A novel TRPV4 variant in spondylometaphyseal dysplasia, kozlowski type reveals a previously unreported loss-of-function mechanism
Year: 2025
Type: article
Study design: Case Report
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.
Authors: Han Wang, Shuang Li, Yiming Xu, Bin Feng, Xiuli Zhao, Xisheng Weng
Language: English
Topic: Ion Channels and Receptors
Subfield: Sensory Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,990
Funders: Natural Science Foundation of Beijing Municipality, Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences and Peking Union Medical College, National Key Research and Development Program of China, High-level Hospital Construction Project of Guangdong Provincial People's Hospital
OpenAlex ID: W4416145083