SCN9A Mutations in Paroxysmal Extreme Pain Disorder: Allelic Variants Underlie Distinct Channel Defects and Phenotypes

摘要: Paroxysmal extreme pain disorder (PEPD), previously known as familial rectal (FRP, or OMIM 167400), is an inherited condition characterized by paroxysms of rectal, ocular, submandibular with flushing. A genome-wide linkage search followed mutational analysis the candidate gene SCN9A, which encodes hNaV(1.7) identified eight missense mutations in 11 families and 2 sporadic cases. Functional vitro three these mutant Na(V)1.7 channels revealed a reduction fast inactivation, leading to persistent sodium current. Other SCN9A associated more negative activation thresholds are cause primary erythermalgia (PE). Carbamazepine, drug that effective PEPD, but not PE, showed selective block current PEPD mutants, did affect threshold PE mutant. allelic variants distinct underlying biophysical mechanisms represent separate class peripheral neuronal channelopathy.