Functional Assessment of Lipoyltransferase-1 Deficiency in Cells, Mice, and Humans
Min Ni,
Ashley Solmonson,
Chunxiao Pan,
Chendong Yang,
Dan Li,
Ashley Notzon,
Ling Cai,
Gerardo Guevara,
Lauren G. Zacharias,
Brandon Faubert,
Hieu S. Vu,
Lei Jiang,
Bookyung Ko,
Noriko Merida Morales,
Jimin Pei,
Gonçalo Vale,
Dinesh Rakheja,
Nick V. Grishin,
Jeffrey G. McDonald,
Garrett K. Gotway,
Markey C. McNutt,
Juan M. Pascual,
Ralph J. DeBerardinis
Affiliations
Min Ni
Children’s Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Corresponding author
Ashley Solmonson
Children’s Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Chunxiao Pan
Children’s Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Chendong Yang
Children’s Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Dan Li
Children’s Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Ashley Notzon
Children’s Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Ling Cai
Children’s Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Quantitative Biomedical Research Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Gerardo Guevara
Children’s Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Lauren G. Zacharias
Children’s Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Brandon Faubert
Children’s Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Hieu S. Vu
Children’s Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Lei Jiang
Department of Molecular and Cellular Endocrinology, City of Hope, Duarte, CA 91010, USA
Bookyung Ko
Children’s Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Noriko Merida Morales
Children’s Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Jimin Pei
Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Gonçalo Vale
Department of Molecular Genetics, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Dinesh Rakheja
Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Nick V. Grishin
Department of Biophysics, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Jeffrey G. McDonald
Department of Molecular Genetics, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Garrett K. Gotway
Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Eugene McDermott Center for Human Growth and Development, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Markey C. McNutt
Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Eugene McDermott Center for Human Growth and Development, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Juan M. Pascual
Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Eugene McDermott Center for Human Growth and Development, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Physiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Ralph J. DeBerardinis
Children’s Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Eugene McDermott Center for Human Growth and Development, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Corresponding author
Summary: 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. : Ni et al. investigate human LIPT1 deficiency, which results in developmental delay, epilepsy, and broad metabolic abnormalities, including lactic acidosis, L- and D-2-hydroxyglutaric aciduria, defective lipogenesis, and an altered balance between oxidative and reductive glutamine metabolism. Keywords: inborn errors of metabolism, metabolomics, genomics, lactic acidosis, epilepsy,developmental delay, 2-ketoacid dehydrogenase, lipoylation, lipogenesis, fatty acid oxidation
