1. De novo substitutions of TRPM3 cause intellectual disability and epilepsy
- Author
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Kristian Tveten, Sara Ellingwood, Paulien A. Terhal, Kirsty McWalter, Christopher C. Griffith, Marwan Shinawi, Koen L.I. van Gassen, A. Micheil Innes, Rosemarie Smith, Cecilie F. Rustad, David A. Dyment, Matthew A. Lines, and Parul Jayakar
- Subjects
Male ,Models, Molecular ,Nonsynonymous substitution ,Proband ,Adolescent ,Protein Conformation ,TRPM Cation Channels ,Biology ,Brief Communication ,Severity of Illness Index ,03 medical and health sciences ,Epilepsy ,Intellectual Disability ,Intellectual disability ,Genetics ,medicine ,Humans ,Genetics(clinical) ,Allele ,Child ,Exome ,Alleles ,Genetic Association Studies ,Genetics (clinical) ,0303 health sciences ,Medical genetics ,030305 genetics & heredity ,Facies ,medicine.disease ,Hypotonia ,Phenotype ,Child, Preschool ,Mutation ,Female ,medicine.symptom ,Haploinsufficiency - 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.
- Published
- 2019
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