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