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

Claudia Fecher-Trost,Ulrich Wissenbach,Daniel S Klawitter,Heidi Löhr,Karin Wolske,Manuel Winter,Christine Wesely,Christine P Burren,Petra Weissgerber,Elise Gradhand,Anna E Mason

doi:10.3390/ijms222312694

Abstract

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 (R510stop) that leads to a truncated, nonfunctional TRPV6 channel, and the second in a point mutation (G660R) that, surprisingly, does not affect the Ca2+ permeability of TRPV6. We mimicked the subunit composition of the unaffected heterozygous parent and child by coexpressing the TRPV6 G660R and R510stop mutants and combinations with wild type TRPV6. We show that both the G660R and R510stop 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.

Highlights

We recently described the case of an infant who suffers from neonatal severe under mineralizing skeletal dysplasia due to underlying severe transient hyperparathyroidism
One TRPV6 allele of the child contained a mutation that leads to a G660 R mutation in the very C-terminus of the coding sequence, whereas the second allele contained an in frame stop codon, R510 stop, which leads to a truncated protein without the pore region of the TRPV6 channel
TRPV6 channels consist of four identical subunits and, in the human placenta, both

Summary

Introduction

TRPV6 is a Ca2+ selective ion channel which shows a very restricted expression pattern. Human TRPV6 is expressed in a few glands, including acinar salivary and lacrimal glands, in parts of the small intestine, and in the trophoblast layer of the placenta [1,2,3]. Two TRPV6 alleles, TRPV6a and TRPV6b, exist, leading to a coupled polymorphism with three distinct amino acid exchanges detected in TRPV6a (R197 V418 T721 ) and TRPV6b (C197 M418 M721 ) [1,11,12]. Dysfunction of TRPV6 channels leads to transient neonatal hyperparathyroidism (HRPTTN) and is listed in the OMIM database

Methods

Results

Conclusion