Functional analyses of a novel missense and other mutations of the vitamin D receptor in association with alopecia

Abstract Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) is a rare disorder, caused by bialellic mutations of the vitamin D receptor (VDR) gene, sometimes associated with alopecia. The aim of this study is to elucidate the mechanism of functional disruption of a novel mutation, detected...

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Autores principales:	Mayuko Tamura, Michiyasu Ishizawa, Tsuyoshi Isojima, Samim Özen, Akira Oka, Makoto Makishima, Sachiko Kitanaka
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/67b0c95e7a4a40ed9a8df3d6cecab278
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spelling	oai:doaj.org-article:67b0c95e7a4a40ed9a8df3d6cecab2782021-12-02T15:04:52ZFunctional analyses of a novel missense and other mutations of the vitamin D receptor in association with alopecia10.1038/s41598-017-05081-x2045-2322https://doaj.org/article/67b0c95e7a4a40ed9a8df3d6cecab2782017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-05081-xhttps://doaj.org/toc/2045-2322Abstract Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) is a rare disorder, caused by bialellic mutations of the vitamin D receptor (VDR) gene, sometimes associated with alopecia. The aim of this study is to elucidate the mechanism of functional disruption of a novel mutation, detected in a patient with HVDRR, comparing to other mutations with or without alopecia. The patient was a 2-year-old girl with alopecia, who was clinically diagnosed as HVDRR. Genetic analysis revealed a novel homozygous mutation, S360P, located in ligand binding domain (LBD). The mutation was predicted as not disease causing by Polyphen2 and SIFT. But the transcriptional activity of S360P was disrupted as well as other reported mutations, Q152X (located in the hinge lesion), and R274L, H305Q (located in LBD). Following assays revealed no ligand binding affinity, no interaction with cofactors or RXR and no functioning of nuclear localization signals. Our results provide an additional evidence for the previous findings suggesting that DNA binding by the VDR/RXR heterodimer is essential for the function of the VDR in hair development. In conclusion, we identified a novel missense mutation of VDR causing HVDRR with alopecia. Functional analyses revealed that the single amino acid substitution could disrupt the function of the protein.Mayuko TamuraMichiyasu IshizawaTsuyoshi IsojimaSamim ÖzenAkira OkaMakoto MakishimaSachiko KitanakaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-10 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mayuko Tamura Michiyasu Ishizawa Tsuyoshi Isojima Samim Özen Akira Oka Makoto Makishima Sachiko Kitanaka Functional analyses of a novel missense and other mutations of the vitamin D receptor in association with alopecia
description	Abstract Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) is a rare disorder, caused by bialellic mutations of the vitamin D receptor (VDR) gene, sometimes associated with alopecia. The aim of this study is to elucidate the mechanism of functional disruption of a novel mutation, detected in a patient with HVDRR, comparing to other mutations with or without alopecia. The patient was a 2-year-old girl with alopecia, who was clinically diagnosed as HVDRR. Genetic analysis revealed a novel homozygous mutation, S360P, located in ligand binding domain (LBD). The mutation was predicted as not disease causing by Polyphen2 and SIFT. But the transcriptional activity of S360P was disrupted as well as other reported mutations, Q152X (located in the hinge lesion), and R274L, H305Q (located in LBD). Following assays revealed no ligand binding affinity, no interaction with cofactors or RXR and no functioning of nuclear localization signals. Our results provide an additional evidence for the previous findings suggesting that DNA binding by the VDR/RXR heterodimer is essential for the function of the VDR in hair development. In conclusion, we identified a novel missense mutation of VDR causing HVDRR with alopecia. Functional analyses revealed that the single amino acid substitution could disrupt the function of the protein.
format	article
author	Mayuko Tamura Michiyasu Ishizawa Tsuyoshi Isojima Samim Özen Akira Oka Makoto Makishima Sachiko Kitanaka
author_facet	Mayuko Tamura Michiyasu Ishizawa Tsuyoshi Isojima Samim Özen Akira Oka Makoto Makishima Sachiko Kitanaka
author_sort	Mayuko Tamura
title	Functional analyses of a novel missense and other mutations of the vitamin D receptor in association with alopecia
title_short	Functional analyses of a novel missense and other mutations of the vitamin D receptor in association with alopecia
title_full	Functional analyses of a novel missense and other mutations of the vitamin D receptor in association with alopecia
title_fullStr	Functional analyses of a novel missense and other mutations of the vitamin D receptor in association with alopecia
title_full_unstemmed	Functional analyses of a novel missense and other mutations of the vitamin D receptor in association with alopecia
title_sort	functional analyses of a novel missense and other mutations of the vitamin d receptor in association with alopecia
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/67b0c95e7a4a40ed9a8df3d6cecab278
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Functional analyses of a novel missense and other mutations of the vitamin D receptor in association with alopecia

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