Mutation of ATF6 causes autosomal recessive achromatopsia.

Muhammad Ansar,Deborah A Nickerson,Fareeha Zulfiqar,Zubair M Ahmed,Michael J Bamshad,Sundus Sajid,Xin Wang,Wasim Ahmad,Saima Riazuddin,Ehsan Ullah,Naeem Mahmood Ashraf,Joshua D Smith,Muhammad Arif Nadeem Saqib,Jay Shendure,Kwanghyuk Lee,Regie Lyn P Santos‐Cortez ,Asif Hameed ,Muhammad Aminuddin ,F A Khan

doi:10.1007/s00439-015-1571-4

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.

Highlights

Achromatopsia (ACHM) is an autosomal recessive heterogeneous disorder characterized by symptoms that include the inability to discriminate colors, reduced visual acuity primarily in daylight, nystagmus and severe photophobia (Michaelides et al 2004)
The four affected individuals (III-1, III-4, III-5, IV-1; Fig. 1a) of family MA28 presented with severe photophobia, nystagmus and absence of color discrimination from early childhood
We identified a rare variant in ATF6 that segregates with the ACHM phenotype

Summary

Introduction

Achromatopsia (ACHM) is an autosomal recessive heterogeneous disorder characterized by symptoms that include the inability to discriminate colors, reduced visual acuity primarily in daylight, nystagmus and severe photophobia (Michaelides et al 2004). ACHM was considered as a stationary disorder but recent imaging studies have shown the progressive nature of disease in several patients (Thiadens et al 2010; Aboshiha et al 2014). Mutations in CNGA3 [MIM 600053], CNGB3 [MIM 605080], GNAT2 [MIM 139340], PDE6C [MIM 600827] and PDE6H [MIM 601190] are known to cause ACHM CNGA3 and CNGB3 mutations are the major cause of ACHM worldwide, with mutations in GNAT2, PDE6C and PDE6H playing a lesser role (Kohl et al 2012). The known gene mutations do not account for all cases of ACHM (Saqib et al 2011)

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