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.

A Novel Loss-of-Function SEMA3E Mutation in a Patient with Severe Intellectual Disability and Cognitive Regression / A.J.J. Paganoni, F. Amoruso, J. Porta Pelayo, B. Calleja-Pérez, V. Vezzoli, P. Duminuco, A. Caramello, R. Oleari, A. Fernández-Jaén, A.M. Cariboni. - In: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - ISSN 1422-0067. - 23:10(2022 May 18), pp. 5632.1-5632.16. [10.3390/ijms23105632]

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

F. Amoruso
Secondo
;
R. Oleari;A.M. Cariboni
2022

Abstract

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.
cognitive regression; intellectual disability; neurodevelopmental disorder; semaphorin 3E; Animals; Cognition; Humans; Mice; Mutation; Signal Transduction; Intellectual Disability; Semaphorins;
Settore BIO/13 - Biologia Applicata
DECC18ACORS_01 - Dipartimenti di Eccellenza 2018-2022 - Dipartimento di SCIENZE FARMACOLOGICHE E BIOMOLECOLARI - CORSINI, ALBERTO - DECC - Bando Dipartimenti di Eccellenza - 2018
PSRL222MDILU_01 - Piano di Sostegno alla Ricerca 2015-2017 - Linea 2 "Dotazione annuale per attività istituzionali" (anno 2021) - DILUCA, MONICA MARIA GRAZIA - PSR_LINEA2_ / Piano di sviluppo di ricerca - Dotazioni dipartimentali - Linea 2 - 2022
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/940574
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