Cargando…

A De Novo Missense Variant in TUBG2 in a Child with Global Developmental Delay, Microcephaly, Refractory Epilepsy and Perisylvian Polymicrogyria

Polymicrogyria is a brain malformation characterized by excessive folding of the cortex. To date, numerous causes of polymicrogyria have been identified, including variants in the genes associated with tubulinopathies. Herein, we present a child with severe intellectual disability, refractory to tre...

Descripción completa

Detalles Bibliográficos
Autores principales: Thulasirajah, Salini, Wang, Xueqi, Sell, Erick, Dávila, Jorge, Dyment, David A., Kernohan, Kristin D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9859306/
https://www.ncbi.nlm.nih.gov/pubmed/36672848
http://dx.doi.org/10.3390/genes14010108
_version_ 1784874322335105024
author Thulasirajah, Salini
Wang, Xueqi
Sell, Erick
Dávila, Jorge
Dyment, David A.
Kernohan, Kristin D.
author_facet Thulasirajah, Salini
Wang, Xueqi
Sell, Erick
Dávila, Jorge
Dyment, David A.
Kernohan, Kristin D.
author_sort Thulasirajah, Salini
collection PubMed
description Polymicrogyria is a brain malformation characterized by excessive folding of the cortex. To date, numerous causes of polymicrogyria have been identified, including variants in the genes associated with tubulinopathies. Herein, we present a child with severe intellectual disability, refractory to treatment seizures, microcephaly and MRI findings consistent with polymicrogyria, closed-lip schizencephaly, periventricular heterotopia and a dysplastic corpus callosum. Exome sequencing identified a de novo missense variant in TUBG2, a gene not associated with human disease. The variant, NM_016437.3 c.747G>A p.(Met249Ile), is absent from available control databases and is predicated to be deleterious by in silico prediction programs. Laboratory studies show that cultured lymphoblasts derived from the patient grew significantly faster than controls. Recombinant protein was expressed (recombinant wild type and mutant TUBG2-FLAG) in 293T cells and lower levels of TUBG2 mutant compared with controls were observed. Furthermore, co-immuno-precipitation in cells transfected demonstrated that the TUBG2–GCP2 interaction is increased due to the MUT recombinant protein versus WT recombinant protein. In closing, this work provides preliminary evidence that TUBG2 may represent a novel disease gene responsible for polymicrogyria.
format Online
Article
Text
id pubmed-9859306
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-98593062023-01-21 A De Novo Missense Variant in TUBG2 in a Child with Global Developmental Delay, Microcephaly, Refractory Epilepsy and Perisylvian Polymicrogyria Thulasirajah, Salini Wang, Xueqi Sell, Erick Dávila, Jorge Dyment, David A. Kernohan, Kristin D. Genes (Basel) Case Report Polymicrogyria is a brain malformation characterized by excessive folding of the cortex. To date, numerous causes of polymicrogyria have been identified, including variants in the genes associated with tubulinopathies. Herein, we present a child with severe intellectual disability, refractory to treatment seizures, microcephaly and MRI findings consistent with polymicrogyria, closed-lip schizencephaly, periventricular heterotopia and a dysplastic corpus callosum. Exome sequencing identified a de novo missense variant in TUBG2, a gene not associated with human disease. The variant, NM_016437.3 c.747G>A p.