Second‐hit DEPDC5 mutation is limited to dysmorphic neurons in cortical dysplasia type IIA
Abstract Focal cortical dysplasia (FCD) causes drug‐resistant epilepsy and is associated with pathogenic variants in mTOR pathway genes. How germline variants cause these focal lesions is unclear, however a germline + somatic “2‐hit” model is hypothesized. In a boy with drug‐resistant epilepsy, FCD,...
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2019-07-01
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Series: | Annals of Clinical and Translational Neurology |
Online Access: | https://doi.org/10.1002/acn3.50815 |
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doaj-9a324a5ce8934bbc85b57f18d8559bdd2021-05-02T13:59:55ZengWileyAnnals of Clinical and Translational Neurology2328-95032019-07-01671338134410.1002/acn3.50815Second‐hit DEPDC5 mutation is limited to dysmorphic neurons in cortical dysplasia type IIAWei Shern Lee0Sarah E. M. Stephenson1Katherine B. Howell2Kate Pope3Greta Gillies4Alison Wray5Wirginia Maixner6Simone A. Mandelstam7Samuel F. Berkovic8Ingrid E. Scheffer9Duncan MacGregor10Anthony Simon Harvey11Paul J. Lockhart12Richard J. Leventer13Murdoch Children’s Research Institute Melbourne Victoria AustraliaMurdoch Children’s Research Institute Melbourne Victoria AustraliaMurdoch Children’s Research Institute Melbourne Victoria AustraliaMurdoch Children’s Research Institute Melbourne Victoria AustraliaMurdoch Children’s Research Institute Melbourne Victoria AustraliaMurdoch Children’s Research Institute Melbourne Victoria AustraliaMurdoch Children’s Research Institute Melbourne Victoria AustraliaMurdoch Children’s Research Institute Melbourne Victoria AustraliaUniversity of Melbourne Melbourne Victoria AustraliaMurdoch Children’s Research Institute Melbourne Victoria AustraliaMurdoch Children’s Research Institute Melbourne Victoria AustraliaMurdoch Children’s Research Institute Melbourne Victoria AustraliaMurdoch Children’s Research Institute Melbourne Victoria AustraliaMurdoch Children’s Research Institute Melbourne Victoria AustraliaAbstract Focal cortical dysplasia (FCD) causes drug‐resistant epilepsy and is associated with pathogenic variants in mTOR pathway genes. How germline variants cause these focal lesions is unclear, however a germline + somatic “2‐hit” model is hypothesized. In a boy with drug‐resistant epilepsy, FCD, and a germline DEPDC5 pathogenic variant, we show that a second‐hit DEPDC5 variant is limited to dysmorphic neurons, and the somatic mutation load correlates with both dysmorphic neuron density and the epileptogenic zone. These findings provide new insights into the molecular and cellular correlates of FCD determining drug‐resistant epilepsy and refine conceptualization of the epileptogenic zone.https://doi.org/10.1002/acn3.50815 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Wei Shern Lee Sarah E. M. Stephenson Katherine B. Howell Kate Pope Greta Gillies Alison Wray Wirginia Maixner Simone A. Mandelstam Samuel F. Berkovic Ingrid E. Scheffer Duncan MacGregor Anthony Simon Harvey Paul J. Lockhart Richard J. Leventer |
spellingShingle |
Wei Shern Lee Sarah E. M. Stephenson Katherine B. Howell Kate Pope Greta Gillies Alison Wray Wirginia Maixner Simone A. Mandelstam Samuel F. Berkovic Ingrid E. Scheffer Duncan MacGregor Anthony Simon Harvey Paul J. Lockhart Richard J. Leventer Second‐hit DEPDC5 mutation is limited to dysmorphic neurons in cortical dysplasia type IIA Annals of Clinical and Translational Neurology |
author_facet |
Wei Shern Lee Sarah E. M. Stephenson Katherine B. Howell Kate Pope Greta Gillies Alison Wray Wirginia Maixner Simone A. Mandelstam Samuel F. Berkovic Ingrid E. Scheffer Duncan MacGregor Anthony Simon Harvey Paul J. Lockhart Richard J. Leventer |
author_sort |
Wei Shern Lee |
title |
Second‐hit DEPDC5 mutation is limited to dysmorphic neurons in cortical dysplasia type IIA |
title_short |
Second‐hit DEPDC5 mutation is limited to dysmorphic neurons in cortical dysplasia type IIA |
title_full |
Second‐hit DEPDC5 mutation is limited to dysmorphic neurons in cortical dysplasia type IIA |
title_fullStr |
Second‐hit DEPDC5 mutation is limited to dysmorphic neurons in cortical dysplasia type IIA |
title_full_unstemmed |
Second‐hit DEPDC5 mutation is limited to dysmorphic neurons in cortical dysplasia type IIA |
title_sort |
second‐hit depdc5 mutation is limited to dysmorphic neurons in cortical dysplasia type iia |
publisher |
Wiley |
series |
Annals of Clinical and Translational Neurology |
issn |
2328-9503 |
publishDate |
2019-07-01 |
description |
Abstract Focal cortical dysplasia (FCD) causes drug‐resistant epilepsy and is associated with pathogenic variants in mTOR pathway genes. How germline variants cause these focal lesions is unclear, however a germline + somatic “2‐hit” model is hypothesized. In a boy with drug‐resistant epilepsy, FCD, and a germline DEPDC5 pathogenic variant, we show that a second‐hit DEPDC5 variant is limited to dysmorphic neurons, and the somatic mutation load correlates with both dysmorphic neuron density and the epileptogenic zone. These findings provide new insights into the molecular and cellular correlates of FCD determining drug‐resistant epilepsy and refine conceptualization of the epileptogenic zone. |
url |
https://doi.org/10.1002/acn3.50815 |
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