仅携带 m.11778G>A 突变或 PRICKLE3 p.Arg53Trp 突变的无症状受试者、同时携带 m.11778G>A 和 PRICKLE3 p.Arg53Trp 突变的有症状个体和缺乏这些突变的对照），证明了线粒体功能障碍对 RGC 形态和功能的有害影响。值得注意的是，仅携带 m.11778G>A 或 p.Arg53Trp 突变的 iPSC 在向 RGC 样细胞分化过程中表现出轻度缺陷。仅携带 m.11778G>A 或 p.Arg53Trp 突变的 RGC 样细胞在 RGC 形态方面表现出轻度缺陷，包括体区面积和神经突数量、电生理特性、ATP 含量和凋亡。引人注目的是，源自同时携带 m.11778G>A 和 p.Arg53Trp 突变的有症状个体的那些 RGC 样细胞在发育、形态和功能方面表现出比携带单个突变的细胞更大的缺陷。这些发现为 m.11778G>A 和 PRICKLE3 p.Arg53Trp 突变协同导致 RGC 缺陷引起的 LHON 病理生理学提供了新的见解。
