An ACVR1 activating mutation causes neuropathic pain and sensory neuron hyperexcitability in humans.

Altered bone morphogenetic protein (BMP) signaling is associated with many musculoskeletal diseases. However, it remains unknown whether BMP dysfunction has direct contribution to debilitating pain reported in many of these disorders. Here we identified a novel neuropathic pain phenotype in patients with fibrodysplasia ossificans progressiva (FOP), a rare autosomal-dominant musculoskeletal disorder characterized by progressive heterotopic ossification. Ninety-seven percent of these patients carry an R206H gain-of-function point mutation in the bone morphogenetic protein (BMP) type I receptor ACVR1 (ACVR1R206H), which causes neofunction to Activin A and constitutively activates signaling through phosphorylated SMAD1/5/8. Although FOP patients can harbor pathological lesions in the peripheral and central nervous system, their etiology is unclear. Quantitative Sensory Testing (QST) of patients with FOP revealed significant heat and mechanical pain hypersensitivity. Although there was no major impact of ACVR1R206H on differentiation and maturation of nociceptive sensory neurons (iSNs) derived from FOP induced pluripotent stem cells (iPSCs), both intracellular and extracellular electrophysiology analysis of the ACVR1R206H iSNs displayed ACVR1-dependent hyperexcitability, a hallmark of neuropathic pain. Consistent with this phenotype, we recorded enhanced responses of ACVR1R206H iSNs to TRPV1 and TRPA1 agonists. Thus, activated ACVR1 signaling can modulate pain processing in humans and may represent a potential target for pain management in FOP and related BMP pathway diseases.