Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia

• DOI: 10.1038/ng.3319
• Publication Date: 2015-06-01T19:20:00Z
• Authors: Susanne Kohl; Ditta Zobor; Wei-Chieh Chiang; Nicole Weisschuh; Jennifer Staller; Irene Gonzalez Me...; Stanley Chang; Susanne C Beck; Marina Garcia Gar...; Vithiyanjali Soth...; Mathias W Seeliger; Franco Stanzial; Francesco Benedic...; Francesca Inzana; Elise Héon; Ajoy Vincent; Jill Beis; Tim M Strom; Günther Rudolph; Susanne Roosing; Anneke I den Holl...; Frans P M Cremers; Irma Lopez; Huanan Ren; Anthony T Moore; Andrew R Webster; Michel Michaelides; Robert K Koenekoop; Eberhart Zrenner; Randal J Kaufman; Stephen H Tsang; Bernd Wissinger; Jonathan H Lin
• Keywords: Adult; Male; 0301 basic medicine; Adolescent; Transcription, Genetic; Knockout; Mutation, Missense; Color Vision Defects; Inbred C57BL; Mice; Young Adult; 03 medical and health sciences; Genetic; 80 and over; Animals; Humans; Child; Genetic Association Studies; Aged; Aged, 80 and over; Mice, Knockout; Radboudumc 12: Sensory disorders RIMLS: Radboud Institute for Molecular Life Sciences; Middle Aged; Activating Transcription Factor 6; Pedigree; Mice, Inbred C57BL; HEK293 Cells; Mutation; Retinal Cone Photoreceptor Cells; Unfolded Protein Response; Female; Missense; Transcription

Achromatopsia (ACHM) is an autosomal recessive disorder characterized by color blindness, photophobia, nystagmus and severely reduced visual acuity. Using homozygosity mapping and whole-exome and candidate gene sequencing, we identified ten families carrying six homozygous and two compound-heterozygous mutations in the ATF6 gene (encoding activating transcription factor 6A), a key regulator of the unfolded protein response (UPR) and cellular endoplasmic reticulum (ER) homeostasis. Patients had evidence of foveal hypoplasia and disruption of the cone photoreceptor layer. The ACHM-associated ATF6 mutations attenuate ATF6 transcriptional activity in response to ER stress. Atf6(-/-) mice have normal retinal morphology and function at a young age but develop rod and cone dysfunction with increasing age. This new ACHM-related gene suggests a crucial and unexpected role for ATF6A in human foveal development and cone function and adds to the list of genes that, despite ubiquitous expression, when mutated can result in an isolated retinal photoreceptor phenotype.