Mutations in the KDM5C ARID Domain and Their Plausible Association with Syndromic Claes-Jensen-Type Disease
Mutations in KDM5C gene are linked to X-linked mental retardation, the syndromic Claes-Jensen-type disease. This study focuses on non-synonymous mutations in the KDM5C ARID domain and evaluates the effects of two disease-associated missense mutations (A77T and D87G) and three not-yet-classified miss...
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doaj-373619d7d4dc4c3bb73993763b99113e2020-11-24T21:59:53ZengMDPI AGInternational Journal of Molecular Sciences1422-00672015-11-011611272702728710.3390/ijms161126022ijms161126022Mutations in the KDM5C ARID Domain and Their Plausible Association with Syndromic Claes-Jensen-Type DiseaseYunhui Peng0Jimmy Suryadi1Ye Yang2Tugba G. Kucukkal3Weiguo Cao4Emil Alexov5Computational Biophysics and Bioinformatics, Department of Physics, Clemson University, Clemson, SC 29634, USADepartment of Genetics and Biochemistry, Clemson University, Clemson, SC 29634, USADepartment of Genetics and Biochemistry, Clemson University, Clemson, SC 29634, USAComputational Biophysics and Bioinformatics, Department of Physics, Clemson University, Clemson, SC 29634, USADepartment of Genetics and Biochemistry, Clemson University, Clemson, SC 29634, USAComputational Biophysics and Bioinformatics, Department of Physics, Clemson University, Clemson, SC 29634, USAMutations in KDM5C gene are linked to X-linked mental retardation, the syndromic Claes-Jensen-type disease. This study focuses on non-synonymous mutations in the KDM5C ARID domain and evaluates the effects of two disease-associated missense mutations (A77T and D87G) and three not-yet-classified missense mutations (R108W, N142S, and R179H). We predict the ARID domain’s folding and binding free energy changes due to mutations, and also study the effects of mutations on protein dynamics. Our computational results indicate that A77T and D87G mutants have minimal effect on the KDM5C ARID domain stability and DNA binding. In parallel, the change in the free energy unfolding caused by the mutants A77T and D87G were experimentally measured by urea-induced unfolding experiments and were shown to be similar to the in silico predictions. The evolutionary conservation analysis shows that the disease-associated mutations are located in a highly-conserved part of the ARID structure (N-terminal domain), indicating their importance for the KDM5C function. N-terminal residues’ high conservation suggests that either the ARID domain utilizes the N-terminal to interact with other KDM5C domains or the N-terminal is involved in some yet unknown function. The analysis indicates that, among the non-classified mutations, R108W is possibly a disease-associated mutation, while N142S and R179H are probably harmless.http://www.mdpi.com/1422-0067/16/11/26022X-linked syndromic Claes-Jensen type diseasesequence variantsfolding free energy changesbinding free energy changesmolecular dynamicsfree energy perturbation |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Yunhui Peng Jimmy Suryadi Ye Yang Tugba G. Kucukkal Weiguo Cao Emil Alexov |
spellingShingle |
Yunhui Peng Jimmy Suryadi Ye Yang Tugba G. Kucukkal Weiguo Cao Emil Alexov Mutations in the KDM5C ARID Domain and Their Plausible Association with Syndromic Claes-Jensen-Type Disease International Journal of Molecular Sciences X-linked syndromic Claes-Jensen type disease sequence variants folding free energy changes binding free energy changes molecular dynamics free energy perturbation |
author_facet |
Yunhui Peng Jimmy Suryadi Ye Yang Tugba G. Kucukkal Weiguo Cao Emil Alexov |
author_sort |
Yunhui Peng |
title |
Mutations in the KDM5C ARID Domain and Their Plausible Association with Syndromic Claes-Jensen-Type Disease |
title_short |
Mutations in the KDM5C ARID Domain and Their Plausible Association with Syndromic Claes-Jensen-Type Disease |
title_full |
Mutations in the KDM5C ARID Domain and Their Plausible Association with Syndromic Claes-Jensen-Type Disease |
title_fullStr |
Mutations in the KDM5C ARID Domain and Their Plausible Association with Syndromic Claes-Jensen-Type Disease |
title_full_unstemmed |
Mutations in the KDM5C ARID Domain and Their Plausible Association with Syndromic Claes-Jensen-Type Disease |
title_sort |
mutations in the kdm5c arid domain and their plausible association with syndromic claes-jensen-type disease |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1422-0067 |
publishDate |
2015-11-01 |
description |
Mutations in KDM5C gene are linked to X-linked mental retardation, the syndromic Claes-Jensen-type disease. This study focuses on non-synonymous mutations in the KDM5C ARID domain and evaluates the effects of two disease-associated missense mutations (A77T and D87G) and three not-yet-classified missense mutations (R108W, N142S, and R179H). We predict the ARID domain’s folding and binding free energy changes due to mutations, and also study the effects of mutations on protein dynamics. Our computational results indicate that A77T and D87G mutants have minimal effect on the KDM5C ARID domain stability and DNA binding. In parallel, the change in the free energy unfolding caused by the mutants A77T and D87G were experimentally measured by urea-induced unfolding experiments and were shown to be similar to the in silico predictions. The evolutionary conservation analysis shows that the disease-associated mutations are located in a highly-conserved part of the ARID structure (N-terminal domain), indicating their importance for the KDM5C function. N-terminal residues’ high conservation suggests that either the ARID domain utilizes the N-terminal to interact with other KDM5C domains or the N-terminal is involved in some yet unknown function. The analysis indicates that, among the non-classified mutations, R108W is possibly a disease-associated mutation, while N142S and R179H are probably harmless. |
topic |
X-linked syndromic Claes-Jensen type disease sequence variants folding free energy changes binding free energy changes molecular dynamics free energy perturbation |
url |
http://www.mdpi.com/1422-0067/16/11/26022 |
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