Acute infantile liver failure due to mutations in the TRMU gene.
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.
Zeharia
Avraham
A
Department of Human Genetics and Metabolic Diseases, Hadassah, the Hebrew University Medical Center, Jerusalem, Israel.
Shaag
Avraham
A
Pappo
Orit
O
Mager-Heckel
Anne-Marie
AM
Saada
Ann
A
Beinat
Marine
M
Karicheva
Olga
O
Mandel
Hanna
H
Ofek
Noa
N
Segel
Reeval
R
Marom
Daphna
D
Rötig
Agnes
A
Tarassov
Ivan
I
Elpeleg
Orly
O
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*
D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D013438:Sulfhydryl Compounds; D012343:RNA, Transfer; D012359:tRNA Methyltransferases; C496706:TRMU protein, human