ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy.

Area of Science:

• Molecular Biology
• Genetics
• Neuroscience

Background:

• The vacuolar H+-ATPase (V-ATPase) complex acidifies organelles, crucial for cellular functions.
• V-ATPases utilize ATP hydrolysis to pump protons, maintaining pH gradients essential for membrane trafficking.

Purpose of the Study:

• To investigate the role of ATP6V0C, encoding the V-ATPase c-subunit, in neurodevelopmental disorders.
• To characterize the clinical phenotype and molecular mechanisms associated with ATP6V0C variants.

Main Methods:

• Analysis of heterozygous point variants in ATP6V0C in 27 patients with neurodevelopmental abnormalities.
• In silico modeling to predict the impact of variants on V-ATPase function.
• Functional studies in Saccharomyces cerevisiae, Drosophila, and Caenorhabditis elegans.

Main Results:

• Identified 27 patients with ATP6V0C variants presenting with neurodevelopmental abnormalities, epilepsy, corpus callosum hypoplasia, and cardiac defects.
• In silico modeling suggested patient variants disrupt ATP6V0C-ATP6V0A subunit interactions.
• Functional assays demonstrated reduced V-ATPase activity, impaired growth, increased seizure duration, motor dysfunction, and reduced lifespan in model organisms.

Conclusions:

• ATP6V0C is established as a significant disease gene for neurodevelopmental disorders.
• The study elucidates the clinical spectrum and provides mechanistic insights into V-ATPase dysfunction-related diseases.