Pathogenic TRPM3variants are heterozygous, typically arising de novo, and affect the coding regions of the gene. Genotype–phenotype correlations are emerging, although considerable variability exists even among individuals carrying the same variant. The specific variant p.Val1002Met, affecting a residue in the fifth transmembrane domain, accounts for more than half of reported cases. Overall, variants tend to cluster within transmembrane segments and cytoplasmic domains, whereas N‑terminal variants have been associated with comparatively milder clinical presentations.
Functional studies indicate that the pathogenic TRPM3variants exert a gain‑of‑function effect, which can involve higher basal activity, increased sensitivity to agonists and heat, as well as reduced sensitivity to the inhibitory action of G-protein coupled receptors. This dysregulated channel activity leads to increased Na+ and Ca²⁺ entry, which is thought to disturb neuronal excitability and synaptic signaling, thereby lowering seizure threshold and contributing to the developmental and epileptic encephalopathy observed in many affected individuals.
Diagnostic confirmation relies on genomic testing, typically through whole exome or whole genome sequencing, with subsequent interpretation according to established variant‑classification frameworks. In research settings, electrophysiological recordings or calcium‑imaging assays may be used to validate gain‑of‑function effects at the channel level.
TRPM3