TY - JOUR TI - Gain of channel function and modified gating properties in TRPM3 mutants causing intellectual disability and epilepsy AU - Van Hoeymissen, Evelien AU - Held, Katharina AU - Nogueira Freitas, Ana Cristina AU - Janssens, Annelies AU - Voets, Thomas AU - Vriens, Joris A2 - Islas, Leon D A2 - Swartz, Kenton J A2 - Islas, Leon D A2 - Xu, Haoxing VL - 9 PY - 2020 DA - 2020/05/19 SP - e57190 C1 - eLife 2020;9:e57190 DO - 10.7554/eLife.57190 UR - https://doi.org/10.7554/eLife.57190 AB - Developmental and epileptic encephalopathies (DEE) are a heterogeneous group of disorders characterized by epilepsy with comorbid intellectual disability. Recently, two de novo heterozygous mutations in the gene encoding TRPM3, a calcium permeable ion channel, were identified as the cause of DEE in eight probands, but the functional consequences of the mutations remained elusive. Here we demonstrate that both mutations (V990M and P1090Q) have distinct effects on TRPM3 gating, including increased basal activity, higher sensitivity to stimulation by the endogenous neurosteroid pregnenolone sulfate (PS) and heat, and altered response to ligand modulation. Most strikingly, the V990M mutation affected the gating of the non-canonical pore of TRPM3, resulting in large inward cation currents via the voltage sensor domain in response to PS stimulation. Taken together, these data indicate that the two DEE mutations in TRPM3 result in a profound gain of channel function, which may lie at the basis of epileptic activity and neurodevelopmental symptoms in the patients. KW - trp channel KW - TRPM3 KW - developmental and epileptic encephalopathies JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -