IBA57 – Mitochondrial Disease

Biallelic pathogenic variants in IBA57 cause an autosomal recessive mitochondrial disorder (MONDO:0044970) characterized by variable onset from infancy to adulthood. A total of 16 affected individuals across five unrelated families have been reported, including infantile-onset optic atrophy with asymptomatic leukodystrophy, severe perinatal encephalopathy, hereditary spastic paraplegia with optic atrophy, and fatal infantile leukoencephalopathy. Cases include three sibs in two families with novel frameshift and missense variants [PMID:30258207], two siblings with homozygous p.Gln314Pro showing perinatal lethality [PMID:23462291], ten members of a consanguineous family with a splice-site defect c.678A>G (p.Gln226=) and slow-progressive SPOAN phenotype [PMID:25609768], and a fatal infantile case with homozygous p.Arg146Trp [PMID:25971455].

Genetic evidence supports autosomal recessive inheritance with segregation of biallelic IBA57 variants in ten additional relatives beyond index cases. A spectrum of loss-of-function (frameshift, nonsense, splice-site) and missense changes has been observed. One recurring founder allele c.262dup (p.Ala88fs) was identified in Sepharadi Jewish siblings ([PMID:30258207]). Segregation analysis in consanguineous families and genotype–phenotype correlations across multiple cohorts confirm the pathogenicity of biallelic IBA57 defects.

Functional and experimental studies demonstrate that IBA57 deficiency impairs mitochondrial [4Fe-4S] protein assembly, leading to combined respiratory chain complex I/II deficiency, loss of lipoic acid–dependent enzyme maturation, and proteolytic degradation of mutant IBA57. HeLa cell complementation assays rescued biochemical phenotypes with wild-type but not mutant IBA57 ([PMID:23462291]). Structural SAXS and docking studies of the ISCA2–IBA57 complex revealed destabilization by the p.Arg146Trp defect, providing a molecular basis for MMDS3 phenotypes ([PMID:31831856]).

No conflicting evidence has been reported refuting the association of IBA57 with mitochondrial disease. Reports are consistent across multiple ethnic groups and methodologies.

In summary, there is strong clinical validity and genetic evidence for an autosomal recessive IBA57-related mitochondrial disorder, supported by concordant functional data. IBA57 variant screening is recommended in patients with unexplained leukodystrophy, spastic paraplegia, encephalopathy, and combined respiratory chain deficiencies.

Key take-home: Biallelic IBA57 variants reliably predict a spectrum of mitochondrial disease and guide diagnostic testing and genetic counseling.

References

• Journal of human genetics • 2018 • Expanding the phenotype of IBA57 mutations: related leukodystrophy can remain asymptomatic. PMID:30258207
• Human molecular genetics • 2013 • Mutation of the iron-sulfur cluster assembly gene IBA57 causes severe myopathy and encephalopathy. PMID:23462291
• Neurology • 2015 • Fe/S protein assembly gene IBA57 mutation causes hereditary spastic paraplegia. PMID:25609768
• Journal of inherited metabolic disease • 2015 • Mutation of the iron-sulfur cluster assembly gene IBA57 causes fatal infantile leukodystrophy. PMID:25971455
• Scientific reports • 2019 • Structural properties of [2Fe-2S] ISCA2-IBA57: a complex of the mitochondrial iron-sulfur cluster assembly machinery. PMID:31831856

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