SLC25A4 – Mitochondrial Disease

SLC25A4 encodes the mitochondrial ADP/ATP carrier AAC1, a key component of oxidative phosphorylation responsible for exchanging cytosolic ADP and mitochondrial ATP. Pathogenic variants in SLC25A4 have been linked to a spectrum of mitochondrial diseases (MONDO:0044970), ranging from adult-onset progressive external ophthalmoplegia to severe neonatal mitochondrial DNA (mtDNA) depletion syndromes.

Genetic studies have identified seven unrelated individuals with recurrent de novo heterozygous SLC25A4 variants c.239G>A (p.Arg80His) and c.703C>G (p.Arg235Gly), all presenting at birth with ventilator-dependent respiratory chain deficiencies and marked mtDNA copy number loss ([PMID:27693233]). In a consanguineous family, a homozygous c.653A>C (p.Gln218Pro) variant was reported in a young man with mitochondrial myopathy, hypertrophic cardiomyopathy, lactic acidosis, and L-2-hydroxyglutaric aciduria ([PMID:29654543]). A de novo stop variant c.97A>T (p.Lys33Ter) was also described in a child with mild childhood-onset myopathy and classic muscle biopsy findings of mitochondrial disease ([PMID:30046662]).

The variant spectrum is dominated by missense substitutions targeting conserved substrate-binding or translocation domains, with hotspots p.Arg80His and p.Arg235Gly observed in multiple patients. Loss-of-function alleles such as c.523del (p.Gln175ArgfsTer?) have been modelled in mice and occasionally identified in patients, supporting both haploinsufficiency and dominant-negative mechanisms. To date, nine unrelated probands across autosomal dominant and autosomal recessive inheritance have been documented, with no evidence of a founder effect.

Functional assays demonstrate that recombinant AAC1 mutants p.Arg80His and p.Arg235Gly have severely impaired ADP/ATP transport activity and cause loss of respiratory complexes I–V in patient skeletal muscle ([PMID:27693233]). Expression of the p.Lys33Gln variant in Lactococcus lactis vesicles revealed significantly reduced transport kinetics, and patient muscle showed COX-deficient and ragged-blue fibers with decreased complex I, III, and IV protein levels despite preserved total AAC content ([PMID:30046662]).

Mouse models further reveal that mtDNA background modulates disease expressivity: Slc25a4−/− mice carrying the mtDNA ND6P25L variant exhibit exacerbated cardiomyopathy with impaired complex I activity, increased oxidative damage, and shortened lifespan, whereas a COIV421A background is phenotypically neutral ([PMID:30174309]). These findings underscore the dosage sensitivity and genetic background dependence of AAC1 function in mitochondrial maintenance.

No studies have refuted the pathogenic role of SLC25A4 variants in mitochondrial disease. The convergence of robust de novo and recessive genetic evidence with concordant functional assays supports a Strong ClinGen classification. Screening of SLC25A4 should be prioritized in patients with suspected mtDNA depletion syndromes or early-onset multisystem mitochondrial disease to guide diagnosis and management.

References

• American journal of human genetics • 2016 • Recurrent De Novo Dominant Mutations in SLC25A4 Cause Severe Early-Onset Mitochondrial Disease and Loss of Mitochondrial DNA Copy Number. PMID:27693233
• Neurology. Genetics • 2018 • Expanding the phenotype of de novo SLC25A4-linked mitochondrial disease to include mild myopathy. PMID:30046662
• JIMD reports • 2019 • Muscle Weakness, Cardiomyopathy, and L-2-Hydroxyglutaric Aciduria Associated with a Novel Recessive SLC25A4 Mutation. PMID:29654543
• Cell metabolism • 2019 • Mitochondrial DNA Variation Dictates Expressivity and Progression of Nuclear DNA Mutations Causing Cardiomyopathy. PMID:30174309

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