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Bioinformatics analysis of CYP1B1 mutation hotspots in Chinese primary congenital glaucoma patients

Primary congenital glaucoma (PCG) is an inherited blinding eye disease. The CYP1B1 gene was identified as a causal gene for PCG, and many mutations have been found, but no studies have focussed on the molecular epidemiology of CYP1B1 in Chinese populations. We aimed to explore the CYP1B1 mutation ho...

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Autores principales: Ou, Zhiying, Liu, Guangjian, Liu, Wenping, Deng, Yehua, Zheng, Ling, Zhang, Shu, Feng, Guangqiang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435531/
https://www.ncbi.nlm.nih.gov/pubmed/29903728
http://dx.doi.org/10.1042/BSR20180056
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author Ou, Zhiying
Liu, Guangjian
Liu, Wenping
Deng, Yehua
Zheng, Ling
Zhang, Shu
Feng, Guangqiang
author_facet Ou, Zhiying
Liu, Guangjian
Liu, Wenping
Deng, Yehua
Zheng, Ling
Zhang, Shu
Feng, Guangqiang
author_sort Ou, Zhiying
collection PubMed
description Primary congenital glaucoma (PCG) is an inherited blinding eye disease. The CYP1B1 gene was identified as a causal gene for PCG, and many mutations have been found, but no studies have focussed on the molecular epidemiology of CYP1B1 in Chinese populations. We aimed to explore the CYP1B1 mutation hotspots in Chinese PCG patients and the possible impact of these mutations on the protein structure and function. First, we performed a meta-analysis on seven datasets of Chinese populations and found L107V and R390H to be the most common CYP1B1 mutations with allele frequencies of 3.19% and 3.09%, respectively. Then, a series of bioinformatics tools were applied to determine the sequence conservative properties, model the 3D structures, and study the dynamics changes. L107 and R390 are highly conserved residues in close proximity to the hemoglobin-binding region and the active site cavity (ASC), respectively. The mutations changed the distribution of hydrogen bonds and the local electrostatic potential. Long-term molecular dynamics (MD) simulations demonstrated the destabilization of the mutant proteins, especially at the ASC, whose solvent-accessible surface areas (SASAs) were significantly decreased. Compared with the wild-type (WT) protein, the overall structures of the mutants are associated with subtle but significant changes, and the ASC seems to adopt such structures that are not able to perform the WT-like functionality. Therefore, L107V and R390H might be the most important pathogenic mutations in Chinese PCG patients.
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spelling pubmed-64355312019-04-12 Bioinformatics analysis of CYP1B1 mutation hotspots in Chinese primary congenital glaucoma patients Ou, Zhiying Liu, Guangjian Liu, Wenping Deng, Yehua Zheng, Ling Zhang, Shu Feng, Guangqiang Biosci Rep Research Articles Primary congenital glaucoma (PCG) is an inherited blinding eye disease. The CYP1B1 gene was identified as a causal gene for PCG, and many mutations have been found, but no studies have focussed on the molecular epidemiology of CYP1B1 in Chinese populations. We aimed to explore the CYP1B1 mutation hotspots in Chinese PCG patients and the possible impact of these mutations on the protein structure and function. First, we performed a meta-analysis on seven datasets of Chinese populations and found L107V and R390H to be the most common CYP1B1 mutations with allele frequencies of 3.19% and 3.09%, respectively. Then, a series of bioinformatics tools were applied to determine the sequence conservative properties, model the 3D structures, and study the dynamics changes. L107 and R390 are highly conserved residues in close proximity to the hemoglobin-binding region and the active site cavity (ASC), respectively. The mutations changed the distribution of hydrogen bonds and the local electrostatic potential. Long-term molecular dynamics (MD) simulations demonstrated the destabilization of the mutant proteins, especially at the ASC, whose solvent-accessible surface areas (SASAs) were significantly decreased. Compared with the wild-type (WT) protein, the overall structures of the mutants are associated with subtle but significant changes, and the ASC seems to adopt such structures that are not able to perform the WT-like functionality. Therefore, L107V and R390H might be the most important pathogenic mutations in Chinese PCG patients. Portland Press Ltd. 2018-07-06 /pmc/articles/PMC6435531/ /pubmed/29903728 http://dx.doi.org/10.1042/BSR20180056 Text en © 2018 The Author(s). http://creativecommons.org/licenses/by/4.0/This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY) (http://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Articles
Ou, Zhiying
Liu, Guangjian
Liu, Wenping
Deng, Yehua
Zheng, Ling
Zhang, Shu
Feng, Guangqiang
Bioinformatics analysis of CYP1B1 mutation hotspots in Chinese primary congenital glaucoma patients
title Bioinformatics analysis of CYP1B1 mutation hotspots in Chinese primary congenital glaucoma patients
title_full Bioinformatics analysis of CYP1B1 mutation hotspots in Chinese primary congenital glaucoma patients
title_fullStr Bioinformatics analysis of CYP1B1 mutation hotspots in Chinese primary congenital glaucoma patients
title_full_unstemmed Bioinformatics analysis of CYP1B1 mutation hotspots in Chinese primary congenital glaucoma patients
title_short Bioinformatics analysis of CYP1B1 mutation hotspots in Chinese primary congenital glaucoma patients
title_sort bioinformatics analysis of cyp1b1 mutation hotspots in chinese primary congenital glaucoma patients
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435531/
https://www.ncbi.nlm.nih.gov/pubmed/29903728
http://dx.doi.org/10.1042/BSR20180056
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