Phenotypic spectrum of the recurrent TRPM3 p.(Val837Met) substitution in seven individuals with global developmental delay and hypotonia

Abstract

TRPM3 encodes a transient receptor potential cation channel of the melastatin family, expressed in the central nervous system and in peripheral sensory neurons of the dorsal root ganglia. The recurrent substitution in TRPM3: c.2509G>A, p.(Val837Met) has been associated with syndromic intellectual disability and seizures.

Gain-of-function variants in the ion channel gene TRPM3 underlie a spectrum of neurodevelopmental disorders

“…We propose to use the latter transcript as the reference for variant numbering, as it represents the longest functional splice variant that includes all exons that are frequently used in human brain tissue and covers all human disease-associated TRPM3 variants. For instance, according to this nomenclature, the recurrent variant initially indicated as p.Val837Met ( de Sainte Agathe et al, 2020 ; Dyment et al, 2019 ; Gauthier et al, 2021 ; Lines et al, 2022 ) will be named p.Val1002Met.…”

“…It functions as a heat- and neurosteroid-activated channel in peripheral sensory neurons of the trigeminal and dorsal root ganglia ( Vangeel et al, 2020 ) but is also expressed in other tissues, including the CNS ( Figure 5—figure supplement 1 ). Recently, three de novo variants in the TRPM3 gene were identified in patients with DEE ( de Sainte Agathe et al, 2020 ; Dyment et al, 2019 ; Gauthier et al, 2021 ; Kang et al, 2021 ; Lines et al, 2022 ). The 16 patients heterozygous for the common recurrent variant (V1002M), share a number of clinical features including GDD, moderate to severe ID, with or without childhood-onset epilepsy ( Lines et al, 2022 ).…”

“…Recently, three de novo variants in the TRPM3 gene were identified in patients with DEE ( de Sainte Agathe et al, 2020 ; Dyment et al, 2019 ; Gauthier et al, 2021 ; Kang et al, 2021 ; Lines et al, 2022 ). The 16 patients heterozygous for the common recurrent variant (V1002M), share a number of clinical features including GDD, moderate to severe ID, with or without childhood-onset epilepsy ( Lines et al, 2022 ).…”

“…The human TRPM3 gene contains 28 exons, and alternative splicing of the primary transcripts gives rise to a large number of splice isoforms, leading to ambiguity in the numbering of gene variants. Most of the previous reports based the numbering of disease-associated variants on the NM_020952.4 reference sequence ( de Sainte Agathe et al, 2020 ; Dyment et al, 2019 ; Gauthier et al, 2021 ; Lines et al, 2022 ), including the Human Gene Mutation Database ( Stenson et al, 2017 ) and OMIM ( https://www.omim.org/ ), whereas NM_001007471.2 was used as reference by others ( Van Hoeymissen et al, 2020 ; Zhao et al, 2020 ). In this report, we based the numbering of the TRPM3 variants on the Mane transcript NM_001366145.2 sequence (see explanation in the section ‘Organization of the human TRPM3 gene and alternative splicing in the cerebellum’ in Results).…”

“…Rare de novo nonsynonymous coding variants in neuronally expressed genes are frequent causes of global developmental delay (GDD) and intellectual disability (ID) ( Rauch et al, 2012 ). Recently, de novo variants in TRPM3 were reported in patients with developmental and epileptic encephalopathy (DEE), including 16 patients with the recurrent missense variant p.Val1002Met and two additional patients with the variants p.Pro1102Gln and p.Ser1367Thr, respectively ( de Sainte Agathe et al, 2020 ; Dyment et al, 2019 ; Gauthier et al, 2021 ; Kang et al, 2021 ; Lines et al, 2022 ; see results and Figure 1 for further discussion and details on numbering of TRPM3 variants). These patients consistently present with moderate-to-severe GDD and ID, variably associated with other clinical features such as childhood-onset epilepsy, hypotonia, altered heat, and/or pain sensitivity and variable facial dysmorphism.…”