Muscarinic acetylcholine receptor M1 mutations causing neurodevelopmental disorder and epilepsy

Abstract

Encefalopatia epilèptica; Receptor muscarínic; Seqüenciació de l'exoma complet

Encefalopatía epiléptica; Receptor muscarínico; Secuenciación del exoma completo

Epileptic encephalopathy; Muscarinic receptor; Whole-exome sequencing

De novo rare damaging variants in genes involved in critical developmental pathways, notably regulation of synaptic transmission, have emerged as a frequent cause of neurodevelopmental disorders (NDD). NDD show great locus heterogeneity and for many of the associated genes, there is substantial phenotypic diversity, including epilepsy, intellectual disability, autism spectrum disorder, movement disorders, and combinations thereof. We report two unrelated patients, a young girl with early-onset refractory epilepsy, severe disability, and progressive cerebral and cerebellar atrophy, and a second girl with mild dysmorphism, global developmental delay, and moderate intellectual disability in whom trio-based whole-exome sequencing analysis uncovered de novo missense variants in CHRM1. Biochemical analyses of one of the NDD-associated variants proved that it caused a reduction in protein levels and impaired cellular trafficking. In addition, the mutated receptor showed defective activation of intracellular signaling pathways. Our data strengthen the concept that brain-reduced muscarinic signaling lowers the seizure threshold and severely impairs neurodevelopment.

Anna Marcé-Grau received a predoctoral scholarship from Vall d'Hebron Research Institute, Barcelona, Spain. Work funded by grant PI15/01791 to Alfons Macaya from Instituto Carlos III, Spain. This study was also supported by RTI2018-093493-B-I00 to Raúl Estévez. Raúl Estévez is a recipient of an ICREA Academia Prize.