Myogenesis defects in a patient-derived iPSC model of hereditary GNE myopathy.
Myogenesis defects in a patient-derived iPSC model of hereditary GNE myopathy.
复制标题
遗传性卵病的患者衍生的IPSC模型中的肌发生缺陷。
DOI：
10.1038/s41536-022-00238-3
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发表时间：
2022-09-09
影响因子：
7.2
通讯作者：
Doles, Jason D.
中科院分区：
文献类型：
--
作者：
Schmitt, Rebecca E.;Smith, Douglas Y.;Cho, Dong Seong;Kirkeby, Lindsey A.;Resch, Zachary T.;Liewluck, Teerin;Niu, Zhiyv;Milone, Margherita;Doles, Jason D.
Hereditary muscle diseases are disabling disorders lacking effective treatments. UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE) myopathy (GNEM) is an autosomal recessive distal myopathy with rimmed vacuoles typically manifesting in late adolescence/early adulthood. GNE encodes the rate-limiting enzyme in sialic acid biosynthesis, which is necessary for the proper function of numerous biological processes. Outside of the causative gene, very little is known about the mechanisms contributing to the development of GNE myopathy. In the present study, we aimed to address this knowledge gap by querying the underlying mechanisms of GNE myopathy using a patient-derived induced pluripotent stem-cell (iPSC) model. Control and patient-specific iPSCs were differentiated down a skeletal muscle lineage, whereby patient-derived GNEM iPSC clones were able to recapitulate key characteristics of the human pathology and further demonstrated defects in myogenic progression. Single-cell RNA sequencing time course studies revealed clear differences between control and GNEM iPSC-derived muscle precursor cells (iMPCs), while pathway studies implicated altered stress and autophagy signaling in GNEM iMPCs. Treatment of GNEM patient-derived iMPCs with an autophagy activator improved myogenic differentiation. In summary, we report an in vitro, iPSC-based model of GNE myopathy and implicate defective myogenesis as a contributing mechanism to the etiology of GNE myopathy.
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