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Mutations Found in Autosomal Dominant Brachyolmia

Mutations in TRPV4 in skeletal dysplasia point to possible therapy with calcium channel inhibitors

MONDAY, July 7 (HealthDay News) -- Mutations in the TRPV4 gene have been linked to an autosomal dominant form of brachyolmia marked by severe kyphoscoliosis and irregular, flattened cervical vertebrae, according to research published online June 29 in Nature Genetics.

Matthew J. Rock, of the Cedars-Sinai Medical Center in Los Angeles, and colleagues discuss their investigation involving a family with autosomal dominant brachyolmia involving scoliosis with platyspondyly and overfaced pedicles. A two-stage genome scan found a locus for the phenotype on chromosome 12q24.1-24.2.

The researchers chose TRPV4, which encodes a calcium permeable cation channel of the transient receptor potential vanilloid family, because it's selectively expressed in cartilage. In this family and another with a similar phenotype, researchers identified two mutations that resulted in gain of function with an increased fraction of constitutively open channels and increased channel activation.

"This study describes activating mutations in TRPV4 that produce an autosomal dominant form of brachyolmia. The mutations increase constitutive TRPV4 activity, and identify an essential role for cation channel activity in the growth plate. Abnormal skeletogenesis resulting from alterations in calcium homeostasis represents a novel mechanism in the skeletal dysplasias, and the specific skeletal abnormalities observed in brachyolmia reveal a particularly important function for this process in the growth and stability of the spine. The nature of the mutations also suggests that modulation of TRPV4 activity using calcium channel inhibitors could represent an avenue for treatment," the authors conclude.

Abstract
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