A Prospective Longitudinal Study of Retinal Structure and Function in Achromatopsia

Aboshiha, Jonathan; Dubis, Adam M.; Cowing, Jill A.; Fahy, Rachel T. A.; Sundaram, V.; Bainbridge, James; Ali, Robin R.; Dubra, Alfredo; Nardini, Marko; Webster, Andrew R.; Moore, Anthony T.; Rubin, Gary S.; Carroll, Joseph; Michaelides, Michel

doi:10.1167/iovs.14-14937

Cited by 78 publications

(134 citation statements)

References 41 publications

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“…Our identification of distinct pathomechanisms of ATF6 disease mutations enables prospective longitudinal study of retinal structure and phenotype to identify possible differences in achromatopsia disease phenotype and severity between carriers with different classes of ATF6 mutations. Evaluation with adaptive optics and other retinal imaging modalities may reveal cone phenotype differences corresponding to different classes of ATF6 mutations (25,26).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Several clinical studies in recent years have investigated outer retinal architecture and foveal morphology in detail using high-resolution optical coherence tomography (OCT) and adaptive optics [12,13,14,27,29,30,31,32,33,34]. The macular appearance in OCT can show either normal lamination or variable degrees of disruption of the photoreceptor layers and loss of retinal pigment epithelium.…”

Section: Clinical Manifestation and Diagnosticsmentioning

confidence: 99%

“…In recent years, several studies have investigated photoreceptor morphology in ACHM [29,30,31,32,33,34]. Carroll et al [32] observed a severely disrupted cone mosaic in the fovea and parafoveal area of a single patient with mutations in CNGB3.…”

Section: Some Inconsistencies Regarding the Progressive Nature Of Mormentioning

confidence: 99%

“…Although the retinal structure seems to show great variability and a slow progressive cone loss has been suggested [12,13,14,33,35,36,37,38,39], no clear association between retinal structure and function could be described [12]. Therefore, ACHM can be best described as a functionally stationary disorder with slow degeneration of cone photoreceptors.…”

Section: Some Inconsistencies Regarding the Progressive Nature Of Mormentioning

confidence: 99%

“…ACHM has long been considered an ideal target for gene therapy based on the observation that - in contrast to other progressive retinal dystrophies - functioning photoreceptors are expected to be largely preserved [27,28,29,30,31,32,33,34]. A further advantage is that small- (mouse) and large- (dog and sheep) animal models exist for all three major genetic forms (CNGA3, CNGB3, and GNAT2) of the disease in which this hypothesis could be tested [15,16,17,18,19].…”

Section: Therapeutic Perspectivesmentioning

confidence: 99%

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Achromatopsia: On the Doorstep of a Possible Therapy

Zobor

Zobor²,

Kohl³

2015

Ophthalmic Res

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Achromatopsia (ACHM) is a rare autosomal recessive inherited retinal disorder with an incidence of approximately 1 in 30,000. It presents at birth or early infancy and is typically characterized by reduced visual acuity, nystagmus, photophobia, and very poor or absent color vision. The symptoms arise from isolated cone dysfunction, which can be caused by mutations in the crucial components of the cone phototransduction cascade. Although ACHM is considered a functionally nonprogressive disease affecting only the cone system, recent studies have described progressive age-dependent changes in retinal architecture. Currently, no specific therapy is available for ACHM; however, gene replacement therapy performed on animal models for three ACHM genes has shown promising results. Accurate genetic and clinical diagnosis of patients may therefore enhance and enable therapeutic intervention in the near future. This short review summarizes the genetic background, pathophysiology, clinical findings, diagnostics, and therapeutic perspectives in ACHM.

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Measuring Central Retinal Sensitivity Using Microperimetry

Talib

Jolly

Boon

2017

Methods in Molecular Biology

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Microperimetry is an increasingly often used method of assessing the sensitivity of the central macula, analyzing fixation capabilities and loci, and accurately combining structural and functional information, even in the absence of stable fixation. Ongoing gene therapy trials have targeted the central retina, and utilized microperimetry as a main outcome measure for changes in retinal function. In retinal treatment planning, microperimetry has been used to assess the potential therapeutic window of opportunity. In the following pages, we briefly review the necessary steps to perform the Macular Integrity Assessment (MAIA) microperimetry.

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A Prospective Longitudinal Study of Retinal Structure and Function in Achromatopsia

Cited by 78 publications

References 41 publications

Achromatopsia mutations target sequential steps of ATF6 activation

Achromatopsia mutations target sequential steps of ATF6 activation

Achromatopsia: On the Doorstep of a Possible Therapy

Measuring Central Retinal Sensitivity Using Microperimetry

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