Homozygous missense mutation in BOLA3 causes multiple mitochondrial dysfunctions syndrome in two siblings
Homozygous missense mutation in BOLA3 causes multiple mitochondrial dysfunctions syndrome in two siblings
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DOI：
10.1007/s10545-012-9489-7
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发表时间：
2013-01-01
影响因子：
4.2
通讯作者：
Prokisch, Holger
中科院分区：
文献类型：
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作者：
Haack, Tobias B.;Rolinski, Boris;Prokisch, Holger
线粒体氧化磷酸化缺陷构成了一组临床和遗传异质性疾病，影响不同年龄的多个器官系统。活检材料的生化分析表明线粒体呼吸链酶复合物的单独或联合缺乏。丙酮酸脱氢酶复合物的活性受损的共同发生迄今为止很少报道，并且尚未完全理解。我们调查了两个兄弟姐妹，他们都患有严重的新生儿乳酸性酸中毒、肌张力低下和顽固性心肌病;两人都在出生后的头几个月内死亡。肌肉活检发现了一种特殊的生化缺陷，由呼吸链复合物I，II和II+III的组合缺陷伴随丙酮酸脱氢酶复合物的缺陷组成。两个受影响的兄弟姐妹的联合外显子组分析发现了BOLA 3的纯合错义突变。通过慢病毒介导的患者成纤维细胞中野生型BOLA 3的线粒体同种型的表达来验证突变的因果作用，这导致残留酶活性和硫辛酸水平的增加。我们的研究结果表明，BOLA 3在呼吸链和2-酮酸脱氢酶复合物的正常功能所必需的铁硫簇的生物发生中起着至关重要的作用。我们的结论是，广泛的测序方法结合适当的优先过滤器和实验验证，使有效的分子诊断，并有可能发现新的疾病位点。
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.