Mutations in the TRPV4 Gene Are Not Associated With Sporadic Progressive Muscular Atrophy

Progressive muscular atrophy (PMA) is an adult-onset neurodegenerative disease characterized by progressive loss of lower motor neurons (LMNs). Its disease course ranges from slowly progressive in many years to rapid progression rates similar to those observed in patients with amyotrophic lateral sclerosis (ALS).¹ Whether PMA is a distinct disease identity separate from ALS remains the question, especially because upper motor neuron signs may develop over time¹ and mutations in the superoxide dismutase 1 gene, which are known causes of ALS, have also been identified in patients with familial PMA.² Moreover, mutations in the charged multivesicular protein 2B gene have been reported in 3 patients with sporadic LMN-predominant ALS.³ Nonsynonymous mutations in the transient receptor potential vanilloid 4 (TRPV4) gene, which encodes a calcium permeable protein channel, have recently been identified in patients with LMN disorders such as congenital distal spinal muscular atrophy, scapuloperoneal spinal muscular atrophy, and Charcot-Marie-Tooth/hereditary motor and sensory neuropathy type 2c.^4- 5 These disorders are characterized by predominant LMN degeneration. The TRPV4 gene is of special interest because mutations may lead to neurotoxicity induced by intracellular hypercalcemia and therefore, pharmacological blockade of TRPV4 channels may offer a target for therapy of TRPV4-associated disorders.⁶ We hypothesized that TRPV4 may be a candidate gene for susceptibility to PMA and screened a Dutch cohort of patients with sporadic PMA and control subjects for nonsynonymous mutations.