Abstrakt
Calcium channelopathies are a group of human diseases resulting from the dysfunction of calcium channels or their regulatory subunits and are caused by either genetic or acquired factors. Hence, many pathogenic mutations in genes encoding voltage-gated calcium channels (VGCCs) are linked to a large spectrum of neurological, cardiac, and metabolic disorders [5, 7].
Of the 10 mammalian VGCCs, the Cav1.3 channel is abundantly expressed in neuroendocrine cells including pancreatic β and adrenal chromaffin cells, but is also found in brain, retina, ovaries, cochlear hair cells of the ear, and in cardiac atrial myocytes. It is involved in diverse physiological functions such as neurotransmitter and hormone release, synaptic plasticity, and control of cardiac rhythm and atrioventricular node conductance [10].
Over the recent years, thank to next-generation sequencing approaches, numerous CACNA1D variants have been identified and are associated with an increase in allelic burden in neurological and neuroendocrine disorders. Importantly, a number of rare de novo disease-causing variants were identified [3].
These variants are localized in the cytoplasmic ends of the first and second S6 segments of Cav1.3 which form the activation and inactivation gate and cause alterations in the gating properties that are in general consistent with a gain-of-function (GoF) of the channel.