Pathogenic heterozygous TRPM7 variants and hypomagnesemia with developmental delay.

Area of Science:

• Genetics
• Molecular Biology
• Neuroscience

Background:

• Transient receptor potential melastatin type 7 (TRPM7) encodes a crucial cation channel.
• Heterozygous TRPM7 variants are suspected to cause hypomagnesemia, but evidence is limited.
• The full phenotypic spectrum of TRPM7-related disorders remains unclear.

Purpose of the Study:

• To investigate the role of TRPM7 variants in hypomagnesemia.
• To identify and characterize novel TRPM7 variants.
• To expand the understanding of TRPM7-related disorders.

Main Methods:

• Whole-exome sequencing in individuals with unexplained hypomagnesemia.
• Phenotypic, functional, and in silico analyses of identified TRPM7 variants.
• In vitro assessment of TRPM7-mediated magnesium uptake.

Main Results:

• Three novel heterozygous missense TRPM7 variants (p.Met1000Thr, p.Gly1046Arg, p.Leu1081Arg) were identified in individuals with hypomagnesemia.
• Autism spectrum disorder, developmental delay (speech and motor), and seizures were observed in affected individuals.
• In vitro studies demonstrated a loss-of-function in TRPM7-mediated magnesium uptake for these variants.

Conclusions:

• Provides further evidence linking heterozygous TRPM7 variants to hypomagnesemia.
• Adds developmental delay to the phenotypic spectrum of TRPM7-related disorders.
• Suggests further research into the mechanisms by which specific TRPM7 variants cause disease.