Transient neonatal hyperparathyroidism caused by a monoallelic TRPV6 dominant negative variant

Area of Science:

• Genetics
• Neonatal Health
• Calcium Metabolism

Background:

• Transient neonatal hyperparathyroidism (TNHP) is a rare condition causing severe skeletal issues in newborns due to placental calcium transport problems.
• The TRPV6 channel is crucial for placental calcium transport, and its biallelic variants are linked to TNHP.

Purpose of the Study:

• To investigate the genetic basis of TNHP in a neonate of Malay descent with severe skeletal abnormalities.
• To characterize a novel TRPV6 variant and its functional impact on placental calcium transport.

Main Methods:

• Whole exome sequencing to identify genetic variants.
• Functional studies including cell transfection, immunocytochemistry, Western blot, coimmunoprecipitation, calcium imaging, and patch-clamp analysis.

Main Results:

• A novel paternally inherited heterozygous missense variant (p.Val625Glu) in the TRPV6 gene was identified.
• The p.Val625Glu variant demonstrated a dominant-negative effect, impairing TRPV6 channel function by interacting with the wild-type subunit.

Conclusions:

• This is the first report of a monoallelic TRPV6 variant associated with TNHP.
• The findings expand the understanding of TNHP's genetic underpinnings and highlight the role of TRPV6 in placental calcium transport.