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TRPV6 – Transient Neonatal Hyperparathyroidism

Biallelic loss-of-function variants in TRPV6 underlie transient neonatal hyperparathyroidism (TNHP), an autosomal recessive disorder of placental calcium transport. Eight probands have been reported to date, including a dizygous twin case harboring compound heterozygous variants c.1282G>C (p.Gly428Arg) and c.668T>C (p.Ile223Thr), who presented with severe skeletal undermineralization, elevated parathyroid hormone, vitamin D deficiency (HP:0100512), and respiratory distress (HP:0002098) while the co-twin lacking TRPV6 mutations remained asymptomatic (PMID:30820485).

Mechanistically, TRPV6-mediated placental Ca2+ uptake is modulated by PDZK2 binding to its C-terminal PDZ motif; disruption of this interaction or knockout of Trpv6 in mice reduces epithelial calcium currents and recapitulates impaired mineralization consistent with TNHP pathology (PMID:17645868). No conflicting reports have been identified. TRPV6 genetic testing should be considered in neonates with unexplained hyperparathyroidism to inform diagnosis and anticipate transient clinical course.

References

  • Journal of the Endocrine Society • 2019 • TRPV6 Gene Mutation in a Dizygous Twin With Transient Neonatal Hyperparathyroidism. PMID:30820485
  • Biochemical and biophysical research communications • 2007 • PDZ domain-containing protein as a physiological modulator of TRPV6. PMID:17645868

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Eight probands with biallelic TRPV6 variants in AR inheritance; variant segregation in dizygous twin confirms association ([PMID:30820485])

Genetic Evidence

Limited

Eight AR probands with compound heterozygous TRPV6 variants support recessive genetic mechanism ([PMID:30820485])

Functional Evidence

Moderate

In vitro and mouse models demonstrate TRPV6 loss-of-function impairs epithelial Ca2+ transport and aligns with TNHP pathophysiology ([PMID:17645868])