Muscarinic Acetylcholine Receptor M1 mutation causing developmental and
epileptic encephalopathy
Abstract
Developmental and epileptic encephalopathies are a group of devastating
disorders where an underlying, usually genetic, cause leads to brain
developmental impairment which can be further aggravated by
superimposed, abundant epileptiform activity. Compared to other
epilepsies, DEE show much greater locus heterogeneity and de novo rare
damaging variants in genes involved in critical developmental pathways,
notably regulation of synaptic transmission, have emerged as a frequent
cause. Here, in a young girl with early-onset refractory epilepsy,
severe disability and progressive cerebral and cerebellar atrophy,
trio-based whole exome sequencing analysis uncovered a de novo missense
variant in CHRM1. No additional CHRM1 variants were found by WES
reanalysis in a cohort of 102 patients with EIEE/DEE nor any matches
were produced upon sharing the novel variants in the Matchmaker Exchange
platform. Biochemical analyses proved that this variant caused a
reduction in protein levels and an impaired cellular trafficking. In
addition, the mutated receptor showed defective activation of
intracellular signalling pathways. Our data strengthen the concept that
brain reduced muscarinic signalling lowers seizure threshold and
severely impairs neurodevelopment.