A Novel Loss-of-Function SEMA3E Mutation in a Patient with Severe Intellectual Disability and Cognitive Regression

Autor: Cariboni, Alyssa J. J. Paganoni, Federica Amoruso, Javier Porta Pelayo, Beatriz Calleja-Pérez, Valeria Vezzoli, Paolo Duminuco, Alessia Caramello, Roberto Oleari, Alberto Fernández-Jaén, Anna
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: International Journal of Molecular Sciences; Volume 23; Issue 10; Pages: 5632
ISSN: 1422-0067
DOI: 10.3390/ijms23105632
Popis: Intellectual disability (ID) is a neurological disorder arising from early neurodevelopmental defects. The underlying genetic and molecular mechanisms are complex, but are thought to involve, among others, alterations in genes implicated in axon guidance and/or neural circuit formation as demonstrated by studies on mouse models. Here, by combining exome sequencing with in silico analyses, we identified a patient affected by severe ID and cognitive regression, carrying a novel loss-of-function variant in the semaphorin 3E (SEMA3E) gene, which encodes for a key secreted cue that controls mouse brain development. By performing ad hoc in vitro and ex vivo experiments, we found that the identified variant impairs protein secretion and hampers the binding to both embryonic mouse neuronal cells and tissues. Further, we revealed SEMA3E expression during human brain development. Overall, our findings demonstrate the pathogenic impact of the identified SEMA3E variant and provide evidence that clinical neurological features of the patient might be due to a defective SEMA3E signaling in the brain.
Databáze: OpenAIRE
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