Abstract
Mitochondrial disorders are a heterogeneous group of often multisystemic and early fatal diseases caused by defects in the oxidative phosphorylation (OXPHOS) system. Given the complexity and intricacy of the OXPHOS system, it is not surprising that the underlying molecular defect remains unidentified in many patients with a mitochondrial disorder. Here, we report the clinical features and diagnostic workup leading to the elucidation of the genetic basis for a combined complex I and IV OXPHOS deficiency secondary to a mitochondrial translational defect in an infant who presented with rapidly progressive liver failure, encephalomyopathy, and severe refractory lactic acidemia. Sequencing of the GFM1 gene revealed two inherited novel, heterozygous mutations: a.539delG (p.Gly180AlafsX11) in exon 4 which resulted in a frameshift mutation, and a second c.688G > A (p.Gly230Ser) mutation in exon 5. This missense mutation is likely to be pathogenic since it affects an amino acid residue that is highly conserved across species and is absent from the dbSNP and 1,000 genomes databases. Review of literature and comparison were made with previously reported cases of this recently identified mitochondrial disorder encoded by a nuclear gene. Although limited in number, nuclear gene defects causing mitochondrial translation abnormalities represent a new, rapidly expanding field of mitochondrial medicine and should potentially be considered in the diagnostic investigation of infants with progressive hepatoencephalomyopathy and combined OXPHOS disorders.
Competing interests: None declared.
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References
Antonicka H, Sasarman F, Kennaway NG et al (2006) The molecular basis for tissue specificity of the oxidative phosphorylation deficiencies in patients with mutations in the mitochondrial translation factor EFG1. Hum Mol Genet 15:1835–1846
Antonicka H, Ostergaard E, Sasarman F, Weraarpachai W, Wibrand F, Anne Pedersen AM, Rodenburg RJ, van der Knaap MS, Smeitink JA, Chrzanowska-Lightowlers AM, Shoubridge EA (2010) Mutations in C12orf65 in patients with encephalomyopathy and a mitochondrial translation defect. Am J Hum Genet 87:115–122
Brandon M, Baldi P, Wallace DC (2006) Mitochondrial mutations in cancer. Oncogene 25:4647–4662
Coenen MJ, Antonicka H, Ugalde C et al (2004) Mutant mitochondrial elongation factor G1 and combined oxidative phosphorylation deficiency. N Engl J Med 351:2080–2086
Cooperstein SJ, Lazarow A (1951) A microspectrophotometric method for the determination of cytochrome oxidase. J Biol Chem 189(2):665–670
Cwerman-Thibault H, Sahel JA, Corral-Debrinski M (2011) Mitochondrial medicine: to a new era of gene therapy for mitochondrial DNA mutations. J Inherit Metab Dis 34(2):327–344
Gao J, Yu L, Zhang P et al (2001) Cloning and characterization of human and mouse mitochondrial elongation factor G, GFM and Gfm, and mapping of GFM to human chromosome 3q25.1-q26.2. Genomics 74:109–114
Gerbitz KD, Gempel K, Brdiczka D (1996) Mitochondria and diabetes: genetic, biochemical, and clinical implications of the cellular energy circuit. Diabetes 45(2):113–126
Gonzalez-Vioque E, Torres-Torronteras J, Andreu AL, Martı R (2011) Limited dCTP availability accounts for mitochondrial DNA depletion in mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). PLoS Genet 7(3):e1002035
Gray MW, Burger G, Lang BF (1999) Mitochondrial evolution. Science 283(5407):1476–1481
Janssen AJ, Trijbels FJ, Sengers RC et al (2007) Spectrophotometric assay for complex I of the respiratory chain in tissue samples and cultured fibroblasts. Clin Chem 53:729–734
Jonckheere AI, Hogeveen M, Nijtmans LG, van den Brand MA, Janssen AJ, Diepstra JH, van den Brandt FC, van den Heuvel LP, Hol FA, Hofste TG, Kapusta L, Dillmann U, Shamdeen MG, Smeitink JA, Rodenburg RJ (2008) A novel mitochondrial ATP8 gene mutation in a patient with apical hypertrophic cardiomyopathy and neuropathy. J Med Genet 45(3):129–133
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
Koc EC, Spremulli LL (2002) Identification of mammalian mitochondrial translational initiation factor 3 and examination of its role in initiation complex formation with natural mRNAs. J Biol Chem 277:35541–35549
Ling M, Merante F, Chen HS et al (1997) The human mitochondrial elongation factor tu (EF-Tu) gene: cDNA sequence, genomic localization, genomic structure, and identification of a pseudogene. Gene 197:325–336
Ma L, Spremulli LL (1995) Cloning and sequence analysis of the human mitochondrial translational initiation factor 2 cDNA. J Biol Chem 270:1859–1865
Mandemakers W, Morais VA, De Strooper B (2007) A cell biological perspective on mitochondrial dysfunction in Parkinson disease and other neurodegenerative diseases. J Cell Sci 120(10):1707–1716
Mizuno Y, Ikebe S, Hattori N et al (1995) Role of mitochondria in the etiology and pathogenesis of Parkinson’s disease. Biochim Biophys Acta 1271:265–274
Mourmans J, Wendel U, Bentlage HA, Trijbels JM, Smeitink JA, de Coo IF, Gabreëls FJ, Sengers RC, Ruitenbeek WJ (1997) Clinical heterogeneity in respiratory chain complex III deficiency in childhood. J Neurol Sci 149(1):111–117
Munnich A, Rustin P, Rötig A et al (1992) Clinical aspects of mitochondrial disorders. J Inherit Metab Dis 15(4):448–455
