Advertisement

Journal of Inherited Metabolic Disease

, Volume 36, Issue 1, pp 55–62 | Cite as

Homozygous missense mutation in BOLA3 causes multiple mitochondrial dysfunctions syndrome in two siblings

  • Tobias B. Haack
  • Boris Rolinski
  • Birgit Haberberger
  • Franz Zimmermann
  • Jessica Schum
  • Valentina Strecker
  • Elisabeth Graf
  • Uwe Athing
  • Thomas Hoppen
  • Ilka Wittig
  • Wolfgang Sperl
  • Peter Freisinger
  • Johannes A. Mayr
  • Tim M. Strom
  • Thomas Meitinger
  • Holger Prokisch
Original Article

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.

Keywords

Lipoic Acid Respiratory Chain Complex Pyruvate Dehydrogenase Complex Severe Lactic Acidosis Aconitic Acid 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

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.

Conflict of interest

None.

Supplementary material

10545_2012_9489_MOESM1_ESM.doc (62 kb)
ESM 1 (DOC 62 kb)

References

  1. 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):65ra4PubMedCrossRefGoogle Scholar
  2. 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):118ra10PubMedCrossRefGoogle Scholar
  3. 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):486–495PubMedCrossRefGoogle Scholar
  4. 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):191–199PubMedCrossRefGoogle Scholar
  5. 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):161–166PubMedCrossRefGoogle Scholar
  6. 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):1744–1756PubMedCrossRefGoogle Scholar
  7. Elstner M, Andreoli C, Klopstock T, Meitinger T, Prokisch H (2009) The mitochondrial proteome database: MitoP2. Methods Enzymol 457:3–20PubMedCrossRefGoogle Scholar
  8. 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):1131–1134PubMedCrossRefGoogle Scholar
  9. 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):351–361PubMedGoogle Scholar
  10. 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):867–876PubMedCrossRefGoogle Scholar
  11. 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):209–219PubMedCrossRefGoogle Scholar
  12. 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):806–812PubMedCrossRefGoogle Scholar
  13. 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):792–797PubMedCrossRefGoogle Scholar
  14. Munnich A, Rustin P (2001) Clinical spectrum and diagnosis of mitochondrial disorders. Am J Med Genet 106(1):4–17, SpringPubMedCrossRefGoogle Scholar
  15. 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):656–667PubMedCrossRefGoogle Scholar
  16. 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 MetabGoogle Scholar
  17. 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):3697–3707PubMedCrossRefGoogle Scholar
  18. 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):386–396PubMedCrossRefGoogle Scholar
  19. Skladal D, Halliday J, Thorburn DR (2003) Minimum birth prevalence of mitochondrial respiratory chain disorders in children. Brain 126(Pt 8):1905–1912PubMedCrossRefGoogle Scholar
  20. 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):428–434PubMedCrossRefGoogle Scholar

Copyright information

© SSIEM and Springer 2012

Authors and Affiliations

  • Tobias B. Haack
    • 1
    • 2
  • Boris Rolinski
    • 3
    • 4
  • Birgit Haberberger
    • 1
    • 2
  • Franz Zimmermann
    • 5
  • Jessica Schum
    • 2
  • Valentina Strecker
    • 6
  • Elisabeth Graf
    • 2
  • Uwe Athing
    • 4
  • Thomas Hoppen
    • 7
  • Ilka Wittig
    • 6
  • Wolfgang Sperl
    • 5
  • Peter Freisinger
    • 8
  • Johannes A. Mayr
    • 5
  • Tim M. Strom
    • 1
    • 2
  • Thomas Meitinger
    • 1
    • 2
  • Holger Prokisch
    • 1
    • 2
  1. 1.Institute of Human GeneticsTechnische Universität MünchenMunichGermany
  2. 2.Institute of Human Genetics, Helmholtz Zentrum MünchenGerman Research Center for Environmental HealthNeuherbergGermany
  3. 3.ElblandklinikenElblandkliniken GmbhRiesaGermany
  4. 4.Department Klinische ChemieStädtisches Klinikum München GmbHMunichGermany
  5. 5.Department of PaediatricsParacelsus Medical UniversitySalzburgAustria
  6. 6.Molekulare Bioenergetik, Zentrum der Biologischen ChemieGoethe-Universität FrankfurtFrankfurt am MainGermany
  7. 7.Department of PaediatricsGemeinschaftsklinikum Koblenz-MayenKoblenzGermany
  8. 8.Department of PaediatricsStädtisches Klinikum ReutlingenReutlingenGermany

Personalised recommendations