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Homozygous missense mutation in BOLA3 causes multiple mitochondrial dysfunctions syndrome in two siblings
Author(s) -
Haack Tobias B.,
Rolinski Boris,
Haberberger Birgit,
Zimmermann Franz,
Schum Jessica,
Strecker Valentina,
Graf Elisabeth,
Athing Uwe,
Hoppen Thomas,
Wittig Ilka,
Sperl Wolfgang,
Freisinger Peter,
Mayr Johannes A.,
Strom Tim M.,
Meitinger Thomas,
Prokisch Holger
Publication year - 2013
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1007/s10545-012-9489-7
Subject(s) - missense mutation , respiratory chain , mitochondrial disease , lactic acidosis , mitochondrial respiratory chain , biology , hypotonia , phosphoglycerate mutase , exome sequencing , pyruvate dehydrogenase complex , mutation , mitochondrion , genetics , mitochondrial dna , endocrinology , biochemistry , glycolysis , gene , enzyme
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.