Apr 3, 2020

Gain of channel function and modified gating properties in TRPM3 mutants causing intellectual disability and epilepsy

BioRxiv : the Preprint Server for Biology
E. Van HoeymissenJoris Vriens

Abstract

Developmental and epileptic encephalopathies (DEE) are a heterogeneous group of disorders characterized by epilepsy with comorbid intellectual disability. Recently, two 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 pregnenolone sulphate (PS) and heat, and altered response to ligand modulation. Most strikingly, V990M mutation affected the gating of the non-canonical pore of TRPM3, resulting in large inward 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.

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Mentioned in this Paper

Genome-Wide Association Study
Study
Classification
DNA Probes
Genes
DNA, Ribosomal
Nucleic Acid Sequencing
Evaluation
Recombinant DNA
Sequencing

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