Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia.
Susanne KohlDitta ZoborWei-Chieh ChiangNicole WeisschuhJennifer StallerIrene Gonzalez MenendezStanley ChangSusanne C BeckMarina Garcia GarridoVithiyanjali SothilingamMathias W SeeligerFranco StanzialFrancesco BenedicentiFrancesca InzanaElise HéonAjoy VincentJill BeisTim M StromGünther RudolphSusanne RoosingAnneke I den HollanderFrans P M CremersIrma LopezHuanan RenAnthony T MooreAndrew R WebsterMichel MichaelidesRobert K KoenekoopEberhart ZrennerRandal J KaufmanStephen H TsangBernd WissingerJonathan H LinPublished in: Nature genetics (2015)
Achromatopsia (ACHM) is an autosomal recessive disorder characterized by color blindness, photophobia, nystagmus and severely reduced visual acuity. Using homozygosity mapping and whole-exome and candidate gene sequencing, we identified ten families carrying six homozygous and two compound-heterozygous mutations in the ATF6 gene (encoding activating transcription factor 6A), a key regulator of the unfolded protein response (UPR) and cellular endoplasmic reticulum (ER) homeostasis. Patients had evidence of foveal hypoplasia and disruption of the cone photoreceptor layer. The ACHM-associated ATF6 mutations attenuate ATF6 transcriptional activity in response to ER stress. Atf6(-/-) mice have normal retinal morphology and function at a young age but develop rod and cone dysfunction with increasing age. This new ACHM-related gene suggests a crucial and unexpected role for ATF6A in human foveal development and cone function and adds to the list of genes that, despite ubiquitous expression, when mutated can result in an isolated retinal photoreceptor phenotype.
Keyphrases
- transcription factor
- genome wide identification
- endoplasmic reticulum
- endoplasmic reticulum stress
- optical coherence tomography
- copy number
- genome wide
- dna binding
- diabetic retinopathy
- end stage renal disease
- newly diagnosed
- protein protein
- endothelial cells
- signaling pathway
- oxidative stress
- ejection fraction
- binding protein
- poor prognosis
- prognostic factors
- high resolution
- early onset
- chronic kidney disease
- single cell
- genome wide analysis
- dna methylation
- gene expression
- optic nerve
- intellectual disability
- patient reported outcomes
- autism spectrum disorder
- small molecule
- mass spectrometry
- high fat diet induced
- duchenne muscular dystrophy