Peripheral temperature dysregulation associated with functionally altered Na_V1.8 channels.

Area of Science:

• Neuroscience
• Genetics
• Ion Channel Physiology

Background:

• Voltage-gated sodium channel Na_V1.8, encoded by SCN10A, is crucial for sensory neuron function.
• SCN10A variants are linked to peripheral pain and autonomic dysfunction, often via gain-of-function mechanisms.
• Loss-of-function SCN10A variants are less common but impact neuronal excitability.

Purpose of the Study:

• To investigate a rare SCN10A missense variant (p.V1287I) in Na_V1.8 found in a patient with peripheral sensory and autonomic symptoms.
• To determine the functional consequences of the Na_V1.8 p.V1287I variant on channel activity and neuronal excitability.

Main Methods:

• Whole-exome sequencing to identify the SCN10A variant.
• Voltage-clamp electrophysiology to assess channel gating properties (activation, inactivation).
• Current-clamp recordings in mouse dorsal root ganglion neurons to evaluate action potential characteristics and firing rates.

Main Results:

• The Na_V1.8 p.V1287I variant exhibited dual loss- and gain-of-function properties, with altered voltage dependence of activation and inactivation.
• In transfected neurons, the variant broadened action potentials and increased firing rates, indicating gain-of-function in a heterozygous state.
• These cellular effects correlate with the patient's symptoms of temperature dysregulation, tingling, numbness, and hyperhidrosis.

Conclusions:

• The Na_V1.8 p.V1287I variant is pathogenic and causative for the patient's complex peripheral neuropathy.
• This case expands the clinical spectrum of SCN10A-associated disorders to include non-painful peripheral paresthesias.
• Understanding Na_V1.8 variant function is critical for diagnosing and managing sensory neuron disorders.