Abstract
Defects of mitochondrial oxidative phosphorylation constitute a clinical and genetic heterogeneous group of disorders affecting multiple organ systems at varying age. Biochemical analysis of biopsy material demonstrates isolated or combined deficiency of mitochondrial respiratory chain enzyme complexes. Co-occurrence of impaired activity of the pyruvate dehydrogenase complex has been rarely reported so far and is not yet fully understood. We investigated two siblings presenting with severe neonatal lactic acidosis, hypotonia, and intractable cardiomyopathy; both died within the first months of life. Muscle biopsy revealed a peculiar biochemical defect consisting of a combined deficiency of respiratory chain complexes I, II, and II+III accompanied by a defect of the pyruvate dehydrogenase complex. Joint exome analysis of both affected siblings uncovered a homozygous missense mutation in BOLA3. The causal role of the mutation was validated by lentiviral-mediated expression of the mitochondrial isoform of wildtype BOLA3 in patient fibroblasts, which lead to an increase of both residual enzyme activities and lipoic acid levels. Our results suggest that BOLA3 plays a crucial role in the biogenesis of iron-sulfur clusters necessary for proper function of respiratory chain and 2-oxoacid dehydrogenase complexes. We conclude that broad sequencing approaches combined with appropriate prioritization filters and experimental validation enable efficient molecular diagnosis and have the potential to discover new disease loci.
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References
Bell CJ, Dinwiddie DL, Miller NA, Hateley SL, Ganusova EE, Mudge J et al (2011) Carrier testing for severe childhood recessive diseases by next-generation sequencing. Sci Transl Med 3(65):65ra4
Calvo SE, Compton AG, Hershman SG, Lim SC, Lieber DS, Tucker EJ et al (2012) Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing. Sci Transl Med 4(118):118ra10
Cameron JM, Janer A, Levandovskiy V, Mackay N, Rouault TA, Tong WH et al (2011a) Mutations in iron-sulfur cluster scaffold genes NFU1 and BOLA3 cause a fatal deficiency of multiple respiratory chain and 2-oxoacid dehydrogenase enzymes. Am J Hum Genet 89(4):486–495
Cameron JM, Levandovskiy V, Mackay N, Ackerley C, Chitayat D, Raiman J et al (2011b) Complex V TMEM70 deficiency results in mitochondrial nucleoid disorganization. Mitochondrion 11(1):191–199
Danhauser K, Iuso A, Haack TB, Freisinger P, Brockmann K, Mayr JA et al (2011) Cellular rescue-assay aids verification of causative DNA-variants in mitochondrial complex I deficiency. Mol Genet Metab 103(2):161–166
De Praeter CM, Gerwig GJ, Bause E, Nuytinck LK, Vliegenthart JF, Breuer W et al (2000) A novel disorder caused by defective biosynthesis of N-linked oligosaccharides due to glucosidase I deficiency. Am J Hum Genet 66(6):1744–1756
Elstner M, Andreoli C, Klopstock T, Meitinger T, Prokisch H (2009) The mitochondrial proteome database: MitoP2. Methods Enzymol 457:3–20
Haack TB, Danhauser K, Haberberger B, Hoser J, Strecker V, Boehm D et al (2010) Exome sequencing identifies ACAD9 mutations as a cause of complex I deficiency. Nat Genet 42(12):1131–1134
Koyata H, Hiraga K (1991) The glycine cleavage system: structure of a cDNA encoding human H-protein, and partial characterization of its gene in patients with hyperglycinemias. Am J Hum Genet 48(2):351–361
Li H, Mapolelo DT, Dingra NN, Keller G, Riggs-Gelasco PJ, Winge DR et al (2010) Histidine 103 in Fra2 is an iron-sulfur cluster ligand in the [2Fe-2S] Fra2-Grx3 complex and is required for in vivo iron signaling in yeast. J Biol Chem 286(1):867–876
Lissens W, De Meirleir L, Seneca S, Liebaers I, Brown GK, Brown RM et al (2000) Mutations in the X-linked pyruvate dehydrogenase (E1) alpha subunit gene (PDHA1) in patients with a pyruvate dehydrogenase complex deficiency. Hum Mutat 15(3):209–219
