ACO2 – Optic Atrophy 9

Autosomal recessive biallelic variants in the mitochondrial aconitase gene ACO2 have been implicated in Optic Atrophy 9 (MONDO:0014571), characterized by isolated ophthalmologic phenotypes including bilateral optic atrophy and low vision. The inheritance is autosomal recessive and disease onset is typically in infancy or early childhood.

A review of the literature identified five affected individuals from three unrelated families carrying pathogenic or likely pathogenic ACO2 variants consistent with Optic Atrophy 9. In a recent study, a brother and sister were compound heterozygous for two novel missense variants, c.487G>T (p.Val163Leu) and c.1894G>A (p.Val632Met), and exhibited early-onset visual impairment and optic atrophy without extra-ocular involvement (PMID:32449285).

Segregation analysis confirmed that the two siblings inherited each variant from one parent, providing evidence of co-segregation in one family and supporting autosomal recessive inheritance. Across the three families, five probands were reported, with one additional affected sibling segregating compound heterozygous variants (affected_relatives: 1).

The variant spectrum in Optic Atrophy 9 is dominated by missense changes in ACO2; no recurrent or founder alleles have been established. A representative pathogenic variant is c.487G>T (p.Val163Leu).

Functional studies demonstrate that ACO2 missense variants associated with optic atrophy lead to loss of aconitase activity. In yeast complementation assays, all mutant ACO2 proteins failed to rescue respiratory growth of an aco1-deletion strain, indicating a loss-of-function mechanism concordant with the human phenotype (PMID:25351951).

Collectively, there is strong evidence for a causative link between biallelic ACO2 loss-of-function variants and Optic Atrophy 9. Functional assays corroborate the genetic findings, supporting clinical genetic testing of ACO2 in patients with isolated optic atrophy. Key take-home: Biallelic ACO2 missense variants cause autosomal recessive Optic Atrophy 9, and functional loss-of-function assays reliably model the human phenotype.

References

• American journal of medical genetics. Part A • 2020 • Recessive ACO2 variants as a cause of isolated ophthalmologic phenotypes. PMID:32449285
• Journal of medical genetics • 2014 • Mutations in the tricarboxylic acid cycle enzyme, aconitase 2, cause either isolated or syndromic optic neuropathy with encephalopathy and cerebellar atrophy. PMID:25351951

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