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 <i>TRPV6</i> gene. One mutation results in an in frame stop codon (R<sub>510</sub>stop) that leads to a truncated, nonfunctional...
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MDPI AG
2021-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/23/12694 |
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| author | Claudia Fecher-Trost Karin Wolske Christine Wesely Heidi Löhr Daniel S. Klawitter Petra Weissgerber Elise Gradhand Christine P. Burren Anna E. Mason Manuel Winter Ulrich Wissenbach |
| author_facet | Claudia Fecher-Trost Karin Wolske Christine Wesely Heidi Löhr Daniel S. Klawitter Petra Weissgerber Elise Gradhand Christine P. Burren Anna E. Mason Manuel Winter Ulrich Wissenbach |
| author_sort | Claudia Fecher-Trost |
| collection | DOAJ |
| description | Recently, we reported a case of an infant with neonatal severe under-mineralizing skeletal dysplasia caused by mutations within both alleles of the <i>TRPV6</i> gene. One mutation results in an in frame stop codon (R<sub>510</sub>stop) that leads to a truncated, nonfunctional TRPV6 channel, and the second in a point mutation (G<sub>660</sub>R) that, surprisingly, does not affect the Ca<sup>2+</sup> permeability of TRPV6. We mimicked the subunit composition of the unaffected heterozygous parent and child by coexpressing the TRPV6 G<sub>660</sub>R and R<sub>510</sub>stop mutants and combinations with wild type TRPV6. We show that both the G<sub>660</sub>R and R<sub>510</sub>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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| id | doaj.art-8f6a05403ce741bbabc2309a7a127101 |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T04:53:27Z |
| publishDate | 2021-11-01 |
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| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-8f6a05403ce741bbabc2309a7a1271012023-11-23T02:26:31ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-11-0122231269410.3390/ijms222312694Mutations That Affect the Surface Expression of TRPV6 Are Associated with the Upregulation of Serine Proteases in the Placenta of an InfantClaudia Fecher-Trost0Karin Wolske1Christine Wesely2Heidi Löhr3Daniel S. Klawitter4Petra Weissgerber5Elise Gradhand6Christine P. Burren7Anna E. Mason8Manuel Winter9Ulrich Wissenbach10Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University, Buildings 61.4 and 46, 66421 Homburg, GermanyExperimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University, Buildings 61.4 and 46, 66421 Homburg, GermanyExperimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University, Buildings 61.4 and 46, 66421 Homburg, GermanyExperimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University, Buildings 61.4 and 46, 66421 Homburg, GermanyExperimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University, Buildings 61.4 and 46, 66421 Homburg, GermanyExperimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University, Buildings 61.4 and 46, 66421 Homburg, GermanyKinder- und Perinatalpathologie Dr. Senckenberg, Institut für Pathologie Universitätsklinikum Frankfurt/Main Theodor-Stern-Kai 7, 60590 Frankfurt, GermanyDepartment of Translational Health Sciences, Bristol Medical School, University of Bristol, University Hospitals Bristol and Weston NHS Foundation Trust, Upper Maudlin St, Bristol BS2 8BJ, UKHistopathology Department, Aneurin Bevan University Health Board, Royal Gwent Hospital, Cardiff NP20 2UB, UKExperimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University, Buildings 61.4 and 46, 66421 Homburg, GermanyExperimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University, Buildings 61.4 and 46, 66421 Homburg, GermanyRecently, we reported a case of an infant with neonatal severe under-mineralizing skeletal dysplasia caused by mutations within both alleles of the <i>TRPV6</i> gene. One mutation results in an in frame stop codon (R<sub>510</sub>stop) that leads to a truncated, nonfunctional TRPV6 channel, and the second in a point mutation (G<sub>660</sub>R) that, surprisingly, does not affect the Ca<sup>2+</sup> permeability of TRPV6. We mimicked the subunit composition of the unaffected heterozygous parent and child by coexpressing the TRPV6 G<sub>660</sub>R and R<sub>510</sub>stop mutants and combinations with wild type TRPV6. We show that both the G<sub>660</sub>R and R<sub>510</sub>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.https://www.mdpi.com/1422-0067/22/23/12694TRPV6placentacalcium transportskeletal dysplasiaserine proteasessubunit assembly |
| spellingShingle | Claudia Fecher-Trost Karin Wolske Christine Wesely Heidi Löhr Daniel S. Klawitter Petra Weissgerber Elise Gradhand Christine P. Burren Anna E. Mason Manuel Winter Ulrich Wissenbach Mutations That Affect the Surface Expression of TRPV6 Are Associated with the Upregulation of Serine Proteases in the Placenta of an Infant International Journal of Molecular Sciences TRPV6 placenta calcium transport skeletal dysplasia serine proteases subunit assembly |
| 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 | TRPV6 placenta calcium transport skeletal dysplasia serine proteases subunit assembly |
| url | https://www.mdpi.com/1422-0067/22/23/12694 |
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