Altered NaV1.9 channel activity in two Tyr66Ser variant carriers with small fiber dysfunction

Area of Science:

• Neuroscience
• Genetics
• Channelopathies

Background:

• Voltage-gated sodium channels, including NaV1.9, are crucial for pain perception.
• Pathogenic variants in SCN11A (encoding NaV1.9) are linked to pain disorders.
• Small fiber neuropathy presents with sensory and autonomic symptoms.

Purpose of the Study:

• To describe a novel SCN11A variant (c.197A>C; p.(Tyr66Ser)) associated with small fiber neuropathy.
• To investigate the functional consequences of the p.(Tyr66Ser) variant on NaV1.9 channel activity.
• To present longitudinal data on disease progression in affected individuals.

Main Methods:

• Genetic analysis to identify and confirm the SCN11A variant in a mother-son duo.
• Quantitative sensory testing and electrophysiological studies (nerve conduction, pain-related evoked potentials).
• In vitro patch-clamp analysis and overexpression studies in mouse sensory neurons.

Main Results:

• The heterozygous SCN11A variant p.(Tyr66Ser) cosegregated with small fiber neuropathy.
• Patients exhibited progressive sensory deficits (hypoesthesia, hyperalgesia) and autonomic signs.
• Functional studies showed altered NaV1.9 channel gating, including shifts in activation/inactivation potentials and kinetics.

Conclusions:

• The SCN11A p.(Tyr66Ser) variant is a strong candidate cause of the observed small fiber neuropathy and pain phenotype.
• The variant leads to altered NaV1.9 channel function, contributing to hyperexcitability and sensory abnormalities.
• This study provides translational evidence linking a specific genetic variant to a complex pain disorder.