Calcium Channel Family of Bone Dysplasias

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Brachyolmia is a relatively mild bone dysplasia that primarily affects vertebral body growth leading to mild to moderate short trunk dwarfism. One form of autosomal dominant brachyolmia (MIM 113500) was recently shown to result from activating mutations of TRPV4, a calcium-permeable ion channel protein that has been implicated in skeletal development.¹ Qualitatively similar but more severe radiographic changes are found in 2 other dominantly inherited bone dysplasias. The first, spondylometaphyseal dysplasia Kozlowski type (SMDK, MIM 1842522), is characterized by postnatal onset of short stature, kyphoscoliosis and progressive deformity. The second, metatropic dysplasia (MIM 156530), presents in newborn infants with short limbs, but evolves to a short trunk clinical phenotype as a result of severe and progressive kyphoscoliosis typically compromising neurologic and respiratory functions. The clinical and radiographic similarities prompted Krakow and colleagues to search for mutations of TRPV4 in the latter disorders, which they have now reported.

Typical radiographic manifestations of SMDK (A,B) and metatropic dysplasia (C).
Modified from Krakow D, et al. Am J Hum Genet. 2009;84:307-315. Copyright © Elsevier 2009. All rights reserved.

Heterozygous missense mutations TRPV4 were detected in all 8 patients who were studied, 6 with SMDK and 2 with metatropic dysplasia. One mutation was recurrent in 4 patients with SMDK. It and 2 other mutations mapped to the cytoplasmic domain of the channel protein where the brachyolmia mutations had mapped, but 2 mapped to so-called ankyrin repeats, a common molecular motif thought to be involved in folding and direct interactions between proteins.
Since gain of channel function had been implicated in the brachyolmia-associated mutations of TRPV4, the investigators analyzed basal channel activity and responses to known TRPV4 agonists and antagonists of the 4 SMDK-associated mutations. Three displayed increased basal channel activity. The responses to agonists and antagonists were less clear and the authors concluded that the mutations most likely act through increasing basal intracellular calcium. They also noted that genetically engineered mice lacking TRPV4 function exhibit a defect in osteoclast function associated with overmineralized bone and suggest that the clinical phenotype in brachyolmia, SMDK and metatropic dysplasia may reflect disturbed TRPV4 function in both chondrocytes and osteoblasts during bone growth.

Krakow D, Vriens J, Camacho N, et al. Mutations in the gene encoding the calcium-permeable ion channel TRPV4 produce spondylometaphyseal dysplasia, Kozlowski type and metatropic dysplasia. Am J Hum Genet. 2009;84:307-315.

Editor’s Comment

The family concept that disorders that exhibit qualitatively similar clinical phenotypes result from mutations of the same gene function continues to be borne out, in this case with TRPV4. It will be interesting to watch this story unfold regarding how abnormal calcium channel activity or increased intracellular calcium, as the authors proposed, alters the biology of bone growth. There are a number of drugs used to treat various diseases unrelated to bone growth and there are health food constituents that are thought to affect intracellular calcium concentrations. One wonders if these agents could counter the adverse effects of disturbed TRPV4 channel function in cells that contribute to bone growth.

William A. Horton, MD

Reference - (linked to )

Rock MJ, Prenen J, Funari VA, et al. Gain of function mutations in TRPV4 cause autosomal dominant brachyolmia. Nat Genet. 2008;40:999-1003.

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Last Updated: 6/12/2009