title: Acute infantile liver failure due to mutations in the TRMU gene.
abstract: Acute liver failure in infancy accompanied by lactic acidemia was previously shown to result from mtDNA depletion. We report on 13 unrelated infants who presented with acute liver failure and lactic acidemia with normal mtDNA content. Four died during the acute episodes, and the survivors never had a recurrence. The longest follow-up period was 14 years. Using homozygosity mapping, we identified mutations in the TRMU gene, which encodes a mitochondria-specific tRNA-modifying enzyme, tRNA 5-methylaminomethyl-2-thiouridylate methyltransferase. Accordingly, the 2-thiouridylation levels of the mitochondrial tRNAs were markedly reduced. Given that sulfur is a TRMU substrate and its availability is limited during the neonatal period, we propose that there is a window of time whereby patients with TRMU mutations are at increased risk of developing liver failure.
authors.affiliation: Department of Human Genetics and Metabolic Diseases, Hadassah, the Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Avraham
authors.initials: A
authors.lastname: Zeharia
authors.forename: Avraham
authors.initials: A
authors.lastname: Shaag
authors.forename: Orit
authors.initials: O
authors.lastname: Pappo
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Mager-Heckel
authors.forename: Ann
authors.initials: A
authors.lastname: Saada
authors.forename: Marine
authors.initials: M
authors.lastname: Beinat
authors.forename: Olga
authors.initials: O
authors.lastname: Karicheva
authors.forename: Hanna
authors.initials: H
authors.lastname: Mandel
authors.forename: Noa
authors.initials: N
authors.lastname: Ofek
authors.forename: Reeval
authors.initials: R
authors.lastname: Segel
authors.forename: Daphna
authors.initials: D
authors.lastname: Marom
authors.forename: Agnes
authors.initials: A
authors.lastname: Rötig
authors.forename: Ivan
authors.initials: I
authors.lastname: Tarassov
authors.forename: Orly
authors.initials: O
authors.lastname: Elpeleg
mesh_terms: D004272:DNA, Mitochondrial / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008099:Liver / Q000473:pathology; D017114:Liver Failure, Acute / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D008928:Mitochondria / Q000201:enzymology; D024101:Mitochondrial Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D014176:Protein Biosynthesis; D012343:RNA, Transfer / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism; D012359:tRNA Methyltransferases / Q000235:genetics*
chemical_list: D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D013438:Sulfhydryl Compounds; D012343:RNA, Transfer; D012359:tRNA Methyltransferases; C496706:TRMU protein, human