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

Kari A Mattison1,2, Gilles Tossing3, Fred Mulroe4

  • 1Genetics and Molecular Biology Graduate Program, Graduate Division of Biological and Biomedical Sciences, Laney Graduate School, Emory University, Atlanta, GA, USA.

Brain : a Journal of Neurology
|September 8, 2022
PubMed

Insights

Genetic variants in ATP6V0C cause neurodevelopmental disorders. This study identifies ATP6V0C as a crucial gene, detailing the associated clinical features and underlying disease mechanisms.

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.

Keywords:
ATP6V0CV-ATPaseVMA3epilepsy geneticsneurodevelopmental disorders

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