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A novel loss-of-function mutation of PBK associated with human kidney stone disease
Kidney stone disease (KSD) is a prevalent disorder that causes human morbidity worldwide. The etiology of KSD is heterogeneous, ranging from monogenic defect to complex interaction between genetic and environmental factors. Since mutations of genes responsible for KSD in a majority of families are s...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314804/ https://www.ncbi.nlm.nih.gov/pubmed/32581305 http://dx.doi.org/10.1038/s41598-020-66936-4 |
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author | Nettuwakul, Choochai Sawasdee, Nunghathai Praditsap, Oranud Rungroj, Nanyawan Pasena, Arnat Dechtawewat, Thanyaporn Deejai, Nipaporn Sritippayawan, Suchai Rojsatapong, Santi Chaowagul, Wipada Yenchitsomanus, Pa-thai |
author_facet | Nettuwakul, Choochai Sawasdee, Nunghathai Praditsap, Oranud Rungroj, Nanyawan Pasena, Arnat Dechtawewat, Thanyaporn Deejai, Nipaporn Sritippayawan, Suchai Rojsatapong, Santi Chaowagul, Wipada Yenchitsomanus, Pa-thai |
author_sort | Nettuwakul, Choochai |
collection | PubMed |
description | Kidney stone disease (KSD) is a prevalent disorder that causes human morbidity worldwide. The etiology of KSD is heterogeneous, ranging from monogenic defect to complex interaction between genetic and environmental factors. Since mutations of genes responsible for KSD in a majority of families are still unknown, our group is identifying mutations of these genes by means of genomic and genetic analyses. In this study, we identified a novel loss-of-function mutation of PBK, encoding the PDZ binding kinase, that was found to be associated with KSD in an affected Thai family. Glycine (Gly) substituted by arginine (Arg) at position 43 (p.Gly43Arg) in PBK cosegregated with the disease in affected members of this family, but was absent in 180 normal control subjects from the same local population. Gly43 is highly evolutionarily conserved in vertebrates, and its substitution affects protein structure by alterations in H-bond forming patterns. This p.Gly43Arg substitution results in instability of the variant PBK protein as examined in HEK293T cells. The variant PBK protein (p.Gly43Arg) demonstrated decreased kinase activity to phosphorylate p38 MAPK as analyzed by immunoblotting and antibody microarray techniques. Taken together, these findings suggest a possible new mechanism of KSD associated with pathogenic PBK variation. |
format | Online Article Text |
id | pubmed-7314804 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-73148042020-06-26 A novel loss-of-function mutation of PBK associated with human kidney stone disease Nettuwakul, Choochai Sawasdee, Nunghathai Praditsap, Oranud Rungroj, Nanyawan Pasena, Arnat Dechtawewat, Thanyaporn Deejai, Nipaporn Sritippayawan, Suchai Rojsatapong, Santi Chaowagul, Wipada Yenchitsomanus, Pa-thai Sci Rep Article Kidney stone disease (KSD) is a prevalent disorder that causes human morbidity worldwide. The etiology of KSD is heterogeneous, ranging from monogenic defect to complex interaction between genetic and environmental factors. Since mutations of genes responsible for KSD in a majority of families are still unknown, our group is identifying mutations of these genes by means of genomic and genetic analyses. In this study, we identified a novel loss-of-function mutation of PBK, encoding the PDZ binding kinase, that was found to be associated with KSD in an affected Thai family. Glycine (Gly) substituted by arginine (Arg) at position 43 (p.Gly43Arg) in PBK cosegregated with the disease in affected members of this family, but was absent in 180 normal control subjects from the same local population. Gly43 is highly evolutionarily conserved in vertebrates, and its substitution affects protein structure by alterations in H-bond forming patterns. This p.Gly43Arg substitution results in instability of the variant PBK protein as examined in HEK293T cells. The variant PBK protein (p.Gly43Arg) demonstrated decreased kinase activity to phosphorylate p38 MAPK as analyzed by immunoblotting and antibody microarray techniques. Taken together, these findings suggest a possible new mechanism of KSD associated with pathogenic PBK variation. Nature Publishing Group UK 2020-06-24 /pmc/articles/PMC7314804/ /pubmed/32581305 http://dx.doi.org/10.1038/s41598-020-66936-4 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Nettuwakul, Choochai Sawasdee, Nunghathai Praditsap, Oranud Rungroj, Nanyawan Pasena, Arnat Dechtawewat, Thanyaporn Deejai, Nipaporn Sritippayawan, Suchai Rojsatapong, Santi Chaowagul, Wipada Yenchitsomanus, Pa-thai A novel loss-of-function mutation of PBK associated with human kidney stone disease |
title | A novel loss-of-function mutation of PBK associated with human kidney stone disease |
title_full | A novel loss-of-function mutation of PBK associated with human kidney stone disease |
title_fullStr | A novel loss-of-function mutation of PBK associated with human kidney stone disease |
title_full_unstemmed | A novel loss-of-function mutation of PBK associated with human kidney stone disease |
title_short | A novel loss-of-function mutation of PBK associated with human kidney stone disease |
title_sort | novel loss-of-function mutation of pbk associated with human kidney stone disease |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314804/ https://www.ncbi.nlm.nih.gov/pubmed/32581305 http://dx.doi.org/10.1038/s41598-020-66936-4 |
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