AARS2 – Combined Oxidative Phosphorylation Deficiency 8

Combined oxidative phosphorylation deficiency type 8 (COXPD8) is a lethal autosomal recessive mitochondrial disorder characterized by childhood-onset hypertrophic cardiomyopathy and multisystem OXPHOS defects. Biallelic mutations in AARS2, encoding the mitochondrial alanyl-tRNA synthetase (mt-AlaRS), impair aminoacylation of mt-tRNA^Ala and disrupt mitochondrial translation, leading to near-absent complex I and IV activities in cardiac tissue.

Autosomal recessive inheritance is supported by homozygous and compound heterozygous AARS2 variants identified in multiple unrelated families. A set of five probands across four families has been reported with either homozygous c.1774C>T (p.Arg592Trp) or compound heterozygous c.2188G>A (p.Val730Met) and c.2872C>T (p.Arg958Ter) alleles ([PMID:21549344]; [PMID:34088003]). Two affected sibs segregating the same homozygous mutation further confirm recessive transmission.

The variant spectrum in COXPD8 includes missense changes within the editing and catalytic domains (e.g., c.1774C>T (p.Arg592Trp), c.2188G>A (p.Val730Met)) and early stop codons (e.g., c.2872C>T (p.Arg958Ter)). All three recurrent alleles have been observed in patient fibroblasts, muscle, or hiPSC models, demonstrating consistent genotype–phenotype correlation without evidence of founder events.

Functional studies support a loss-of-function mechanism. Exome sequencing and protein modeling demonstrated that p.Arg592Trp disrupts the editing domain, whereas p.Val730Met compromises catalytic activity, both leading to defective mt-tRNA aminoacylation and OXPHOS failure in patient heart ([PMID:21549344]). Generation of patient-derived hiPSCs carrying c.1774C>T, c.2188G>A, and c.2872C>T mutations showed preserved pluripotency and differentiation capacity but recapitulated mitochondrial respiratory deficits, validating disease modeling in vitro ([PMID:34088003]).

No reports to date dispute the association of AARS2 biallelic variants with COXPD8. Experimental concordance across cellular and structural assays strengthens pathogenicity assessments.

Given robust genetic and functional data, AARS2 meets ClinGen criteria for a strong gene–disease association in COXPD8. Identification of biallelic AARS2 variants facilitates molecular diagnosis, enables carrier screening, and supports future therapeutic targeting of mitochondrial dysfunction.

References

• Stem cell research • 2021 • Generation of three human induced pluripotent stem cell lines, LUMCi024-A, LUMCi025-A, and LUMCi026-A, from two patients with combined oxidative phosphorylation deficiency 8 and a related control. PMID:34088003
• American journal of human genetics • 2011 • Exome sequencing identifies mitochondrial alanyl-tRNA synthetase mutations in infantile mitochondrial cardiomyopathy. PMID:21549344

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