Case Report: Lennox–Gastaut Epileptic Encephalopathy Responsive to Cannabidiol Treatment Associated With a Novel de novo Mosaic SHANK1 Variant

The SH3 and multiple ankyrin repeat domains (SHANKs) are a family of scaffolding proteins located in excitatory synapses required for their development and function. Molecular defects of SHANK3 are a well-known cause of several neurodevelopmental entities, in particular autism spectrum disorders and...

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Autores principales:	Justyna Paprocka, Szymon Ziętkiewicz, Joanna Kosińska, Ewa Kaczorowska, Rafał Płoski
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	epilepsy Lennox–Gastaut syndrome Rap1 treatment SHANK1 Genetics QH426-470
Acceso en línea:	https://doaj.org/article/75abd66cdb7046878bf295c956b98ebf
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spelling	oai:doaj.org-article:75abd66cdb7046878bf295c956b98ebf2021-12-01T13:25:31ZCase Report: Lennox–Gastaut Epileptic Encephalopathy Responsive to Cannabidiol Treatment Associated With a Novel de novo Mosaic SHANK1 Variant1664-802110.3389/fgene.2021.735292https://doaj.org/article/75abd66cdb7046878bf295c956b98ebf2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fgene.2021.735292/fullhttps://doaj.org/toc/1664-8021The SH3 and multiple ankyrin repeat domains (SHANKs) are a family of scaffolding proteins located in excitatory synapses required for their development and function. Molecular defects of SHANK3 are a well-known cause of several neurodevelopmental entities, in particular autism spectrum disorders and epilepsy, whereas relatively little is known about disease associations of SHANK1. Here, we propose a novel de novo mosaic p.(Gly126Arg) SHANK1 variant as the monogenic cause of disease in a patient who presented, from the age of 2 years, moderate intellectual disability, autism, and refractory epilepsy of the Lennox–Gastaut type. The epilepsy responded remarkably well to cannabidiol add-on therapy. In silico analyses including homology modeling and molecular dynamics simulations indicated the deleterious effect of SHANK1 p.(Gly126Arg) on the protein structure and the related function associated with protein–protein interactions. In particular, the variant was predicted to disrupt a hitherto unknown conserved region of SHANK1 protein with high homology to a recently recognized functionally relevant domain in SHANK3 implicated in ligand binding, including the “non-canonical” binding of Rap1.Justyna PaprockaSzymon ZiętkiewiczSzymon ZiętkiewiczJoanna KosińskaEwa KaczorowskaRafał PłoskiFrontiers Media S.A.articleepilepsyLennox–Gastaut syndromeRap1treatmentSHANK1GeneticsQH426-470ENFrontiers in Genetics, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	epilepsy Lennox–Gastaut syndrome Rap1 treatment SHANK1 Genetics QH426-470
spellingShingle	epilepsy Lennox–Gastaut syndrome Rap1 treatment SHANK1 Genetics QH426-470 Justyna Paprocka Szymon Ziętkiewicz Szymon Ziętkiewicz Joanna Kosińska Ewa Kaczorowska Rafał Płoski Case Report: Lennox–Gastaut Epileptic Encephalopathy Responsive to Cannabidiol Treatment Associated With a Novel de novo Mosaic SHANK1 Variant
description	The SH3 and multiple ankyrin repeat domains (SHANKs) are a family of scaffolding proteins located in excitatory synapses required for their development and function. Molecular defects of SHANK3 are a well-known cause of several neurodevelopmental entities, in particular autism spectrum disorders and epilepsy, whereas relatively little is known about disease associations of SHANK1. Here, we propose a novel de novo mosaic p.(Gly126Arg) SHANK1 variant as the monogenic cause of disease in a patient who presented, from the age of 2 years, moderate intellectual disability, autism, and refractory epilepsy of the Lennox–Gastaut type. The epilepsy responded remarkably well to cannabidiol add-on therapy. In silico analyses including homology modeling and molecular dynamics simulations indicated the deleterious effect of SHANK1 p.(Gly126Arg) on the protein structure and the related function associated with protein–protein interactions. In particular, the variant was predicted to disrupt a hitherto unknown conserved region of SHANK1 protein with high homology to a recently recognized functionally relevant domain in SHANK3 implicated in ligand binding, including the “non-canonical” binding of Rap1.
format	article
author	Justyna Paprocka Szymon Ziętkiewicz Szymon Ziętkiewicz Joanna Kosińska Ewa Kaczorowska Rafał Płoski
author_facet	Justyna Paprocka Szymon Ziętkiewicz Szymon Ziętkiewicz Joanna Kosińska Ewa Kaczorowska Rafał Płoski
author_sort	Justyna Paprocka
title	Case Report: Lennox–Gastaut Epileptic Encephalopathy Responsive to Cannabidiol Treatment Associated With a Novel de novo Mosaic SHANK1 Variant
title_short	Case Report: Lennox–Gastaut Epileptic Encephalopathy Responsive to Cannabidiol Treatment Associated With a Novel de novo Mosaic SHANK1 Variant
title_full	Case Report: Lennox–Gastaut Epileptic Encephalopathy Responsive to Cannabidiol Treatment Associated With a Novel de novo Mosaic SHANK1 Variant
title_fullStr	Case Report: Lennox–Gastaut Epileptic Encephalopathy Responsive to Cannabidiol Treatment Associated With a Novel de novo Mosaic SHANK1 Variant
title_full_unstemmed	Case Report: Lennox–Gastaut Epileptic Encephalopathy Responsive to Cannabidiol Treatment Associated With a Novel de novo Mosaic SHANK1 Variant
title_sort	case report: lennox–gastaut epileptic encephalopathy responsive to cannabidiol treatment associated with a novel de novo mosaic shank1 variant
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/75abd66cdb7046878bf295c956b98ebf
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Case Report: Lennox–Gastaut Epileptic Encephalopathy Responsive to Cannabidiol Treatment Associated With a Novel de novo Mosaic SHANK1 Variant

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