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Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia

Abstract

The brachyolmias constitute a clinically and genetically heterogeneous group of skeletal dysplasias characterized by a short trunk, scoliosis and mild short stature1. Here, we identify a locus for an autosomal dominant form of brachyolmia on chromosome 12q24.1–12q24.2. Among the genes in the genetic interval, we selected TRPV4, which encodes a calcium permeable cation channel of the transient receptor potential (TRP) vanilloid family, as a candidate gene because of its cartilage-selective gene expression pattern. In two families with the phenotype, we identified point mutations in TRPV4 that encoded R616Q and V620I substitutions, respectively. Patch clamp studies of transfected HEK cells showed that both mutations resulted in a dramatic gain of function characterized by increased constitutive activity and elevated channel activation by either mechano-stimulation or agonist stimulation by arachidonic acid or the TRPV4-specific agonist 4α-phorbol 12,13-didecanoate (4αPDD). This study thus defines a previously unknown mechanism, activation of a calcium-permeable TRP ion channel, in skeletal dysplasia pathogenesis.

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Figure 1: Pedigree and haplotypes for family R99-102.
Figure 2: Radiographs of the proband at age 8 years, 3 months.
Figure 3: Gene expression analysis throughout the linked region of chromosome 12.
Figure 4: Expression of human TRPV4 and the R616Q mutant in HEK293 cells.
Figure 5: Expression of TRPV4 in HEK 293 cells.

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Acknowledgements

This work was supported in part by grants from the National Institutes of Health (HD22657) and the Human Frontiers Science Program (HFSP Research Grant Ref. RGP 32/2004), the Belgian Federal Government, the Flemish Government, the Onderzoeksraad KU Leuven (GOA 2004/07, F.W.O. G.0136.00; F.W.O. G.0172.03, Interuniversity Poles of Attraction Program, Prime Ministers Office IUAP Nr.3P4/23, Excellentiefinanciering EF/95/010) to B.N. Microarray data were generated and analyses were performed within the University of California, Los Angeles DNA microarray facility. We thank the families for their active participation.

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M.J.R., J.P., T.V., B.N., S.F.N. and D.H.C. designed the experiments. M.J.R., J.P., G.O., A.J., B.M. and V.A.F. carried out the experiments. T.L.F., R.S.L., W.R.W., S.R., R.Q., A.V., S.I., T.N. and D.L.R. ascertained and diagnosed the subjects. M.J.R., B.N. and D.H.C. wrote the manuscript.

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Correspondence to Daniel H Cohn.

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Rock, M., Prenen, J., Funari, V. et al. Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia. Nat Genet 40, 999–1003 (2008). https://doi.org/10.1038/ng.166

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