Pathogenic heterozygous TRPM7 variants and hypomagnesemia with developmental delay

This collection contains the data for the study "Pathogenic heterozygous TRPM7 variants and hypomagnesemia with developmental delay", which was published as part of a thesis and in Clinical Kidney Journal (PMID: 39099563).

Heterozygous variants in TRPM7, encoding an essential and ubiquitously expressed cation channel, may cause hypomagnesemia, but current evidence is insufficient to draw definite conclusions and it is unclear whether any other phenotypes can occur. Therefore, whole exome sequencing was employed in individuals with unexplained hypomagnesemia to identify additional TRPM7 variants. Pathogenicity of the identified variants was assessed by combining phenotypic, functional and in silico analyses. We report three new heterozygous missense variants in TRPM7 (p.Met1000Thr, p.Gly1046Arg, p.Leu1081Arg) in individuals with hypomagnesemia. Strikingly, autism spectrum disorder and developmental delay, mainly affecting speech and motor skills, was observed in all three individuals, while two out of three also presented with seizures. The three variants are predicted to be severely damaging by in silico prediction tools and structural modeling. Furthermore, these variants result in a clear loss-of-function of TRPM7-mediated magnesium uptake in vitro, while not affecting TRPM7 expression or insertion into the plasma membrane. In conclusion, this study provides additional evidence for the association between heterozygous TRPM7 variants and hypomagnesemia and adds developmental delay to the phenotypic spectrum of TRPM7-related disorders.

In this collection, you can find the data supporting the loss-of-function of the three variants, which was shown using a magnesium transport assay. In addition, you can find the data showing the (cell membrane) expression of the variants, which was obtained using Western blot and biotinylation assays.