IBA57 – Multiple Mitochondrial Dysfunction Syndrome Type 3

IBA57 encodes a mitochondrial iron–sulfur (Fe-S) cluster assembly factor essential for maturation of [4Fe-4S] proteins required by respiratory complexes I and II, lipoic acid synthase and aconitase. Biallelic pathogenic variants in IBA57 cause multiple mitochondrial dysfunctions syndrome 3 (multiple mitochondrial dysfunctions syndrome 3), an autosomal recessive leukoencephalopathy with infantile psychomotor regression, optic atrophy and hyperglycinemia.

Autosomal recessive inheritance is supported by seven unrelated probands identified to date: a female with prenatal IUGR and microcephaly presenting psychomotor regression (1 proband) (PMID:37903659), two Chinese patients with acute regression and cavitating leukoencephalopathy (2 probands) (PMID:34709542), one 14-month-old child with motor decline (1 proband) (PMID:38923322), two perinatally affected siblings (2 probands) (PMID:23462291), and a fatal infantile leukodystrophy case (1 proband) (PMID:25971455). All carried compound heterozygous or homozygous IBA57 variants.

Segregation analysis in a consanguineous family demonstrated co-segregation of a homozygous c.339C>G (p.Tyr113Ter) variant with lethal perinatal encephalopathy in two siblings, providing one additional affected relative supporting pathogenicity (PMID:23462291).

The variant spectrum includes at least four missense changes (e.g., c.310G>T (p.Gly104Cys)[PMID:39408793], c.436C>T (p.Arg146Trp)[PMID:25971455], c.286T>C (p.Tyr96His)[PMID:34709542], c.992T>A (p.Leu331Gln)[PMID:38923322]) and three loss-of-function alleles (c.339C>G (p.Tyr113Ter)[PMID:23462291], c.192del (p.Asp65ThrfsTer7)[PMID:34709542], c.454G>T (p.Glu152Ter)[PMID:23462291]). Recurrent and private alleles reflect both founder and de novo events.

Functional assays in patient fibroblasts and HeLa cells depleted of IBA57 recapitulate combined complex I/II deficiency, loss of protein lipoylation and reduced stability of mutant IBA57 protein. Rescue with wild-type but not mutant alleles confirms loss-of-function; structural studies of the p.Gly104Cys variant demonstrate impaired holo-protein stability (PMID:23462291, PMID:25971455, PMID:39408793).

Collectively, seven probands, familial segregation and concordant cellular and biophysical data support a Strong ClinGen gene–disease association. Biallelic IBA57 testing should be considered in infants with early regression, leukoencephalopathy and hyperglycinemia. Key take-home: IBA57 variants reliably predict MMDS3 diagnosis and inform genetic counseling and management.

References

• Molecular Genetics and Metabolism • 2023 • Clinical, radiological, biochemical and molecular characterization of a new case with multiple mitochondrial dysfunction syndrome due to IBA57: Lysine and tryptophan metabolites as potential biomarkers. PMID:37903659
• Metabolic Brain Disease • 2022 • Novel IBA57 mutations in two chinese patients and literature review of multiple mitochondrial dysfunction syndrome. PMID:34709542
• Molecular Genetics & Genomic Medicine • 2024 • Clinical characteristics of a case of multiple mitochondrial dysfunction syndrome 3. PMID:38923322
• Human Molecular Genetics • 2013 • Mutation of the iron-sulfur cluster assembly gene IBA57 causes severe myopathy and encephalopathy. PMID:23462291
• Journal of Inherited Metabolic Disease • 2015 • Mutation of the iron-sulfur cluster assembly gene IBA57 causes fatal infantile leukodystrophy. PMID:25971455
• International Journal of Molecular Sciences • 2024 • Defects in the Maturation of Mitochondrial Iron-Sulfur Proteins: Biophysical Investigation of the MMDS3 Causing Gly104Cys Variant of IBA57. PMID:39408793

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