ATF6 – Achromatopsia

Achromatopsia is an early-onset autosomal recessive cone dysfunction disorder characterized by photophobia, nystagmus, color blindness and severely reduced visual acuity. Pathogenic variants in ATF6 (HGNC:791), a ubiquitously expressed transcription factor that mediates the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress, have been implicated in isolated achromatopsia without systemic involvement. Clinical diagnosis is supported by characteristic retinal findings, including foveal hypoplasia and absent cone responses on electroretinography.

Genetic evidence supporting ATF6–achromatopsia includes biallelic loss-of-function and missense variants identified in at least 13 unrelated probands from ten families ([PMID:26029869]). Segregation analysis in a consanguineous Pakistani family showed complete cosegregation of c.355_356dupG (p.Glu119GlyfsTer8) with disease, and two affected siblings harboring homozygous exon 8–14 deletions were reported in another pedigree ([PMID:26063662]; [PMID:32271167]). A compound heterozygous 1-year-old patient carried c.533C>A (p.Ser178Ter) and c.82+1G>T, confirmed by parental testing and predicted pathogenic by ACMG criteria ([PMID:37747165]).

The ATF6 variant spectrum in achromatopsia is dominated by predicted loss-of-function alleles: nonsense (e.g., c.1450C>T (p.Arg484Ter)), frameshift (e.g., c.1763_1770dup (p.Met591fs)), splice-site (e.g., c.160-2A>G) and multiexon deletions, with fewer missense changes (e.g., c.970C>T (p.Arg324Cys)). Several recurrent splice mutations (e.g., c.82+1G>T) have been observed across diverse populations.

Functional studies demonstrate that achromatopsia-associated ATF6 alleles impair UPR signaling: mutant proteins show defective ER-to-Golgi trafficking, reduced regulated intramembrane proteolysis and attenuated transcriptional activation of ER chaperones. Recombinant proteins bearing exon deletions exhibited markedly reduced transcriptional activity by qPCR and RNA-Seq, and patient‐derived retinal organoids and ATF6−/− mice develop cone dysfunction and foveal hypoplasia mirroring the human phenotype ([PMID:32271167]; [PMID:26029869]; [PMID:28028229]).

No conflicting reports have disputed the ATF6–achromatopsia link. The concordance of genetic, segregation and functional data supports a loss-of-function mechanism of pathogenicity.

Key take-home: Biallelic ATF6 mutations cause autosomal recessive achromatopsia via impaired UPR signaling in cone photoreceptors; ATF6 should be included in diagnostic gene panels for cone dysfunction disorders.

References

• Nature genetics • 2015 • Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia PMID:26029869
• Human genetics • 2015 • Mutation of ATF6 causes autosomal recessive achromatopsia PMID:26063662
• JCI insight • 2020 • Multiexon deletion alleles of ATF6 linked to achromatopsia PMID:32271167
• Proceedings of the National Academy of Sciences of the United States of America • 2017 • Achromatopsia mutations target sequential steps of ATF6 activation PMID:28028229
• Journal of pediatric ophthalmology and strabismus • 2023 • Achromatopsia Showing Compound Heterozygous Mutations in ATF6 by Whole Exome Sequencing: A Rare Case Report. PMID:37747165

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