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Susanne Kohl, Ditta Zobor, Wei-Chieh Chiang, Nicole Weisschuh, Mathias W Seeliger, Stanley Chang, Randal J. Kaufman, Stephen H Tsang, Bernd Wissinger, Jonathan H. Lin, ACHM Study Group; Mutations in the Unfolded Protein Response regulator, ATF6, cause Achromatopsia. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2865.
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© ARVO (1962-2015); The Authors (2016-present)
Achromatopsia (ACHM) is an autosomal recessive disorder characterized by color blindness, marked photophobia, nystagmus, and severely reduced visual acuity. In our cohort, disease-causing variants in genes encoding components of the cone phototransduction cascade cause ~75% of cases. Here, we examined patients with ACHM lacking disease-causing variants in the known ACHM genes to identify additional genes associated with this rare disorder.
Genetic analysis included autozygosity mapping, whole exome sequencing, and Sanger-sequencing of ATF6 in over 300 ACHM patients. These studies were complemented by cDNA analysis out of patients’ PaxGene blood to investigate the effect of putative splice site mutations, functional studies to assess the pathogenic effect of a ATF6 missense mutation, as well as functional analysis of the homologous Atf6-/- mouse model.
We identified ten independent ACHM families with 18 affected individuals carrying six homozygous and two compound-heterozygous disease-causing variants in the Activating Transcription Factor 6 (ATF6) gene, a key regulator of the Unfolded Protein Response (UPR) and cellular endoplasmic reticulum (ER) homeostasis. The mutations included two missense, three frame-shifting indel, and three true splice site mutations - as proven by cDNA analysis. Clinically and on optical coherence tomography the patients had evidence of foveal hypoplasia with an essentially absent foveal pit and a variable degree of disruption of the cone photoreceptor layer at the macula. Functionally, we found that an ACHM-associated ATF6 missense variant leads to attenuated ATF6 transcriptional activity in response to ER stress. Young Atf6-/- mice have normal retinal morphology and function, with both rod and cone dysfunction in older mice.
Mutations in ATF6 account for 1% of ACHM cases in our cohort of over 950 independent ACHM families. Inactivating mutations in ATF6 can result in an isolated retinal photoreceptor phenotype despite its ubiquitous expression. This study suggests a crucial and unexpected role of ATF6 in human foveal development and cone photoreceptor function.
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