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

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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Bibliographic Details
Main Authors: 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
Format: Article
Language:English
Published: MDPI AG 2021-11-01
Series:International Journal of Molecular Sciences
Subjects:
TRPV6
placenta
calcium transport
skeletal dysplasia
serine proteases
subunit assembly
Online Access:https://www.mdpi.com/1422-0067/22/23/12694
Description
Summary: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.
ISSN:1661-6596
1422-0067

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