SLC25A46 – Leigh syndrome

SLC25A46 is implicated in autosomal recessive Leigh syndrome, supported by two unrelated probands harboring biallelic variants. The first subject exhibited a homozygous missense variant c.425C>T (p.Thr142Ile) destabilizing the protein, leading to disrupted cristae architecture and impaired respiration (PMID:27390132). The second infant with Leigh syndrome harbored a compound heterozygous c.1039C>T (p.Arg347Cys) and a donor splice region variant c.283+5G>A, both predicted damaging, with reduced transcript/protein expression and increased mitochondrial fragmentation (PMID:34945750). These cases establish recessive inheritance with consistent clinical phenotypes.

Functional assays across studies demonstrate that pathogenic missense mutations in SLC25A46 reduce protein stability, alter interactions with mitochondrial dynamics machinery, and perturb lipid composition and organellar contacts, concordant with the neurodegenerative phenotype. No segregation beyond probands has been reported. While evidence includes strong experimental concordance, the small number of cases limits genetic confirmation. Key take-home: Biallelic SLC25A46 variants disrupt mitochondrial dynamics, underpinning recessive Leigh syndrome, informing molecular diagnosis and variant interpretation.

References

• EMBO Molecular Medicine • 2016 • SLC25A46 is required for mitochondrial lipid homeostasis and cristae maintenance and is responsible for Leigh syndrome. PMID:27390132
• Journal of Personalized Medicine • 2021 • Reanalysis of Exome Data Identifies Novel SLC25A46 Variants Associated with Leigh Syndrome. PMID:34945750

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