Mayr JA, Freisinger P, Schlachter K, Rolinski B, Zimmermann FA, Scheffner T et al (2011a) Thiamine pyrophosphokinase deficiency in encephalopathic children with defects in the pyruvate oxidation pathway. Am J Hum Genet 89(6):806–812
Mayr JA, Zimmermann FA, Fauth C, Bergheim C, Meierhofer D, Radmayr D et al (2011b) Lipoic acid synthetase deficiency causes neonatal-onset epilepsy, defective mitochondrial energy metabolism, and glycine elevation. Am J Hum Genet 89(6):792–797
Munnich A, Rustin P (2001) Clinical spectrum and diagnosis of mitochondrial disorders. Am J Med Genet 106(1):4–17, Spring
Navarro-Sastre A, Tort F, Stehling O, Uzarska MA, Arranz JA, Del Toro M et al (2011) A fatal mitochondrial disease is associated with defective NFU1 function in the maturation of a subset of mitochondrial Fe-S proteins. Am J Hum Genet 89(5):656–667
Patel KP, O’Brien TW, Subramony SH, Shuster J, Stacpoole PW (2011) The spectrum of pyruvate dehydrogenase complex deficiency: Clinical, biochemical and genetic features in 371 patients. Mol Genet Metab
Sasarman F, Antonicka H, Shoubridge EA (2008) The A3243G tRNALeu(UUR) MELAS mutation causes amino acid misincorporation and a combined respiratory chain assembly defect partially suppressed by overexpression of EFTu and EFG2. Hum Mol Genet 17(23):3697–3707
Seyda A, Newbold RF, Hudson TJ, Verner A, MacKay N, Winter S et al (2001) A novel syndrome affecting multiple mitochondrial functions, located by microcell-mediated transfer to chromosome 2p14-2p13. Am J Hum Genet 68(2):386–396
Skladal D, Halliday J, Thorburn DR (2003) Minimum birth prevalence of mitochondrial respiratory chain disorders in children. Brain 126(Pt 8):1905–1912
Tucker EJ, Hershman SG, Kohrer C, Belcher-Timme CA, Patel J, Goldberger OA et al (2011) Mutations in MTFMT underlie a human disorder of formylation causing impaired mitochondrial translation. Cell Metab 14(3):428–434
Acknowledgements
We are grateful to the patients and their family for their participation and especially to A. Huber, R. Hellinger and A. Löschner for their technical support.
Web resources
The URLs for data presented herein are as follows:
MitoP2, http://www.mitop.de
MITOPRED, http://bioapps.rit.albany.edu/MITOPRED/
TargetP, http://www.cbs.dtu.dk/services/TargetP/
Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/
Funding
T.M. and H.P. were supported by the Impulse and Networking Fund of the Helmholtz Association in the framework of the Helmholtz Alliance for Mental Health in an Ageing Society (HA-215) and the German Federal Ministry of Education and Research (BMBF) funded German Center for Diabetes Research (DZD e.V.) and Systems Biology of Metabotypes grant (SysMBo #0315494A). H.P. was supported by the grant RF-INN-2007-634163 of the Italian Ministry of Health. T.M., P.F., and H.P. were supported by the BMBF funded German Network for Mitochondrial Disorders (mitoNET #01GM1113C). F.A.Z., W.S., and J.A.M. were supported by the GENOMIT project funded by the FWF (I 920‐B13) and the Vereinigung zur Förderung der pädiatrischen Forschung und Fortbildung Salzburg. I.W. was supported by the Bundesministerium für Bildung und Forschung (BMBF #01GM1113B; mitoNET – Deutsches Netzwerk für mitochondriale Erkrankungen) and by the Deutsche Forschungsgemeinschaft, Sonderforschungsbereich 815, Project Z1 (Redox-Proteomics). T.B.H. was supported by the NBIA disorders association. The authors confirm independence from the sponsors; the content of the article has not been influenced by the sponsors.
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Communicated by: Shamima Rahman
Tobias B. Haack, Boris Rolinski and Birgit Haberberger authors contributed equally.
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Haack, T.B., Rolinski, B., Haberberger, B. et al. Homozygous missense mutation in BOLA3 causes multiple mitochondrial dysfunctions syndrome in two siblings. J Inherit Metab Dis 36, 55–62 (2013). https://doi.org/10.1007/s10545-012-9489-7
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DOI: https://doi.org/10.1007/s10545-012-9489-7