Mutation of ATF6 causes autosomal recessive achromatopsia
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- 作者：Muhammad Ansar ; Regie Lyn P. Santos-Cortez ; Muhammad Arif Nadeem Saqib…
- 刊名：Human Genetics
- 出版年：2015
- 出版时间：September 2015
- 年：2015
- 卷：134
- 期：9
- 页码：941-950
- 全文大小：1,072 KB
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Matise TC, Chen F, Chen W, De La Vega FM, Hansen M, He C, Hyland FC, Kennedy GC, Kong X, - 作者单位：Muhammad Ansar (1) (2)
Regie Lyn P. Santos-Cortez (1)
Muhammad Arif Nadeem Saqib (2)
Fareeha Zulfiqar (3)
Kwanghyuk Lee (1)
Naeem Mahmood Ashraf (2)
Ehsan Ullah (2)
Xin Wang (1)
Sundus Sajid (2)
Falak Sher Khan (2)
Muhammad Amin-ud-Din (4)
Joshua D. Smith (5)
Jay Shendure (5)
Michael J. Bamshad (5)
Deborah A. Nickerson (5)
Abdul Hameed (6)
Saima Riazuddin (3)
Zubair M. Ahmed (3)
Wasim Ahmad (2)
Suzanne M. Leal (1)
University of Washington Center for Mendelian Genomics
1. Department of Molecular and Human Genetics, Center for Statistical Genetics, Baylor College of Medicine, 1 Baylor Plaza 700D, Houston, TX, 77030, USA
2. Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, 45320, Pakistan
3. Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD, 21203, USA
4. University of Education, Dera Ghazi Khan Campus, Lahore, 32200, Pakistan
5. Department of Genome Sciences, University of Washington, Seattle, WA, 98195, USA
6. Institute of Biomedical and Genetic Engineering, Islamabad, 44000, Pakistan - 刊物类别：Biomedical and Life Sciences
- 刊物主题：Biomedicine
Human Genetics
Molecular Medicine
Internal Medicine
Metabolic Diseases - 出版者：Springer Berlin / Heidelberg
- ISSN：1432-1203
文摘
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.