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Mutations That Affect the Surface Expression of TRPV6 Are Associated with the Upregulation of Serine Proteases in the Placenta of an Infant

Recently, we reported a case of an infant with neonatal severe under-mineralizing skeletal dysplasia caused by mutations within both alleles of the TRPV6 gene. One mutation results in an in frame stop codon (R(510)stop) that leads to a truncated, nonfunctional TRPV6 channel, and the second in a poin...

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Autores principales: Fecher-Trost, Claudia, Wolske, Karin, Wesely, Christine, Löhr, Heidi, Klawitter, Daniel S., Weissgerber, Petra, Gradhand, Elise, Burren, Christine P., Mason, Anna E., Winter, Manuel, Wissenbach, Ulrich
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8657554/
https://www.ncbi.nlm.nih.gov/pubmed/34884497
http://dx.doi.org/10.3390/ijms222312694
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author Fecher-Trost, Claudia
Wolske, Karin
Wesely, Christine
Löhr, Heidi
Klawitter, Daniel S.
Weissgerber, Petra
Gradhand, Elise
Burren, Christine P.
Mason, Anna E.
Winter, Manuel
Wissenbach, Ulrich
author_facet Fecher-Trost, Claudia
Wolske, Karin
Wesely, Christine
Löhr, Heidi
Klawitter, Daniel S.
Weissgerber, Petra
Gradhand, Elise
Burren, Christine P.
Mason, Anna E.
Winter, Manuel
Wissenbach, Ulrich
author_sort Fecher-Trost, Claudia
collection PubMed
description Recently, we reported a case of an infant with neonatal severe under-mineralizing skeletal dysplasia caused by mutations within both alleles of the TRPV6 gene. One mutation results in an in frame stop codon (R(510)stop) that leads to a truncated, nonfunctional TRPV6 channel, and the second in a point mutation (G(660)R) that, surprisingly, does not affect the Ca(2+) permeability of TRPV6. We mimicked the subunit composition of the unaffected heterozygous parent and child by coexpressing the TRPV6 G(660)R and R(510)stop mutants and combinations with wild type TRPV6. We show that both the G(660)R and R(510)stop mutant subunits are expressed and result in decreased calcium uptake, which is the result of the reduced abundancy of functional TRPV6 channels within the plasma membrane. We compared the proteomic profiles of a healthy placenta with that of the diseased infant and detected, exclusively in the latter two proteases, HTRA1 and cathepsin G. Our results implicate that the combination of the two mutant TRPV6 subunits, which are expressed in the placenta of the diseased child, is responsible for the decreased calcium uptake, which could explain the skeletal dysplasia. In addition, placental calcium deficiency also appears to be associated with an increase in the expression of proteases.
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spelling pubmed-86575542021-12-10 Mutations That Affect the Surface Expression of TRPV6 Are Associated with the Upregulation of Serine Proteases in the Placenta of an Infant Fecher-Trost, Claudia Wolske, Karin Wesely, Christine Löhr, Heidi Klawitter, Daniel S. Weissgerber, Petra Gradhand, Elise Burren, Christine P. Mason, Anna E. Winter, Manuel Wissenbach, Ulrich Int J Mol Sci Article Recently, we reported a case of an infant with neonatal severe under-mineralizing skeletal dysplasia caused by mutations within both alleles of the TRPV6 gene. One mutation results in an in frame stop codon (R(510)stop) that leads to a truncated, nonfunctional TRPV6 channel, and the second in a point mutation (G(660)R) that, surprisingly, does not affect the Ca(2+) permeability of TRPV6. We mimicked the subunit composition of the unaffected heterozygous parent and child by coexpressing the TRPV6 G(660)R and R(510)stop mutants and combinations with wild type TRPV6. We show that both the G(660)R and R(510)stop mutant subunits are expressed and result in decreased calcium uptake, which is the result of the reduced abundancy of functional TRPV6 channels within the plasma membrane. We compared the proteomic profiles of a healthy placenta with that of the diseased infant and detected, exclusively in the latter two proteases, HTRA1 and cathepsin G. Our results implicate that the combination of the two mutant TRPV6 subunits, which are expressed in the placenta of the diseased child, is responsible for the decreased calcium uptake, which could explain the skeletal dysplasia. In addition, placental calcium deficiency also appears to be associated with an increase in the expression of proteases. MDPI 2021-11-24 /pmc/articles/PMC8657554/ /pubmed/34884497 http://dx.doi.org/10.3390/ijms222312694 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Fecher-Trost, Claudia
Wolske, Karin
Wesely, Christine
Löhr, Heidi
Klawitter, Daniel S.
Weissgerber, Petra
Gradhand, Elise
Burren, Christine P.
Mason, Anna E.
Winter, Manuel
Wissenbach, Ulrich
Mutations That Affect the Surface Expression of TRPV6 Are Associated with the Upregulation of Serine Proteases in the Placenta of an Infant
title Mutations That Affect the Surface Expression of TRPV6 Are Associated with the Upregulation of Serine Proteases in the Placenta of an Infant
title_full Mutations That Affect the Surface Expression of TRPV6 Are Associated with the Upregulation of Serine Proteases in the Placenta of an Infant
title_fullStr Mutations That Affect the Surface Expression of TRPV6 Are Associated with the Upregulation of Serine Proteases in the Placenta of an Infant
title_full_unstemmed Mutations That Affect the Surface Expression of TRPV6 Are Associated with the Upregulation of Serine Proteases in the Placenta of an Infant
title_short Mutations That Affect the Surface Expression of TRPV6 Are Associated with the Upregulation of Serine Proteases in the Placenta of an Infant
title_sort mutations that affect the surface expression of trpv6 are associated with the upregulation of serine proteases in the placenta of an infant
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8657554/
https://www.ncbi.nlm.nih.gov/pubmed/34884497
http://dx.doi.org/10.3390/ijms222312694
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