De novo substitutions of TRPM3 cause intellectual disability and epilepsy

Abstract

The developmental and epileptic encephalopathies (DEE) are a heterogeneous group of chronic encephalopathies frequently associated with rare de novo nonsynonymous coding variants in neuronally expressed genes. Here, we describe eight probands with a DEE phenotype comprising intellectual disability, epilepsy, and hypotonia. Exome trio analysis showed de novo variants in TRPM3, encoding a brain-expressed transient receptor potential channel, in each. Seven probands were identically heterozygous for a recurrent substitution, p.(Val837Met), in TRPM3's S4-S5 linker region, a conserved domain proposed to undergo conformational change during gated channel opening. The eighth individual was heterozygous for a proline substitution, p.(Pro937Gln), at the boundary between TRPM3's flexible pore-forming loop and an adjacent alpha-helix. General-population truncating variants and microdeletions occur throughout TRPM3, suggesting a pathomechanism other than simple haploinsufficiency. We conclude that de novo variants in TRPM3 are a cause of intellectual disability and epilepsy.

Fig. 1

Craniofacial morphology. a Individual 1, (p.Val837Met), age 12.5 years. b Individual 2, (p.Val837Met), age 4.5 years. c Individual 8, (p.Pro937Gln), age 10.8 years

Fig. 2

Predicted effects of TRPM3 substitutions. a Val837 and Pro937 are highly conserved. b Val837 and Pro937 are conserved across multiple TRP(melastatin) subfamily paralogues. c Structural model of residues 340–1098 of TRPM3 (NP_066003.3), based on TRPM7 (PDB:6bwd) (ref. [13]). The modeled portion of TRPM3 is 63% identical to the corresponding TRPM7 peptide sequence. Four monomers are radially arranged around a central channel pore. Distinct structural domains are formed by transmembrane helices S1–S4 (voltage-sensing domain), and helices S5–S6 (pore-forming domain). The selectivity filter is formed by a short “pore helix” situated in the S5–S6 loop. The TRP domain, a horizontal alpha-helix at the position indicated, is proposed to couple the movements of the voltage-sensing and pore-forming domains (ref. [13]). d Overview of the model showing positions of substituted positions Val837 and Pro937. Val837 resides in the S4, S5 linker region, where it is predicted to form a hydrogen bond with Arg978 (TRP domain) and two Van der Waals contacts with Phe720 (helix S1). Arg978 is essential for channel function in TRPM6, and is proposed to make additional intra- and inter-helical contacts as shown (ref. [15]). The Met837-substituted model (not shown) adopts a similar conformation but is capable of making only a single Van der Waals contact with Phe720. Pro937 is situated in the pore-forming domain, at the transition point between helix S5 and the pore-forming S5–S6 loop. In the Gln937-substituted model (not shown), helix S6 extends two residues (one half-turn) further into the S5–S6 pore-forming loop