Whole Exome Sequencing Identifies a Novel Homozygous Missense Mutation in the CSB Protein-Encoding <i>ERCC6</i> Gene in a Taiwanese Boy with Cockayne Syndrome

Background: Cockayne syndrome (CS) is a rare form of dwarfism that is characterized by progressive premature aging. CS is typically caused by mutations in the excision repair cross-complementing protein group 6 (<i>ERCC6</i>) gene that encodes the CS group B (CSB) protein. Using whole ex...

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Autores principales:	Ching-Ming Lin, Jay-How Yang, Hwei-Jen Lee, Yu-Pang Lin, Li-Ping Tsai, Chih-Sin Hsu, G. W. Gant Luxton, Chih-Fen Hu
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	Cockayne syndrome B progeroid <i>ERCC6</i> whole exome sequencing transcription-coupled nucleotide excision repair (TC-NER) Science Q
Acceso en línea:	https://doaj.org/article/2f06896b361347308d379e7f110296a8
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spelling	oai:doaj.org-article:2f06896b361347308d379e7f110296a82021-11-25T18:11:24ZWhole Exome Sequencing Identifies a Novel Homozygous Missense Mutation in the CSB Protein-Encoding <i>ERCC6</i> Gene in a Taiwanese Boy with Cockayne Syndrome10.3390/life111112302075-1729https://doaj.org/article/2f06896b361347308d379e7f110296a82021-11-01T00:00:00Zhttps://www.mdpi.com/2075-1729/11/11/1230https://doaj.org/toc/2075-1729Background: Cockayne syndrome (CS) is a rare form of dwarfism that is characterized by progressive premature aging. CS is typically caused by mutations in the excision repair cross-complementing protein group 6 (<i>ERCC6</i>) gene that encodes the CS group B (CSB) protein. Using whole exome sequencing, we recently identified a novel homozygous missense mutation (Leu536Trp) in CSB in a Taiwanese boy with CS. Since the current database (Varsome) interprets this variant as likely pathogenic, we utilized a bioinformatic tool to investigate the impact of Leu536Trp as well as two other variants (Arg453Ter, Asp532Gly) in similar articles on the CSB protein structure stability. Methods: We used iterative threading assembly refinement (I-TASSER) to generate a predictive 3D structure of CSB. We calculated the change of mutation energy after residues substitution on the protein stability using I-TASSER as well as the artificial intelligence program Alphafold. Results: The Asp532Gly variant destabilized both modeled structures, while the Leu536Trp variant showed no effect on I-TASSER’s model but destabilized the Alphafold’s modeled structure. Conclusions: We propose here the first case of CS associated with a novel homozygous missense mutation (Leu536Trp) in CSB. Furthermore, we suggest that the Asp532Gly and Leu536Trp variants are both pathogenic after bioinformatic analysis of protein stability.Ching-Ming LinJay-How YangHwei-Jen LeeYu-Pang LinLi-Ping TsaiChih-Sin HsuG. W. Gant LuxtonChih-Fen HuMDPI AGarticleCockayne syndrome Bprogeroid<i>ERCC6</i>whole exome sequencingtranscription-coupled nucleotide excision repair (TC-NER)ScienceQENLife, Vol 11, Iss 1230, p 1230 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Cockayne syndrome B progeroid <i>ERCC6</i> whole exome sequencing transcription-coupled nucleotide excision repair (TC-NER) Science Q
spellingShingle	Cockayne syndrome B progeroid <i>ERCC6</i> whole exome sequencing transcription-coupled nucleotide excision repair (TC-NER) Science Q Ching-Ming Lin Jay-How Yang Hwei-Jen Lee Yu-Pang Lin Li-Ping Tsai Chih-Sin Hsu G. W. Gant Luxton Chih-Fen Hu Whole Exome Sequencing Identifies a Novel Homozygous Missense Mutation in the CSB Protein-Encoding <i>ERCC6</i> Gene in a Taiwanese Boy with Cockayne Syndrome
description	Background: Cockayne syndrome (CS) is a rare form of dwarfism that is characterized by progressive premature aging. CS is typically caused by mutations in the excision repair cross-complementing protein group 6 (<i>ERCC6</i>) gene that encodes the CS group B (CSB) protein. Using whole exome sequencing, we recently identified a novel homozygous missense mutation (Leu536Trp) in CSB in a Taiwanese boy with CS. Since the current database (Varsome) interprets this variant as likely pathogenic, we utilized a bioinformatic tool to investigate the impact of Leu536Trp as well as two other variants (Arg453Ter, Asp532Gly) in similar articles on the CSB protein structure stability. Methods: We used iterative threading assembly refinement (I-TASSER) to generate a predictive 3D structure of CSB. We calculated the change of mutation energy after residues substitution on the protein stability using I-TASSER as well as the artificial intelligence program Alphafold. Results: The Asp532Gly variant destabilized both modeled structures, while the Leu536Trp variant showed no effect on I-TASSER’s model but destabilized the Alphafold’s modeled structure. Conclusions: We propose here the first case of CS associated with a novel homozygous missense mutation (Leu536Trp) in CSB. Furthermore, we suggest that the Asp532Gly and Leu536Trp variants are both pathogenic after bioinformatic analysis of protein stability.
format	article
author	Ching-Ming Lin Jay-How Yang Hwei-Jen Lee Yu-Pang Lin Li-Ping Tsai Chih-Sin Hsu G. W. Gant Luxton Chih-Fen Hu
author_facet	Ching-Ming Lin Jay-How Yang Hwei-Jen Lee Yu-Pang Lin Li-Ping Tsai Chih-Sin Hsu G. W. Gant Luxton Chih-Fen Hu
author_sort	Ching-Ming Lin
title	Whole Exome Sequencing Identifies a Novel Homozygous Missense Mutation in the CSB Protein-Encoding <i>ERCC6</i> Gene in a Taiwanese Boy with Cockayne Syndrome
title_short	Whole Exome Sequencing Identifies a Novel Homozygous Missense Mutation in the CSB Protein-Encoding <i>ERCC6</i> Gene in a Taiwanese Boy with Cockayne Syndrome
title_full	Whole Exome Sequencing Identifies a Novel Homozygous Missense Mutation in the CSB Protein-Encoding <i>ERCC6</i> Gene in a Taiwanese Boy with Cockayne Syndrome
title_fullStr	Whole Exome Sequencing Identifies a Novel Homozygous Missense Mutation in the CSB Protein-Encoding <i>ERCC6</i> Gene in a Taiwanese Boy with Cockayne Syndrome
title_full_unstemmed	Whole Exome Sequencing Identifies a Novel Homozygous Missense Mutation in the CSB Protein-Encoding <i>ERCC6</i> Gene in a Taiwanese Boy with Cockayne Syndrome
title_sort	whole exome sequencing identifies a novel homozygous missense mutation in the csb protein-encoding <i>ercc6</i> gene in a taiwanese boy with cockayne syndrome
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/2f06896b361347308d379e7f110296a8
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Whole Exome Sequencing Identifies a Novel Homozygous Missense Mutation in the CSB Protein-Encoding <i>ERCC6</i> Gene in a Taiwanese Boy with Cockayne Syndrome

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