Homozygous missense mutation in BOLA3 causes multiple mitochondrial dysfunctions syndrome in two siblings
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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.
KeywordsLipoic Acid Respiratory Chain Complex Pyruvate Dehydrogenase Complex Severe Lactic Acidosis Aconitic Acid
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.
The URLs for data presented herein are as follows:
Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/
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
- 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