<i>ATF6</i>Is Mutated in Early Onset Photoreceptor Degeneration With Macular Involvement

Xu, Min; Gelowani, Violet; Eblimit, Aiden; Wang, Feng; Young, Marielle P.; Sawyer, Briana L.; Zhao, Li; Jenkins, Glen; Creel, Donnell J.; Wang, Keqing; Ge, Zhongqi; Wang, Hui; Li, Yumei; Hartnett, M. Elizabeth; Chen, Rui

doi:10.1167/iovs.15-16778

Cited by 53 publications

(56 citation statements)

References 25 publications

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“…Since LCA and RP are rare Mendelian disorders, variants with a frequency higher than 1/200 (for a recessive model) or 1/1000 (for a dominant model) were filtered out. After frequency-based filtering, we filtered out synonymous variants, identified known retinal disease-causing variants and predicted the pathogenicity of variants using SIFT (Ng and Henikoff 2003), Polyphen2 (Adzhubei et al 2010), LRT (Chun and Fay 2009), MutationTaster (Schwarz et al 2010), MutationAssessor (Reva et al 2011) as previously described (Wang et al 2014; Xu et al 2015). …”

Section: Methodsmentioning

confidence: 99%

Mutations in human IFT140 cause non-syndromic retinal degeneration

Yang

Wang

et al. 2015

Hum Genet

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Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP) are two genetically heterogeneous retinal degenerative disorders. Despite the identification of a number of genes involved in LCA and RP, the genetic etiology remains unknown in many patients. In this study, we aimed to identify novel disease-causing genes of LCA and RP. Retinal capture sequencing was initially performed to screen mutations in known disease-causing genes in different cohorts of LCA and RP patients. For patients with negative results, we performed whole exome sequencing and applied a series of variant filtering strategies. Sanger sequencing was done to validate candidate causative IFT140 variants. Exome sequencing data analysis led to the identification of IFT140 variants in multiple unrelated non-syndromic LCA and RP cases. All the variants are extremely rare and predicted to be damaging. All the variants passed Sanger validation and segregation tests provided that the family members’ DNA was available. The results expand the phenotype spectrum of IFT140 mutations to non-syndromic retinal degeneration, thus extending our understanding of intraflagellar transport and primary cilia biology in the retina. This work also improves the molecular diagnosis of retinal degenerative disease.

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Section: Methodsmentioning

confidence: 99%

Mutations in human IFT140 cause non-syndromic retinal degeneration

Yang

Wang

et al. 2015

Hum Genet

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“…Pre-capture Illumina libraries were generated as in previous literature. [21][22][23] The targeted DNA was captured, washed, and recovered using Agilent Hybridization and Wash Kits (Agilent Technologies). WES was performed by capturing the DNA with the NimbleGenSeqCap EZ Hybridization and Wash kit.…”

Section: Whole-exome Sequencing and Bioinformatic Analysismentioning

confidence: 99%

Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies

Xie

Abouzeid

et al. 2017

The American Journal of Human Genetics

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Pre-mRNA splicing factors play a fundamental role in regulating transcript diversity both temporally and spatially. Genetic defects in several spliceosome components have been linked to a set of non-overlapping spliceosomopathy phenotypes in humans, among which skeletal developmental defects and non-syndromic retinitis pigmentosa (RP) are frequent findings. Here we report that defects in spliceosome-associated protein CWC27 are associated with a spectrum of disease phenotypes ranging from isolated RP to severe syndromic forms. By whole-exome sequencing, recessive protein-truncating mutations in CWC27 were found in seven unrelated families that show a range of clinical phenotypes, including retinal degeneration, brachydactyly, craniofacial abnormalities, short stature, and neurological defects. Remarkably, variable expressivity of the human phenotype can be recapitulated in Cwc27 mutant mouse models, with significant embryonic lethality and severe phenotypes in the complete knockout mice while mice with a partial loss-of-function allele mimic the isolated retinal degeneration phenotype. Our study describes a retinal dystrophy-related phenotype spectrum as well as its genetic etiology and highlights the complexity of the spliceosomal gene network.

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“…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).…”

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confidence: 99%

Achromatopsia mutations target sequential steps of ATF6 activation

Chiang

Chan

Wissinger

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Achromatopsia is an autosomal recessive disorder characterized by cone photoreceptor dysfunction. We recently identified activating transcription factor 6 (ATF6) as a genetic cause of achromatopsia. ATF6 is a key regulator of the unfolded protein response. In response to endoplasmic reticulum (ER) stress, ATF6 migrates from the ER to Golgi to undergo regulated intramembrane proteolysis to release a cytosolic domain containing a basic leucine zipper (bZIP) transcriptional activator. The cleaved ATF6 fragment migrates to the nucleus to transcriptionally up-regulate protein-folding enzymes and chaperones. ATF6 mutations in patients with achromatopsia include missense, nonsense, splice site, and single-nucleotide deletion or duplication changes found across the entire gene. Here, we comprehensively tested the function of achromatopsia-associated ATF6 mutations and found that they group into three distinct molecular pathomechanisms: class 1 ATF6 mutants show impaired ER-to-Golgi trafficking and diminished regulated intramembrane proteolysis and transcriptional activity; class 2 ATF6 mutants bear the entire ATF6 cytosolic domain with fully intact transcriptional activity and constitutive induction of downstream target genes, even in the absence of ER stress; and class 3 ATF6 mutants have complete loss of transcriptional activity because of absent or defective bZIP domains. Primary fibroblasts from patients with class 1 or class 3 ATF6 mutations show increased cell death in response to ER stress. Our findings reveal that human ATF6 mutations interrupt distinct sequential steps of the ATF6 activation mechanism. We suggest that increased susceptibility to ER stress-induced damage during retinal development underlies the pathology of achromatopsia in patients with ATF6 mutations.cone photoreceptor | achromatopsia | endoplasmic reticulum stress | ATF6 | unfolded protein response A chromatopsia is a heritable blinding disease caused by cone photoreceptor dysfunction that spares the rod system. 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 (1-3). 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). However, the functional consequences of the other ATF6 mutations found in patients with achromatopsia remain unknown.In humans, ATF6 is a 670-amino acid glycosylated transmembrane protein found in the endoplasmic reticulum (ER) (4). In response to protein misfolding in the ER or other forms of ER stress, ATF6 migrates from the ER to the Golgi apparatus, where the site 1 protease (S1P) and site 2 protease (S2P) cleave ATF6 in the transmembrane domain to liberate the cyt...

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ATF6Is Mutated in Early Onset Photoreceptor Degeneration With Macular Involvement

Abstract: Our results support ATF6 as a novel disease-causing gene for PRD and suggest that disrupted protein quality control mechanisms may be a novel pathological mechanism underlying human retinal degeneration.

Cited by 53 publications

References 25 publications

Mutations in human IFT140 cause non-syndromic retinal degeneration

Mutations in human IFT140 cause non-syndromic retinal degeneration

Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies

Achromatopsia mutations target sequential steps of ATF6 activation

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