ATF6 – ATF6-associated Cone-Rod Dystrophy

ATF6 encodes activating transcription factor 6, a 90-kDa ER transmembrane transcriptional activator of the unfolded protein response. Biallelic pathogenic variants in ATF6 have been implicated in autosomal recessive cone-rod dystrophy (MONDO:0015993).

Genetic evidence supports a strong gene–disease association. Three unrelated probands from two families harbor the same homozygous ATF6 missense variant c.1691A>G (p.Asp564Gly): identified in one Polish family (PMID:29769798) and in two affected siblings from a consanguineous pedigree (PMID:28812650). Phasing and segregation analysis confirmed recessive inheritance with both parents as heterozygous carriers and complete co-segregation in the sibship.

The variant c.1691A>G (p.Asp564Gly) is a missense substitution affecting a conserved luminal domain of p90ATF6. Functional studies in patients’ fibroblasts and recombinant protein assays demonstrate impaired S1P/S2P-mediated cleavage and reduced generation of the active p60ATF6 transcription factor under ER stress (PMID:28812650). This loss-of-function mechanism abolishes up-regulation of downstream chaperones necessary for photoreceptor homeostasis.

No conflicting reports have been described. The concordance of genetic segregation and functional impairment fulfills ClinGen criteria for a Strong gene–disease association.

In summary, biallelic ATF6 variants disrupt unfolded protein response activation, leading to autosomal recessive cone-rod dystrophy. ATF6 genetic testing should be considered in patients with early-onset CRD, and functional assays of p.Asp564Gly provide a robust diagnostic marker.

References

• Molecular Vision • 2018 • Novel variants identified with next-generation sequencing in Polish patients with cone-rod dystrophy. PMID:29769798
• European Journal of Human Genetics • 2017 • Autosomal recessive cone-rod dystrophy can be caused by mutations in the ATF6 gene. PMID:28812650

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