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 (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.