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

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.

Clinical and genetic aspects of defects in the mitochondrial iron–sulfur cluster synthesis pathway

“…Optic nerve atrophy was a variably occurring symptom [41, 66, 73]. When available, cerebral MRI showed various degrees of white matter alterations.…”

The spectrum of pyruvate oxidation defects in the diagnosis of mitochondrial disorders

“…All BOLA3 patients published so far suffered from hypertrophic cardiomyopathy (Seyda et al 2001;Haack et al 2013;Baker et al 2014). Mutations in the DLAT gene encoding the E2 subunit have been described in children with episodic dystonia and normal or mildly elevated lactate levels (McWilliam et al 2010;El-Gharbawy et al 2011).…”

“…Seyda et al 2001;Cameron et al 2011;Haack et al 2013; Baker et al 2014): Patients with BOLA3 mutations are described with severe early onset lactic acidosis, progressive encephalopathy with seizures, intractable cardiomyopathy and early death in infancy. Glycine elevation was found in all patients, enzyme investigations in skeletal muscle tissue revealed a combination of PDHC and combined respiratory chain deficiency.…”

Mammalian iron–sulphur proteins: novel insights into biogenesis and function

“…Other potential intermediate Fe-S cluster carriers include ISCA 50 , IBA57 (REFS 51,52), NFU1 (REFS 53,54) and BolAlike 3 (BOLA3) 53,55,56 . NFU1, IBA57 and BOLA3 seem to be particularly important for activity of the Fe-S cluster-containin g enzyme LIAS, which generates the flexible and mobile lipoyl group required for activity of Figure 2 | Initial Fe-S cluster assembly in bacteria.…”

“…Part a adapted from REF. 10 [52][53][54][55][56] . In many cases, the conclusion that an intermediate carrier protein for Fe-S clusters has specific downstream recipients is based on broad inferences, as the effects on putative recipients may not be direct, and many experimental manipulations can alter the activity of Fe-S proteins indirectly by interfering with general mitochondrial function.…”