2026-04-13T01:56:24Zhttps://recercat.cat/oai/request

oai:recercat.cat:11351/69252025-11-08T16:00:26Zcom_2072_378071com_2072_378040col_2072_378097

00925njm 22002777a 4500 dc Marcé Grau, Anna author Elorza‐Vidal, Xabier author Pérez‐Rius, Carla author Ruiz‐Nel·lo, Anna author Sala Coromina, Julia author Gabau, Elisabeth author Macaya Ruíz, Alfons author 2022-01-28T07:44:09Z 2022-01-28T07:44:09Z 2021-10 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. Neurologia pediàtrica - Malalties Genètica del desenvolupament Seqüència de nucleòtids PSYCHIATRY AND PSYCHOLOGY::Mental Disorders::Neurodevelopmental Disorders Other subheadings::Other subheadings::Other subheadings::/genetics ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT::Investigative Techniques::Genetic Techniques::Sequence Analysis::Sequence Analysis, DNA::DNA Mutational Analysis PSIQUIATRÍA Y PSICOLOGÍA::trastornos mentales::trastornos del desarrollo neurológico Otros calificadores::Otros calificadores::Otros calificadores::/genética TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS::técnicas de investigación::técnicas genéticas::análisis de secuencias::análisis de secuencias de ADN::análisis de mutaciones del ADN Muscarinic acetylcholine receptor M1 mutations causing neurodevelopmental disorder and epilepsy