title: Mutations in the lipoyltransferase LIPT1 gene cause a fatal disease associated with a specific lipoylation defect of the 2-ketoacid dehydrogenase complexes.
abstract: Cofactor disorders of mitochondrial energy metabolism are a heterogeneous group of diseases with a wide variety of clinical symptoms, particular metabolic profiles and variable enzymatic defects. Mutations in NFU1, BOLA3, LIAS and IBA57 have been identified in patients with deficient lipoic acid-dependent enzymatic activities and defects in the assembly and activity of the mitochondrial respiratory chain complexes. Here, we report a patient with an early onset fatal lactic acidosis presenting a biochemical phenotype compatible with a combined defect of pyruvate dehydrogenase (PDHC) and 2-ketoglutarate dehydrogenase (2-KGDH) activities, which suggested a deficiency in lipoic acid metabolism. Immunostaining analysis showed that lipoylated E2-PDH and E2-KGDH were extremely reduced in this patient. However, the absence of glycine elevation, the normal activity of the glycine cleavage system and the normal lipoylation of the H protein suggested a defect of lipoic acid transfer to particular proteins rather than a general impairment of lipoic acid biosynthesis as the potential cause of the disease. By analogy with yeast metabolism, we postulated LIPT1 as the altered candidate gene causing the disease. Sequence analysis of the human LIPT1 identified two heterozygous missense mutations (c.212C>T and c.292C>G), segregating in different alleles. Functional complementation experiments in patient's fibroblasts demonstrated that these mutations are disease-causing and that LIPT1 protein is required for lipoylation and activation of 2-ketoacid dehydrogenases in humans. These findings expand the spectrum of genetic defects associated with lipoic acid metabolism and provide the first evidence of a lipoic acid transfer defect in humans.
authors.affiliation: Secció d'Errors Congènits del Metabolisme, Servei de Bioquímica i Genètica Molecular, Hospital Clinic, IDIBAPS, C/Mejía Lequerica s/n, Barcelona 08028, Spain.
authors.forename: Frederic
authors.initials: F
authors.lastname: Tort
authors.forename: Xènia
authors.initials: X
authors.lastname: Ferrer-Cortès
authors.forename: Marta
authors.initials: M
authors.lastname: Thió
authors.forename: Aleix
authors.initials: A
authors.lastname: Navarro-Sastre
authors.forename: Leslie
authors.initials: L
authors.lastname: Matalonga
authors.forename: Ester
authors.initials: E
authors.lastname: Quintana
authors.forename: Núria
authors.initials: N
authors.lastname: Bujan
authors.forename: Angela
authors.initials: A
authors.lastname: Arias
authors.forename: Judit
authors.initials: J
authors.lastname: García-Villoria
authors.forename: Cecile
authors.initials: C
authors.lastname: Acquaviva
authors.forename: Christine
authors.initials: C
authors.lastname: Vianey-Saban
authors.forename: Rafael
authors.initials: R
authors.lastname: Artuch
authors.forename: Àngels
authors.initials: À
authors.lastname: García-Cazorla
authors.forename: Paz
authors.initials: P
authors.lastname: Briones
authors.forename: Antonia
authors.initials: A
authors.lastname: Ribes
mesh_terms: D000140:Acidosis, Lactic / Q000235:genetics / Q000401:mortality; D000217:Acyltransferases / Q000235:genetics*; D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics; D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004734:Energy Metabolism / Q000235:genetics; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007655:Ketoglutarate Dehydrogenase Complex / Q000172:deficiency / Q000235:genetics; D007656:Ketoglutaric Acids / Q000378:metabolism; D054878:Lipoylation / Q000235:genetics*; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D007652:Oxo-Acid-Lyases / Q000235:genetics*; D011768:Pyruvate Dehydrogenase Complex / Q000235:genetics; D008063:Thioctic Acid / Q000378:metabolism
chemical_list: D007656:Ketoglutaric Acids; D011768:Pyruvate Dehydrogenase Complex; D008063:Thioctic Acid; D007655:Ketoglutarate Dehydrogenase Complex; D000217:Acyltransferases; C109735:lipoyltransferase I; D007652:Oxo-Acid-Lyases