Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232, USA.
Feinberg School of Medicine, Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, IL 60611, USA.
Development. 2022 Oct 15;149(20). doi: 10.1242/dev.199914. Epub 2022 Jul 6.
Leigh syndrome (LS) is a rare, inherited neurometabolic disorder that presents with bilateral brain lesions caused by defects in the mitochondrial respiratory chain and associated nuclear-encoded proteins. We generated human induced pluripotent stem cells (iPSCs) from three LS patient-derived fibroblast lines. Using whole-exome and mitochondrial sequencing, we identified unreported mutations in pyruvate dehydrogenase (GM0372, PDH; GM13411, MT-ATP6/PDH) and dihydrolipoyl dehydrogenase (GM01503, DLD). These LS patient-derived iPSC lines were viable and capable of differentiating into progenitor populations, but we identified several abnormalities in three-dimensional differentiation models of brain development. LS patient-derived cerebral organoids showed defects in neural epithelial bud generation, size and cortical architecture at 100 days. The double mutant MT-ATP6/PDH line produced organoid neural precursor cells with abnormal mitochondrial morphology, characterized by fragmentation and disorganization, and showed an increased generation of astrocytes. These studies aim to provide a comprehensive phenotypic characterization of available patient-derived cell lines that can be used to study Leigh syndrome.
Leigh 综合征（LS）是一种罕见的遗传性神经代谢疾病，其特征为线粒体呼吸链和相关核编码蛋白缺陷导致的双侧脑损伤。我们从三个 LS 患者来源的成纤维细胞系中生成了人类诱导多能干细胞（iPSC）。通过全外显子组和线粒体测序，我们在丙酮酸脱氢酶（GM0372，PDH；GM13411，MT-ATP6/PDH）和二氢脂酰脱氢酶（GM01503，DLD）中发现了未报道的突变。这些 LS 患者来源的 iPSC 系具有活力，能够分化为祖细胞群体，但我们在脑发育的三维分化模型中发现了几个异常。LS 患者来源的大脑类器官在 100 天时显示出神经上皮芽生成、大小和皮质结构的缺陷。双突变 MT-ATP6/PDH 系产生的类器官神经前体细胞具有异常的线粒体形态，表现为碎片化和紊乱，并显示出星形胶质细胞生成增加。这些研究旨在提供可用患者来源细胞系的全面表型特征描述，可用于研究 Leigh 综合征。
