Functional Assessment of Lipoyltransferase-1 Deficiency in Cells, Mice, and Humans
Functional Assessment of Lipoyltransferase-1 Deficiency in Cells, Mice, and Humans
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DOI：
10.1016/j.celrep.2019.04.005
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发表时间：
2019-04-30
期刊：
影响因子：
8.8
通讯作者：
DeBerardinis, Ralph J.
中科院分区：
文献类型：
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作者：
Ni, Min;Solmonson, Ashley;DeBerardinis, Ralph J.
先天代谢错误(IEM)将代谢缺陷与人类表型联系起来。现代基因组学加速了IEM的发现，但评估基因组变异的影响仍然具有挑战性。在这里，我们结合基因组学和代谢组学来确定乳酸酸中毒和癫痫的原因。先证者是LIPT1变异的复合杂合子，LIPT1编码2-酮酸脱氢酶(2KDH)功能所需的硫辛基转移酶。代谢组学显示脂类、氨基酸和2-羟基戊二酸异常，与多个2KDH的丢失一致。LIPT1突变的纯合子敲击降低了子宫中2KDH的脂基化，并导致胚胎死亡。在患者成纤维细胞中，2KDH脂基化缺陷和功能缺陷可被野生型LIPT1等位基因纠正，但不能被突变的LIPT1等位基因纠正。同位素示踪显示，LIPT1支持脂肪生成，平衡氧化和还原谷氨酰胺代谢。总之，这些数据扩展了LIPT1在代谢调节中的作用，并展示了整合基因组学和代谢组学如何揭示IEM病理生理学的更广泛方面。
Inborn errors of metabolism (IEMs) link metabolic defects to human phenotypes. Modern genomics has accelerated IEM discovery, but assessing the impact of genomic variants is still challenging. Here, we integrate genomics and metabolomics to identify a cause of lactic acidosis and epilepsy. The proband is a compound heterozygote for variants in LIPT1, which encodes the lipoyltransferase required for 2-ketoacid dehydrogenase (2KDH) function. Metabolomics reveals abnormalities in lipids, amino acids, and 2-hydroxyglutarate consistent with loss of multiple 2KDHs. Homozygous knockin of a LIPT1 mutation reduces 2KDH lipoylation in utero and results in embryonic demise. In patient fibroblasts, defective 2KDH lipoylation and function are corrected by wild-type, but not mutant, LIPT1 alleles. Isotope tracing reveals that LIPT1 supports lipogenesis and balances oxidative and reductive glutamine metabolism. Altogether, the data extend the role of LIPT1 in metabolic regulation and demonstrate how integrating genomics and metabolomics can uncover broader aspects of IEM pathophysiology.