The KCNMA1 gene encodes the alpha subunit of the BK potassium channel. This channel, a voltage- and calcium-activated channel residing on plasma membranes, nuclear membranes, and mitochondrial membranes appears to have several functions in cellular and neuronal physiology. It’s most notable role is in the nervous system, where it plays a role in repolarization and is responsible for the afterhyperpolarization the occurs following action potentials, especially in the cerebellum.
Our group is interested in this channel because of the several types of mutations that have been reported; many result in congenital or progressive cerebellar ataxia. The mutations have been both loss of function, where they lead prominently to ataxia plus developmental delay, and gain of function, where they result predominately in epilepsy. We had the opportunity to study one of these mutations in detail that resulted in congenital and progressive ataxia with cognitive impairment and abnormal movements. With an outstanding team of scientists, we were able to show that the mutation had two effects in cells: causing an alteration in the permeability of sodium and potassium and causing a dominant-negative loss of function. The direct cellular damaged appears to be arising in the mitochondria, pointing our attention towards ionic stressors in the mitochondria as a potential common pathway of cerebellar damage.
We plan to continue this work looking at other KCNMA1 mutations and where they have their effects.
To learn more, read our PNAS publication.