Ng SB, Turner EH, Robertson PD et al (2009) Targeted capture and massively parallel sequencing of 12 human exomes. Nature 461(7261):272–276
Pontarin G, Ferraro P, Rampazzo C et al (2011) Deoxyribonucleotide metabolism in cycling and resting human fibroblasts with a missense mutation in p53R2, a subunit of ribonucleotide reductase. J Biol Chem 286(13):11132–11140
Richter R, Rorbach J, Pajak A, Smith PM, Wessels HJ, Huynen M, Smeitink JA, Lightowlers RN, Chrzanowska-Lightowlers ZM (2010) A functional peptidyltRNA hydrolase, ICT1, has been recruited into the human mitochondrial ribosome. EMBO J 29:1116–1125
Rorbach J, Richter R, Wessels HJ, Wydro M, Pekalski M, Farhoud M, Kuhl I, Gaisne M, Bonnefoy N, Smeitink JA, Lightowlers R, Chrzanowska-Lightowler ZM (2008) The human mitochondrial ribosome recycling factor is essential for cell viability. Nucleic Acids Res 36(18):5787–5799
Skladal D, Halliday J, Thorburn DR (2003) Minimum birth prevalence of mitochondrial respiratory chain disorders in children. Brain 126:1905–1912
Smits P, Antonicka H, van Hasselt PM et al (2010a) Mutation in subdomain G′ of mitochondrial elongation factor G1 is associated with combined OXPHOS deficiency in fibroblasts but not in muscle. Eur J Hum Genet. doi:10.1038/ejhg.2010.208
Smits P, Smeitink J, van den Heuvel L (2010) Mitochondrial translation and beyond: processes implicated in combined oxidative phosphorylation deficiencies. J Biomed Biotechnol (Article ID 737385, 24 pages, Epub 2010 Apr 13). doi:10.1155/2010/737385
Soleimanpour-Lichaei HR, Kuhl I, Gaisne M, Passos JF, Wydro M, Rorbach J, Temperley R, Bonnefoy N, Tate W, Lightowlers R, Chrzanowska-Lightowler ZMA (2007) mtRF1a is a human mitochondrial translation release factor decoding the major termination codons UAA and UAG. Mol Cell 27:745–757
Spinazzola A, Invernizzi F, Carrara F et al (2009) Clinical and molecular features of mitochondrial DNA depletion syndromes. J Inherit Metab Dis 32:143–158
Srere PA (1969) Citrate synthase, EC 4.1.3.7 citrate oxaloacetate lyase (CoA-acetylating). Methods Enzymol 13:3–11
Tsuboi M, Morita H, Nozaki Y, Nozaki Y, Akama K, Ueda T, Ito K, Nierhaus KH, Takeuchi N (2009) EF-G2mt is an exclusive recycling factor in mammalian mitochondrial protein synthesis. Mol Cell 35(4):502–510
Tucker T, Marra M, Friedman JM (2009) Massively parallel sequencing: the next big thing in genetic medicine. Am J Hum Genet 85(2):142–154
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
Wintermeyer W, Peske F, Beringer M et al (2004) Mechanisms of elongation on the ribosome: dynamics of a macromolecular machine. Biochem Soc Trans 32:733–737
Xin H, Woriax V, Burkhart W et al (1995) Cloning and expression of mitochondrial translational elongation factor Ts from bovine and human liver. J Biol Chem 270:17243–17249
Zeviani M, Di Donato S (2004) Mitochondrial disorders. Brain 127(10):2153–2172
Zhang Y, Spremulli LL (1998) Identification and cloning of human mitochondrial translational release factor 1 and the ribosome recycling factor. Biochim Biophys Acta 1443:245–250
Acknowledgments
The authors would like to express their sincere gratitude to the Director General of Health, Ministry of Health, Malaysia for allowing the publication of this case report.
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Communicated by: Shamima Rahman.
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Contributions of Authors
1. Balasubramaniam S – Clinical management of the patient, draft of manuscript, and completed version.
2. YS Choy – Clinical management of patient, review of the draft, and contribution to the completed article.
3. Talib A – Histopathological analysis of liver biopsy, review of the draft, and contribution to the completed article.
4. Norsiah MD – Molecular testing of parental DNA for GFM1 mutation, review of the draft, and contribution to the completed article.
5. van den Heuvel LP – Biochemical analyses of OXPHOS assay and molecular testing in the proband, review of the draft, and contribution to the completed article.
6. Rodenburg RJ – E Biochemical analyses of OXPHOS assay and molecular testing in the proband, review of the draft, and contribution to the completed article.
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This report demonstrates a combined OXPHOS deficiency detected in patient fibroblasts, occurring as a result of a nuclear-encoded mitochondrial translational defect secondary to GFM1 mutation, ultimately leading to mitochondrial hepatoencephalomyopathy and death at 8 months of age.
All authors declare that the answers to all questions on the JIMD competing interest form are “no” and therefore have nothing to declare.
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Balasubramaniam, S., Choy, Y.S., Talib, A., Norsiah, M.D., van den Heuvel, L.P., Rodenburg, R.J. (2011). Infantile Progressive Hepatoencephalomyopathy with Combined OXPHOS Deficiency due to Mutations in the Mitochondrial Translation Elongation Factor Gene GFM1 . In: JIMD Reports - Case and Research Reports, 2012/2. JIMD Reports, vol 5. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2011_107
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DOI: https://doi.org/10.1007/8904_2011_107
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