Deciphering pathogenic mechanisms underlying human calcium channelopathies

Abstract

International audienceThese last years, our group has characterized several calcium channel mutations linked to neurological diseases. We have investigated the pathogenic mechanisms underlying channelopathies, especially for mutations in T-type/Cav3 genes recently discovered. Importantly, such studies provide in turn new clues to identify how these channels are activated, regulated, and how they contribute to physiology. Of note, some of these mutations lead to gain of channel activity, especially Cav3.2 mutations linked to Primary Aldosteronism (Daniil et al 2016, EBioMedicine. 13:225-236). Other mutations, i.e. mutations in the Cav3.1 subunit, are associated to new forms of cerebellar dysfunction, including Autosomal-Dominant Cerebellar Ataxia (Coutelier et al 2015, Am J Hum Genet. 97(5):726-37). Recently, we have also described gain of function mutations in the Cav3.1 subunit. These mutations are linked to Childhood-onset cerebellar atrophy (ChCA), a neurodevelopmental condition associated with cerebellar ataxia and defect in cognitive development (Chemin et al 2018, Brain. 141(7):1998-2013). These mutations markedly impair T-type channel inactivation and promote a larger window current fully inhibited by TTA-P2, a selective T-type channel blocker. These findings reveal that aberrant increased activity of Cav3.1 channels could markedly alter CNS development and suggest that such condition is amenable to treatment