Yuan JH

Kagoshima University

ORCID Profile OpenAlex Profile
2
EM Publications
19
h-index
(1,044 citations, 83 total works)

Research Topics

Hereditary Neurological Disorders (37) Genetic Neurodegenerative Diseases (21) Neurological diseases and metabolism (17) Mitochondrial Function and Pathology (13) RNA regulation and disease (9)

Erythromelalgia Publications

Genetic, electrophysiological, and pathological studies on patients with SCN9A-related pain disorders.

Yuan JH, Cheng X, Matsuura E, Higuchi Y, Ando M , et al.
Journal of the peripheral nervous system : JPNS •

Voltage-gated sodium channel Nav1.7, encoded by the SCN9A gene, has been linked to diverse painful peripheral neuropathies, represented by the inherited erythromelalgia (EM) and paroxysmal extreme pain disorder (PEPD). The aim of this study was to determine the genetic etiology of patients experiencing neuropathic pain, and shed light on the underlying pathogenesis. We enrolled eight patients presenting with early-onset painful peripheral neuropathies, consisting of six cases exhibiting EM/EM-like disorders and two cases clinically diagnosed with PEPD. We conducted a gene-panel sequencing targeting 18 genes associated with hereditary sensory and/or autonomic neuropathy. We introduced novel SCN9A mutation (F1624S) into a GFP-2A-Nav1.7rNS plasmid, and the constructs were then transiently transfected into HEK293 cells. We characterized both wild-type and F1624S Nav1.7 channels using an automated high-throughput patch-clamp system. From two patients displaying EM-like/EM phenotypes, we identified two SCN9A mutations, I136V and P1308L. Among two patients diagnosed with PEPD, we found two additional mutations in SCN9A, F1624S (novel) and A1632E. Patch-clamp analysis of Nav1.7-F1624S revealed depolarizing shifts in both steady-state fast inactivation (17.4 mV, p < .001) and slow inactivation (5.5 mV, p < .001), but no effect on channel activation was observed. Clinical features observed in our patients broaden the phenotypic spectrum of SCN9A-related pain disorders, and the electrophysiological analysis enriches the understanding of genotype-phenotype association caused by Nav1.7 gain-of-function mutations.

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variants and pain modulation: a missense variant in Kv7.3 contributes to pain resilience.

Yuan JH, Estacion M, Mis MA, Tanaka BS, Schulman BR , et al.
Brain communications •

There is a pressing need for understanding of factors that confer resilience to pain. Gain-of-function mutations in sodium channel Nav1.7 produce hyperexcitability of dorsal root ganglion neurons underlying inherited erythromelalgia, a human genetic model of neuropathic pain. While most individuals with erythromelalgia experience excruciating pain, occasional outliers report more moderate pain. These differences in pain profiles in blood-related erythromelalgia subjects carrying the same pain-causative Nav1.7 mutation and markedly different pain experience provide a unique opportunity to investigate potential genetic factors that contribute to inter-individual variability in pain. We studied a patient with inherited erythromelalgia and a Nav1.7 mutation (c.4345T>G, p. F1449V) with severe pain as is characteristic of most inherited erythromelalgia patients, and her mother who carries the same Nav1.7 mutation with a milder pain phenotype. Detailed six-week daily pain diaries of pain episodes confirmed their distinct pain profiles. Electrophysiological studies on subject-specific induced pluripotent stem cell-derived sensory neurons from each of these patients showed that the excitability of these cells paralleled their pain phenotype. Whole-exome sequencing identified a missense variant (c.2263C>T, p. D755N) in (Kv7.3) in the pain resilient mother. Voltage-clamp recordings showed that co-expression of Kv7.2-wild type (WT)/Kv7.3-D755N channels produced larger M-currents than that of Kv7.2-WT/Kv7.3-WT. The difference in excitability of the patient-specific induced pluripotent stem cell-derived sensory neurons was mimicked by modulating M-current levels using the dynamic clamp and a model of the mutant Kv7.2-WT/Kv7.3-D755N channels. These results show that a 'pain-in-a-dish' model can be used to explicate genetic contributors to pain, and confirm that variants can confer pain resilience via an effect on peripheral sensory neurons.

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