title: 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.
authors.affiliation: Department of Molecular and Human Genetics, Center for Statistical Genetics, Baylor College of Medicine, 1 Baylor Plaza 700D, Houston, TX, 77030, USA.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ansar
authors.forename: Regie Lyn P
authors.initials: RL
authors.lastname: Santos-Cortez
authors.forename: Muhammad Arif Nadeem
authors.initials: MA
authors.lastname: Saqib
authors.forename: Fareeha
authors.initials: F
authors.lastname: Zulfiqar
authors.forename: Kwanghyuk
authors.initials: K
authors.lastname: Lee
authors.forename: Naeem Mahmood
authors.initials: NM
authors.lastname: Ashraf
authors.forename: Ehsan
authors.initials: E
authors.lastname: Ullah
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Sundus
authors.initials: S
authors.lastname: Sajid
authors.forename: Falak Sher
authors.initials: FS
authors.lastname: Khan
authors.forename: Muhammad
authors.initials: M
authors.lastname: Amin-ud-Din
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Smith
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bamshad
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.forename: Abdul
authors.initials: A
authors.lastname: Hameed
authors.forename: Saima
authors.initials: S
authors.lastname: Riazuddin
authors.forename: Zubair M
authors.initials: ZM
authors.lastname: Ahmed
authors.forename: Wasim
authors.initials: W
authors.lastname: Ahmad
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Leal
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000818:Animals; D044466:Asian People / Q000235:genetics; D003117:Color Vision Defects / Q000235:genetics* / Q000503:physiopathology; D003241:Consanguinity; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D016368:Frameshift Mutation; D060005:Genotyping Techniques; D006720:Homozygote; D006801:Humans; D057230:Limit of Detection; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010154:Pakistan; D010375:Pedigree; D010641:Phenotype; D012160:Retina / Q000503:physiopathology; D015398:Signal Transduction
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6