Expression pattern analysis and characterization of the hereditary sensory and autonomic neuropathy 2 A (HSAN2A) gene with no lysine kinase (WNK1) in human dorsal root ganglion.

Autor: Sapio MR; Department of Perioperative Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA., King DM; Department of Perioperative Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA., Staedtler ES; Department of Perioperative Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA., Maric D; National Institute of Neurological Disorders and Stroke, Flow and Imaging Cytometry Core Facility, Bethesda, MD 20892, USA., Jahanipour J; National Institute of Neurological Disorders and Stroke, Flow and Imaging Cytometry Core Facility, Bethesda, MD 20892, USA., Kurochkina NA; The School of Theoretical Modeling, Washington, DC 20006, USA., Manalo AP; Department of Perioperative Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA., Ghetti A; Anabios, Corporation, San Diego, CA 92109, USA., Mannes AJ; Department of Perioperative Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA., Iadarola MJ; Department of Perioperative Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: michael.iadarola@nih.gov.
Jazyk: angličtina
Zdroj: Experimental neurology [Exp Neurol] 2023 Dec; Vol. 370, pp. 114552. Date of Electronic Publication: 2023 Oct 02.
DOI: 10.1016/j.expneurol.2023.114552
Abstrakt: Inherited painless neuropathies arise due to genetic insults that either block the normal signaling of or destroy the sensory afferent neurons in the dorsal root ganglion (DRG) responsible for transducing noxious stimuli. Complete loss of these neurons leads to profound insensitivity to all sensory modalities including pain. Hereditary sensory and autonomic neuropathy type 2 (HSNAII) is a rare genetic neuropathy characterized by a progressive distal early onset sensory loss. This syndrome is caused by autosomal recessive mutations in the with-no-lysine protein kinase 1 (WNK1) serine-threonine kinase gene. Of interest, disease-associated mutations are found in the large exon, termed "HSN2," which encodes a 498 amino acid domain C-terminal to the kinase domain. These mutations lead to truncation of the HSN2-containing proteins through the addition of an early stop codon (nonsense mutation) leading to loss of the C-terminal domains of this large protein. The present study evaluates the transcripts, gene structure, and protein structure of HSN2-containing WNK1 splice variants in DRG and spinal cord in order to establish the basal expression patterns of WNK1 and HSN2-containing WNK1 splice variants using multiplex fluorescent situ hybridization. We hypothesized that these transcripts would be enriched in pain-sensing DRG neurons, and, potentially, that enrichment in nociceptive neurons was responsible for the painless phenotypes observed. However, our in-depth analyses revealed that the HSN2-WNK1 splice variants were ubiquitously expressed but were not enriched in tachykinin 1-expressing C-fiber neurons, a class of neurons with a highly nociceptive character. We subsequently identified other subpopulations of DRG neurons with higher levels of HSN2-WNK1 expression, including mechanosensory large fibers. These data are inconsistent with the hypothesis that this transcript is enriched in nociceptive fibers, and instead suggest it may be related to general axon maintenance, or that nociceptive fibers are more sensitive to the genetic insult. These findings clarify the molecular and cellular expression pattern of this painless neuropathy gene in human tissue.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Disclosure statement: Andre Ghetti is an employee and shareholder of AnaBios Corporation.
(Published by Elsevier Inc.)
Databáze: MEDLINE
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