Achromatopsia mutations target sequential steps of ATF6 activation.

Area of Science:

• Genetics
• Molecular Biology
• Ophthalmology

Background:

• Achromatopsia is an inherited retinal disorder causing cone photoreceptor dysfunction.
• Activating transcription factor 6 (ATF6) is crucial for the unfolded protein response (UPR) and endoplasmic reticulum (ER) stress management.
• ATF6 mutations have been identified as a cause of achromatopsia.

Purpose of the Study:

• To comprehensively analyze the functional consequences of achromatopsia-associated ATF6 mutations.
• To classify these mutations based on their impact on ATF6 activation pathways.
• To elucidate the molecular mechanisms linking ATF6 dysfunction to achromatopsia pathology.

Main Methods:

• Functional analysis of ATF6 mutations in patient-derived cells (fibroblasts).
• Assessment of ER-to-Golgi trafficking, regulated intramembrane proteolysis, and transcriptional activity of ATF6 mutants.
• Evaluation of cellular response to ER stress in cells with ATF6 mutations.

Main Results:

• ATF6 mutations causing achromatopsia were categorized into three distinct pathomechanisms affecting ATF6 function.
• Class 1 mutants exhibited impaired trafficking and proteolysis; Class 2 showed constitutive activity; Class 3 had defective transcriptional domains.
• Cells with Class 1 or Class 3 ATF6 mutations displayed increased susceptibility to ER stress-induced cell death.

Conclusions:

• Human ATF6 mutations disrupt specific steps in the ATF6 activation pathway.
• Dysfunctional ATF6 and heightened ER stress sensitivity during retinal development contribute to achromatopsia.
• Understanding these mechanisms may offer therapeutic targets for achromatopsia.