Mitochondrial Infantile Liver Disease due to TRMU Gene Mutations: Three New Cases

Abstract

Combined respiratory chain defect is a common feature in mitochondrial liver disease during early infancy. Mitochondrial DNA depletions, induced by mutations of the nuclear genes POLG, DGUOK, and MPV17, are the major causes of these combined deficiencies. More recently, mutations in TRMU gene encoding the mitochondrial tRNA-specific 2-thiouridylase were found in infantile hepatopathy related to mitochondrial translation defect. It is characterized by a combined defect of respiratory chain complexes without mitochondrial DNA depletion.We report here clinical, biochemical, and genetic findings from three unrelated children presenting with hepatopathy associated with hyperlactatemia and respiratory chain defect due to bi-allelic mutations in TRMU gene. Two patients recovered spontaneously in a few months, whereas the other one died of acute liver failure. Spontaneous remission is a rare feature in mitochondrial liver diseases, and early identification of TRMU mutations could impact on clinical management. Our results extend the small number of TRMU mutations reported in mitochondrial liver disorders and allowed accumulating data for genotype-phenotype correlation.

Fig. 1

Analysis of novel TRMU mutations. (a) Sequencing analysis of TRMU on P1 genomic DNA with the c. 248 + 1G>A heterozygous mutation. (b) Sequencing analysis of TRMU on P1 cDNA showing the exon 3 skipping. (c) Sequencing analysis of TRMU on P2 genomic DNA with the c. 649G>A heterozygous mutation (p.Glu217Lys). (d) Amino acid sequence of the conserved domain of the tRNA methyl-transferase family with the active Cys residue in position 222. Amino acids with carboxylic acid functional group (Glu or Asp) are conserved in position 217