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.
Competing interests: None declared
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Chabi B, Mousson de Camaret B, Duborjal H, Issartel JP, Stepien G (2003) Quantification of mitochondrial DNA deletion, depletion, and overreplication: application to diagnosis. Clin Chem 49:1309–1317
Coenen M, Antonicka H, Ugalde C et al (2004) Mutant mitochondrial elongation factor G1 and combined oxidative phosphorylation deficiency. N Eng J Med 351:2080–2086
Galmiche L, Serre V, Beinat M et al (2012) Toward genotype phenotype correlations in GFM1 mutations. Mitochondrion 12:242–247
García-Cazorla A, De Lonlay P, Nassogne MC, Rustin P, Touati G, Saudubray JM (2005) Long-term follow-up of neonatal mitochondrial cytopathies: a study of 57 patients. Pediatrics 116:1170–1177
Guan MX, Yan Q, Li X et al (2006) Mutation in TRMU related to transfer RNA modification modulates the phenotypic expression of the deafness-associated mitochondrial 12S ribosomal RNA mutations. Am J Hum Genet 79:291–302
Hagervall T, Edmonds C, McCloskey J, Björk G (1987) Transfer RNA(5-methylaminomethyl-2-thiouridine)-methyltransferase from Escherichia coli K-12 has two enzymatic activities. J Biol Chem 262:8488–8495
Kemp J, Smith P, Pyle A et al (2011) Nuclear factors involved in mitochondrial translation cause a subgroup of combined respiratory chain deficiency. Brain 134:183–195
Low E, Crushell E, Harty S, Ryan S, Treacy E (2008) Reversible multiorgan system involvement in a neonate with complex IV deficiency. Pediatr Neurol 39:368–370
Mandel H, Szargel R, Labay V et al (2001) The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA. Nat Genet 29:337–341
Naviaux R, Nguyen KV (2004) POLG mutations associated with Alpers’ syndrome and mitochondrial DNA depletion. Ann Neurol 55:706–712
Rustin P, Chretien D, Bourgeron T et al (1994) Biochemical and molecular investigations in respiratory chain deficiencies. Clin Chim Acta 228:35–51
Sarzi E, Bourdon A, Chrétien D et al (2007) Mitochondrial DNA depletion is a prevalent cause of multiple respiratory chain deficiency in childhood. J Pediatr 150:531–534
Sasarman F, Antonicka H, Horvath R, Shoubridge E (2011) The 2-thiouridylase function of the human MTU1 (TRMU) enzyme is dispensable for mitochondrial translation. Hum Mol Genet 20:4634–4643
Schara U, Von Kleist-Retzow JC, Lainka E et al (2011) Acute liver failure with subsequent cirrhosis as the primary manifestation of TRMU mutations. J Inherit Metab Dis 34:197–201
Spinazzola A, Viscomi C, Fernandez-Vizarra E et al (2006) MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion. Nat Genet 38:570–575
Umeda N, Suzuki T, Yukawa M et al (2005) Mitochondria-specific RNA-modifying enzymes responsible for the biosynthesis of the wobble base in mitochondrial tRNAs. Implications for the molecular pathogenesis of human mitochondrial diseases. J Biol Chem 280:1613–1624
Uusimaa J, Jungbluth H, Fratter C et al (2011) Reversible infantile respiratory chain deficiency is a unique, genetically heterogenous mitochondrial disease. J Med Genet 48:660–668
Valente L, Tiranti V, Marsano RM et al (2007) Infantile encephalopathy and defective mitochondrial DNA translation in patients with mutations of mitochondrial elongation factors EFG1 and EFTu. Am J Hum Genet 80:44–58
Yan Q, Bykhovskaya Y, Li R et al (2006) Human TRMU encoding the mitochondrial 5-methylaminomethyl-2-thiouridylate-methyltransferase is a putative nuclear modifier gene for the phenotypic expression of the deafness-associated 12S rRNA mutations. Biochem Biophys Res Commun 342:1130–1136
Zeharia A, Shaag A, Pappo O et al (2009) Acute infantile liver failure due to mutations in the TRMU gene. Am J Hum Genet 85:401–407
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Additional information
Communicated by: Shamima Rahman, PhD, BMBCh
Appendices
One Sentence Take-Home Message
TRMU gene mutations can induce a mitochondrial liver disease in early infancy which outcome ranges from death to recovery.
Contributions of Individual Authors
GAIGNARD Pauline: identification of patients defect (biochemical analysis and genetic analysis), manuscript writing
GONZALES Emmanuel: diagnosis and follow-up of patient 3, part of the manuscript writing, revising manuscript
ACKERMANN Oanez: diagnosis and follow-up of patient 2, revising manuscript
LABRUNE Philippe: diagnosis and follow-up of patient 1, revising manuscript
CORREIA Isabelle: genetic analysis
THEROND Patrice: revising manuscript
JACQUEMIN Emmanuel: diagnosis and follow-up of patients 2 and 3, revising manuscript
SLAMA Abdelhamid: identification of patients’ defect (biochemical analysis and genetic analysis), manuscript writing, and supervision
Rights and permissions
Copyright information
© 2013 SSIEM and Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Gaignard, P. et al. (2013). Mitochondrial Infantile Liver Disease due to TRMU Gene Mutations: Three New Cases. In: Zschocke, J., Gibson, K., Brown, G., Morava, E., Peters, V. (eds) JIMD Reports - Volume 11. JIMD Reports, vol 11. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2013_230
Download citation
DOI: https://doi.org/10.1007/8904_2013_230
Received:
Revised:
Accepted:
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-37327-5
Online ISBN: 978-3-642-37328-2
eBook Packages: MedicineMedicine (R0)