Key result
The rare SCN10A missense variant p.V1287I in NaV1.8 confers mixed loss- and gain-of-function characteristics that render sensory neurons hyperexcitable, likely causing the patient's peripheral temperature dysregulation.
Why the study?
Pathogenic variants in SCN10A (NaV1.8) cause peripheral pain and autonomic dysfunction, but the functional impact of novel variants presenting with temperature dysregulation and paresthesias required investigation.
Case Report (n=1)
The NaV1.8 p.V1287I variant alters channel gating properties and increases sensory neuron excitability, suggesting a causal role in peripheral temperature dysregulation and nonpainful paresthesias.
The voltage-gated sodium channel Na V 1.8 is prominently expressed in the soma and axons of small-caliber sensory neurons, and pathogenic variants of the corresponding gene SCN10A are associated with peripheral pain and autonomic dysfunction. While most disease-associated SCN10A variants confer gain-of-function properties to Na V 1.8, resulting in hyperexcitability of sensory neurons, a few affect afferent excitability through a loss-of-function mechanism. Using whole-exome sequencing, we here identify a rare heterozygous SCN10A missense variant resulting in alteration p.V1287I in Na V 1.8 in a patient with a 15-year history of progressively worsening temperature dysregulation in the distal extremities, particularly in the feet. Further symptoms include increasingly intensifying tingling and numbness in the fingers and increased sweating. To assess the impact of p.V1287I on channel function, we performed voltage-clamp recordings demonstrating that the alteration confers loss- and gain-of-function characteristics to Na V 1.8 characterized by a right-shifted voltage dependence of channel activation and inactivation. Current-clamp recordings from transfected mouse dorsal root ganglion neurons further revealed that Na V 1.8-V1287I channels broaden the action potentials of sensory neurons and increase their firing rates in response to depolarizing current stimulations, indicating a gain-of-function mechanism of the variant at the cellular level in a heterozygous setting. The data support the hypothesis that the properties of Na V 1.8 p.V1287I are causative for the patient’s symptoms and that nonpainful peripheral paresthesias should be considered part of the clinical spectrum of Na V 1.8-associated disorders.
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Loose et al. (2023) conducted a case report in Peripheral temperature dysregulation (Small fiber neuropathy) (n=1). SCN10A missense variant p.V1287I vs. Wild-type NaV1.8 was evaluated on Channel activation and inactivation properties. The rare SCN10A missense variant p.V1287I in NaV1.8 confers mixed loss- and gain-of-function characteristics that render sensory neurons hyperexcitable, likely causing the patient's peripheral temperature dysregulation.
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