(Met249Ile), is absent from available control databases and is predicated to be deleterious by in silico prediction programs. Laboratory studies show that cultured lymphoblasts derived from the patient grew significantly faster than controls. Recombinant protein was expressed (recombinant wild type and mutant TUBG2-FLAG) in 293T cells and lower levels of TUBG2 mutant compared with controls were observed. Furthermore, co-immuno-precipitation in cells transfected demonstrated that the TUBG2–GCP2 interaction is increased due to the MUT recombinant protein versus WT recombinant protein. In closing, this work provides preliminary evidence that TUBG2 may represent a novel disease gene responsible for polymicrogyria. MDPI 2022-12-29 /pmc/articles/PMC9859306/ /pubmed/36672848 http://dx.doi.org/10.3390/genes14010108 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Case Report
Thulasirajah, Salini
Wang, Xueqi
Sell, Erick
Dávila, Jorge
Dyment, David A.
Kernohan, Kristin D.
A De Novo Missense Variant in TUBG2 in a Child with Global Developmental Delay, Microcephaly, Refractory Epilepsy and Perisylvian Polymicrogyria
title A De Novo Missense Variant in TUBG2 in a Child with Global Developmental Delay, Microcephaly, Refractory Epilepsy and Perisylvian Polymicrogyria
title_full A De Novo Missense Variant in TUBG2 in a Child with Global Developmental Delay, Microcephaly, Refractory Epilepsy and Perisylvian Polymicrogyria
title_fullStr A De Novo Missense Variant in TUBG2 in a Child with Global Developmental Delay, Microcephaly, Refractory Epilepsy and Perisylvian Polymicrogyria
title_full_unstemmed A De Novo Missense Variant in TUBG2 in a Child with Global Developmental Delay, Microcephaly, Refractory Epilepsy and Perisylvian Polymicrogyria
title_short A De Novo Missense Variant in TUBG2 in a Child with Global Developmental Delay, Microcephaly, Refractory Epilepsy and Perisylvian Polymicrogyria
title_sort de novo missense variant in tubg2 in a child with global developmental delay, microcephaly, refractory epilepsy and perisylvian polymicrogyria
topic Case Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9859306/
https://www.ncbi.nlm.nih.gov/pubmed/36672848
http://dx.doi.org/10.3390/genes14010108
work_keys_str_mv AT thulasirajahsalini adenovomissensevariantintubg2inachildwithglobaldevelopmentaldelaymicrocephalyrefractoryepilepsyandperisylvianpolymicrogyria
AT wangxueqi adenovomissensevariantintubg2inachildwithglobaldevelopmentaldelaymicrocephalyrefractoryepilepsyandperisylvianpolymicrogyria
AT sellerick adenovomissensevariantintubg2inachildwithglobaldevelopmentaldelaymicrocephalyrefractoryepilepsyandperisylvianpolymicrogyria
AT davilajorge adenovomissensevariantintubg2inachildwithglobaldevelopmentaldelaymicrocephalyrefractoryepilepsyandperisylvianpolymicrogyria
AT dymentdavida adenovomissensevariantintubg2inachildwithglobaldevelopmentaldelaymicrocephalyrefractoryepilepsyandperisylvianpolymicrogyria
AT kernohankristind adenovomissensevariantintubg2inachildwithglobaldevelopmentaldelaymicrocephalyrefractoryepilepsyandperisylvianpolymicrogyria
AT thulasirajahsalini denovomissensevariantintubg2inachildwithglobaldevelopmentaldelaymicrocephalyrefractoryepilepsyandperisylvianpolymicrogyria
AT wangxueqi denovomissensevariantintubg2inachildwithglobaldevelopmentaldelaymicrocephalyrefractoryepilepsyandperisylvianpolymicrogyria
AT sellerick denovomissensevariantintubg2inachildwithglobaldevelopmentaldelaymicrocephalyrefractoryepilepsyandperisylvianpolymicrogyria
AT davilajorge denovomissensevariantintubg2inachildwithglobaldevelopmentaldelaymicrocephalyrefractoryepilepsyandperisylvianpolymicrogyria
AT dymentdavida denovomissensevariantintubg2inachildwithglobaldevelopmentaldelaymicrocephalyrefractoryepilepsyandperisylvianpolymicrogyria
AT kernohankristind denovomissensevariantintubg2inachildwithglobaldevelopmentaldelaymicrocephalyrefractoryepilepsyandperisylvianpolymicrogyria