Transient neonatal hyperparathyroidism caused by a monoallelic TRPV6 dominant negative variant

Transient neonatal hyperparathyroidism (TNHP) is a rare disorder characterized by severe skeletal abnormalities in newborns, resulting from insufficient maternal-fetal calcium transport across the placenta. Transient receptor potential cation channel, subfamily V, member 6 (TRPV6) plays a significant role in placental calcium transport. While biallelic variants in the TRPV6 gene have been associated with TNHP, we present a case involving a neonate of Malay descent, born to non-consanguineous parents, who exhibited severe skeletal abnormalities at birth that resolved spontaneously within 6 wk. Biochemical evaluation revealed neonatal hyperparathyroidism alongside maternal vitamin D deficiency. Whole exome sequencing identified a novel paternally inherited heterozygous missense variant in the TRPV6 gene resulting in a valine-to-glutamic acid substitution at codon 625 (p.Val625Glu). This variant is situated adjacent to the TRP box, a region where a neighboring subunit is implicated in modulating channel gating via the S4-S5 linker. Functional studies were conducted by transfecting HEK293 cells with TRPV6-DsRed plasmids encoding either the wild-type or mutant protein. Immunocytochemistry demonstrated comparable cellular distribution between the variant and wild-type proteins. Western blot analysis confirmed the presence of both proteins at the plasma membrane. However, coimmunoprecipitation, intracellular calcium imaging, and patch-clamp studies suggested that the p.Val625Glu variant exerts a dominant-negative effect by interacting with the wild-type subunit to form a heteromeric complex, thereby impairing channel function. To our knowledge, this is the first report of a monoallelic TRPV6 variant associated with TNHP, expanding the understanding of its genetic underpinnings.