Mutation of ATF6 causes autosomal recessive achromatopsia

Abstract

Achromatopsia (ACHM) is an early-onset retinal dystrophy characterized by photophobia, nystagmus, color blindness and severely reduced visual acuity. Currently mutations in five genes CNGA3, CNGB3, GNAT2, PDE6C and PDE6H have been implicated in ACHM. We performed homozygosity mapping and linkage analysis in a consanguineous Pakistani ACHM family and mapped the locus to a 15.12-Mb region on chromosome 1q23.1–q24.3 with a maximum LOD score of 3.6. A DNA sample from an affected family member underwent exome sequencing. Within the ATF6 gene, a single-base insertion variant c.355_356dupG (p.Glu119Glyfs*8) was identified, which completely segregates with the ACHM phenotype within the family. The frameshift variant was absent in public variant databases, in 130 exomes from unrelated Pakistani individuals, and in 235 ethnically matched controls. The variant is predicted to result in a truncated protein that lacks the DNA binding and transmembrane domains and therefore affects the function of ATF6 as a transcription factor that initiates the unfolded protein response during endoplasmic reticulum (ER) stress. Immunolabeling with anti-ATF6 antibodies showed localization throughout the mouse neuronal retina, including retinal pigment epithelium, photoreceptor cells, inner nuclear layer, inner and outer plexiform layers, with a more prominent signal in retinal ganglion cells. In contrast to cytoplasmic expression of wild-type protein, in heterologous cells ATF6 protein with the p.Glu119Glyfs*8 variant is mainly confined to the nucleus. Our results imply that response to ER stress as mediated by the ATF6 pathway is essential for color vision in humans.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-015-1571-4) contains supplementary material, which is available to authorized users.

Physiological/pathological ramifications of transcription factors in the unfolded protein response

“…This intriguing result needs further investigation because if TUDCA prevents accumulation of misfolded proteins, it would not be expected to activate ATF6α. It was demonstrated recently that hypomorphic mutations in ATF6α in humans cause a rare syndrome, achromatopsia, that is associated with age-onset color blindness and loss of cone photoreceptors in the retina (Ansar et al 2015;Kohl et al 2015;Chiang et al 2017). Intriguingly, ATF6α deletion did not affect the function of rod photoreceptors, indicating a very selective requirement for ATF6α in cone photoreceptors.…”

Regulating Secretory Proteostasis through the Unfolded Protein Response: From Function to Therapy

“…Recent human genetic evidence has begun to answer this question. Numerous mutations in ATF6α have now been identified in humans presenting with the developmental eye disorder achromatopsia, where alterations in ATF6 activity lead to impaired retinal development [62–64]. Interestingly, these mutations differentially influence ATF6 activity.…”

Achromatopsia mutations target sequential steps of ATF6 activation

“…Using next-generation whole-exome sequencing, we recently discovered autosomal recessive mutations in the activating transcription factor 6 (ATF6) gene in patients with achromatopsia (1). ATF6 mutations span the entire coding region and include missense, nonsense, splice site, and single-nucleotide deletion and duplication changes (1)(2)(3). We previously showed that a missense mutation that introduced an arginine-to-cysteine substitution at amino acid residue 324 of the ATF6 protein compromised ATF6 activity in patient fibroblasts obtained from an achromatopsia family (1).…”