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Functional Assessment of Lipoyltransferase-1 Deficiency in Cells, Mice, and Humans.

ABSTRACT: 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.

SUBMITTER: Ni M

PROVIDER: S-EPMC7351313 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Functional Assessment of Lipoyltransferase-1 Deficiency in Cells, Mice, and Humans.

Ni Min M Solmonson Ashley A Pan Chunxiao C Yang Chendong C Li Dan D Notzon Ashley A Cai Ling L Guevara Gerardo G Zacharias Lauren G LG Faubert Brandon B Vu Hieu S HS Jiang Lei L Ko Bookyung B Morales Noriko Merida NM Pei Jimin J Vale Gonçalo G Rakheja Dinesh D Grishin Nick V NV McDonald Jeffrey G JG Gotway Garrett K GK McNutt Markey C MC Pascual Juan M JM DeBerardinis Ralph J RJ

Cell reports 20190401 5

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 acid ...[more]

PMID: 31042466

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Dataset Information

Functional Assessment of Lipoyltransferase-1 Deficiency in Cells, Mice, and Humans.

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Functional Assessment of Lipoyltransferase-1 Deficiency in Cells, Mice, and Humans.

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