# A novel TRPV4 variant in spondylometaphyseal dysplasia, kozlowski type reveals a previously unreported loss-of-function mechanism

## TL;DR

A new TRPV4 gene variant linked to a skeletal disorder shows a loss-of-function effect, offering a new understanding of disease mechanisms.

## Contribution

This study identifies a novel TRPV4 variant with a loss-of-function mechanism in SMDK, differing from typical gain-of-function mutations.

## Key findings

- The p.Trp785Ser variant in TRPV4 reduces calcium influx and membrane currents, indicating a loss-of-function effect.
- This variant is associated with a milder SMDK phenotype compared to typical TRPV4-related disorders.
- The study establishes a new pathogenic mechanism for SMDK involving reduced TRPV4 activity.

## Abstract

Spondylometaphyseal Dysplasia, Kozlowski Type (SMDK) is an autosomal dominant skeletal disorder characterized by marked scoliosis, platyspondyly, overfaced pedicles, and mild metaphyseal changes. Pathogenic variants in TRPV4, which encodes a calcium-permeable nonselective cation channel, are known to underlie SMDK. In this study, we identified a previously unreported missense variant in NM_021625.5(TRPV4): c.2354G > C (p.Trp785Ser), in a patient clinically diagnosed with SMDK. This variant affects a highly conserved residue and is predicted to alter protein conformation. Functional validation through cellular experiments revealed that the p.W785S substitution markedly reduces agonist-induced calcium influx and membrane currents, indicating a loss-of-function effect on TRPV4 channel activity. This deviates from the typical gain-of-function paradigm observed in most TRPV4-related skeletal dysplasias and may explain the relatively milder phenotype in our case. Our findings establish p.W785S as a novel pathogenic variant and highlight loss of TRPV4 activity as an alternative mechanism contributing to disease pathogenesis in SMDK.

The online version contains supplementary material available at 10.1186/s13023-025-04070-y.