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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...

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Autores principales: Nettuwakul, Choochai, Sawasdee, Nunghathai, Praditsap, Oranud, Rungroj, Nanyawan, Pasena, Arnat, Dechtawewat, Thanyaporn, Deejai, Nipaporn, Sritippayawan, Suchai, Rojsatapong, Santi, Chaowagul, Wipada, Yenchitsomanus, Pa-thai
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
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.
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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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