Fischer TZ

Tetra Therapeutics (United States)

ORCID Profile OpenAlex Profile
3
EM Publications
20
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(1,915 citations, 57 total works)

Research Topics

Parkinson's Disease Mechanisms and Treatments (13) Lysosomal Storage Disorders Research (13) Pain Mechanisms and Treatments (11) Botulinum Toxin and Related Neurological Disorders (10) Multiple Sclerosis Research Studies (5)

Erythromelalgia Publications

Familial pain syndromes from mutations of the NaV1.7 sodium channel.

Fischer TZ, Waxman SG
Annals of the New York Academy of Sciences •

The literature currently suggests that voltage-gated sodium channels play a major role in the pathogenesis of neuropathic pain. Alterations in the expression and targeting of specific sodium channels within injured dorsal root ganglia neurons appear to predispose the neurons to abnormal firing properties, allowing for the development of neuropathic pain. Mutations of one particular sodium channel (Na(v)1.7) have been shown to cause inherited neuropathic pain in humans, specifically in erythromelalgia and paroxysmal extreme pain disorder. Inherited erythromelalgia is the first human pain syndrome to be understood at a molecular level, having been linked to gain-of-function mutations of Na(v)1.7. Conversely, a loss-of-function of the Na(v)1.7 channel can produce channelopathy-associated insensitivity to pain. Therefore, the Na(v)1.7 channel may provide a unique target for the pharmacotherapy of pain in humans. In this review article we summarize current knowledge regarding several different disease manifestations arising from changes within the Na(v)1.7 channel.

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Mutations at opposite ends of the DIII/S4-S5 linker of sodium channel Na V 1.7 produce distinct pain disorders.

Cheng X, Dib-Hajj SD, Tyrrell L, Wright DA, Fischer TZ , et al.
Molecular pain •

Two groups of gain-of-function mutations in sodium channel NaV1.7, which are expressed in dorsal root ganglion (DRG) neurons, produce two clinically-distinct pain syndromes - inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD). IEM is characterized by intermittent burning pain and skin redness in the feet or hands, triggered by warmth or mild exercise, while PEPD is characterized by episodes of rectal, ocular and mandibular pain accompanied with skin flushing, triggered by bowel movement and perianal stimulation. Most of the IEM mutations are located within channel domains I and II, while most of the PEPD mutations are located within domains III and IV. The structural dichotomy parallels the biophysical effects of the two types of mutations, with IEM mutations shifting voltage-dependence of NaV1.7 activation in a hyperpolarized direction, and PEPD mutations shifting fast-inactivation of NaV1.7 in a depolarized direction. While four IEM and four PEPD mutations are located within cytoplasmic linkers joining segments 4 and 5 (S4-S5 linkers) in the different domains (IEM: domains I and II; PEPD: domains III and IV), no S4-S5 linker has been reported to house both IEM and PEPD mutations thus far. We have identified a new IEM mutation P1308L within the C-terminus of the DIII/S4-S5 linker of NaV1.7, ten amino acids from a known PEPD mutation V1298F which is located within the N-terminus of this linker. We used voltage-clamp to compare the biophysical properties of the two mutant channels and current-clamp to study their effects on DRG neuron excitability. We confirm that P1308L and V1298F behave as prototypical IEM and PEPD mutations, respectively. We also show that DRG neurons expressing either P1308L or V1298F become hyperexcitable, compared to DRG neurons expressing wild-type channels. Our results provide evidence for differential roles of the DIII/S4-S5 linker N- and C-termini in channel inactivation and activation, and demonstrate the cellular basis for pain in patients carrying these mutations.

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A novel Nav1.7 mutation producing carbamazepine-responsive erythromelalgia.

Fischer TZ, Gilmore ES, Estacion M, Eastman E, Taylor S , et al.
Annals of neurology •

Human and animal studies have shown that Na(v)1.7 sodium channels, which are preferentially expressed within nociceptors and sympathetic neurons, play a major role in inflammatory and neuropathic pain. Inherited erythromelalgia (IEM) has been linked to gain-of-function mutations of Na(v)1.7. We now report a novel mutation (V400M) in a three-generation Canadian family in which pain is relieved by carbamazepine (CBZ). We extracted genomic DNA from blood samples of eight members of the family, and the sequence of SCN9A coding exons was compared with the reference Na(v)1.7 complementary DNA. Wild-type Na(v)1.7 and V400M cell lines were then analyzed using whole-cell patch-clamp recording for changes in activation, deactivation, steady-state inactivation, and ramp currents. Whole-cell patch-clamp studies of V400M demonstrate changes in activation, deactivation, steady-state inactivation, and ramp currents that can produce dorsal root ganglia neuron hyperexcitability that underlies pain in these patients. We show that CBZ, at concentrations in the human therapeutic range, normalizes the voltage dependence of activation and inactivation of this inherited erythromelalgia mutation in Na(v)1.7 but does not affect these parameters in wild-type Na(v)1.7. Our results demonstrate a normalizing effect of CBZ on mutant Na(v)1.7 channels in this kindred with CBZ-responsive inherited erythromelalgia. The selective effect of CBZ on the mutant Na(v)1.7 channel appears to explain the ameliorative response to treatment in this kindred. Our results suggest that functional expression and pharmacological studies may provide mechanistic insights into hereditary painful disorders.

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