期刊
EPILEPSIA
卷 63, 期 10, 页码 2519-2533出版社
WILEY
DOI: 10.1111/epi.17336
关键词
channelopathy; developmental and epileptic encephalopathy; GABA A receptor; genetic generalized epilepsy
资金
- Jed Foundation
This study describes the phenotypes associated with GABA(A)-receptor subunit variants and investigates potential genotype-phenotype correlations. The results show that despite the similarities in molecular structure and physiological role, GABA(A)-receptor subunit variants are associated with highly variable phenotypes. Furthermore, the location of the variant on the protein may be a marker of severity.
Objective: gamma-Aminobutyric acid (GABA)(A)-receptor subunit variants have recently been associated with neurodevelopmental disorders and/or epilepsy. The phenotype linked with each gene is becoming better known. Because of the common molecular structure and physiological role of these phenotypes, it seemed interesting to describe a putative phenotype associated with GABA(A)-receptor-related disorders as a whole and seek possible genotype-phenotype correlations. Methods: We collected clinical, electrophysiological, therapeutic, and molecular data from patients with GABA(A)-receptor subunit variants (GABRA1, GABRB2, GABRB3, and GABRG2) through a national French collaboration using the EPIGENE network and compared these data to the one already described in the literature. Results: We gathered the reported patients in three epileptic phenotypes: 15 patients with fever-related epilepsy (40%), 11 with early developmental epileptic encephalopathy (30%), 10 with generalized epilepsy spectrum (27%), and 1 patient without seizures (3%). We did not find a specific phenotype for any gene, but we showed that the location of variants on the transmembrane (TM) segment was associated with a more severe phenotype, irrespective of the GABA(A)-receptor subunit gene, whereas N-terminal variants seemed to be related to milder phenotypes. Significance: GABA(A)-receptor subunit variants are associated with highly variable phenotypes despite their molecular and physiological proximity. None of the genes described here was associated with a specific phenotype. On the other hand, it appears that the location of the variant on the protein may be a marker of severity. Variant location may have important weight in the development of targeted therapeutics.
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