Gain-of-Function Mutation of a Voltage-Gated Sodium Channel NaV1.7 Associated with Peripheral Pain and Impaired Limb Development [Neurobiology]

Dominant mutations in voltage-gated sodium channel NaV1.7 cause inherited erythromelalgia (IEM), a debilitating pain disorder characterized by severe burning pain and redness of the distal extremities. NaV1.7 is preferentially expressed within peripheral sensory and sympathetic neurons. Here, we describe a novel NaV1.7 mutation in an 11-year old male with under-development of the limbs, recurrent attacks of burning pain with erythema and swelling in his feet and hands. Frequency and duration of the episodes gradually increased with age and relief by cooling became less effective. The patient′s sister had short stature and reported similar complaints of erythema and burning pain, but with less intensity. Genetic analysis revealed a novel missense mutation in NaV1.7 (2566 G > C; p.Gly856Arg) in both siblings. The G856R mutation, located within the DII/S4-S5 linker of the channel, substitutes a highly conserved non-polar glycine by a positively charged arginine. Voltage-clamp analysis of G856R currents reveals that the mutation hyperpolarizes (-11.2 mV) voltage-dependence of activation and slows deactivation but does not affect fast-inactivation, compared to wild-type channels. A mutation of Gly856 to aspartic acid was previously found in a family with limb pain and limb under-development, and its functional assessment showed hyperpolarized activation, depolarized fast-inactivation and increased ramp current. Structural modeling using the Rosetta computational modeling suite provides structural clues to the divergent effects of the substitution of Gly856 by arginine and aspartic acid. Although the proexcitatory changes in gating properties of G856R contribute to the pathophysiology of IEM, the link to limb under-development is not well understood.

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