BOLA3 – Multiple Mitochondrial Dysfunction Syndrome 2

Biallelic pathogenic variants in BOLA3 cause Multiple Mitochondrial Dysfunction Syndrome 2, a rare autosomal recessive disorder characterized by life‐threatening lactic acidosis, nonketotic hyperglycinemia, hypertrophic cardiomyopathy, and leukoencephalopathy with variable clinical recovery.

Genetic evidence includes 10 unrelated probands: one infant with compound heterozygous c.136C>T (p.Arg46Ter) and c.176G>A (p.Cys59Tyr) (PMID:29654549), one family with homozygous c.123dupA (p.Glu42ArgfsTer13) (PMID:21944046), and eight Japanese patients harboring diverse biallelic BOLA3 variants (PMID:40273865). All reports confirm autosomal recessive segregation.

Functional assays in patient fibroblasts demonstrated deficient pyruvate dehydrogenase activity and reduced subunits of mitochondrial complexes I and II consistent with BOLA3 loss of function (PMID:29654549). Retroviral complementation with mitochondrial isoform 1 of BOLA3 restored both respiratory chain and 2‐oxoacid dehydrogenase activities in BOLA3‐deficient cells (PMID:21944046).

Structural and biochemical studies elucidate the pathogenic mechanism: the Cys59Tyr mutation perturbs the Fe-S cluster‐binding region and disrupts the BOLA3–GLRX5 heterocomplex without abolishing cluster binding (PMID:34063696); the Ile67Asn substitution impairs GLRX5 interaction and downstream cluster reconstitution (PMID:33693876); and the His96Arg variant forms an aberrant, nonfunctional heterocomplex, abrogating [4Fe-4S] assembly on NFU1 (PMID:37511493).

Together, these data provide strong clinical validity: over ten probands with consistent recessive segregation, multiple independent loss‐of‐function variants, and concordant biochemical and cellular rescue experiments. BOLA3 functions in transporting [4Fe-4S] clusters to mitochondrial respiratory complexes and lipoic acid synthetase, with deficiency leading to the MMDS2 phenotype.

Key Take-home: Genetic testing of BOLA3 should be prioritized in infants presenting with hyperglycinemia, cardiomyopathy, and leukoencephalopathy, as biallelic BOLA3 mutations underlie MMDS2 and may inform targeted metabolic and vitamin supplementation strategies.

References

• JIMD Reports | 2019 | Severe Leukoencephalopathy with Clinical Recovery Caused by Recessive BOLA3 Mutations PMID:29654549
• Molecular Genetics and Metabolism | 2025 | Role of BOLA3 in the mitochondrial Fe-S cluster clarified by metabolomic analysis PMID:40273865
• American Journal of Human Genetics | 2011 | Mutations in iron-sulfur cluster scaffold genes NFU1 and BOLA3 cause a fatal deficiency of multiple respiratory chain and 2-oxoacid dehydrogenase enzymes PMID:21944046
• International Journal of Molecular Sciences | 2021 | Molecular Basis of Multiple Mitochondrial Dysfunctions Syndrome 2 Caused by CYS59TYR BOLA3 Mutation PMID:34063696
• Metallomics | 2021 | Biochemical impact of a disease-causing Ile67Asn substitution on BOLA3 protein PMID:33693876
• International Journal of Molecular Sciences | 2023 | Understanding the Molecular Basis of the Multiple Mitochondrial Dysfunctions Syndrome 2: The Disease-Causing His96Arg Mutation of BOLA3 PMID:37511493

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