Mutations in the nervous system-specific HSN2 exon of WNK1 cause hereditary sensory neuropathy type II

Centre of Excellence in Neuromics, University of Montreal, Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada.
Journal of Clinical Investigation (Impact Factor: 13.22). 07/2008; 118(7):2496-505. DOI: 10.1172/JCI34088
Source: PubMed


Hereditary sensory and autonomic neuropathy type II (HSANII) is an early-onset autosomal recessive disorder characterized by loss of perception to pain, touch, and heat due to a loss of peripheral sensory nerves. Mutations in hereditary sensory neuropathy type II (HSN2), a single-exon ORF originally identified in affected families in Quebec and Newfoundland, Canada, were found to cause HSANII. We report here that HSN2 is a nervous system-specific exon of the with-no-lysine(K)-1 (WNK1) gene. WNK1 mutations have previously been reported to cause pseudohypoaldosteronism type II but have not been studied in the nervous system. Given the high degree of conservation of WNK1 between mice and humans, we characterized the structure and expression patterns of this isoform in mice. Immunodetections indicated that this Wnk1/Hsn2 isoform was expressed in sensory components of the peripheral nervous system and CNS associated with relaying sensory and nociceptive signals, including satellite cells, Schwann cells, and sensory neurons. We also demonstrate that the novel protein product of Wnk1/Hsn2 was more abundant in sensory neurons than motor neurons. The characteristics of WNK1/HSN2 point to a possible role for this gene in the peripheral sensory perception deficits characterizing HSANII.

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Available from: Masoud Shekarabi,
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    • "In PHA2, recurrent myalgia and periodic paralysis had been recorded in the original description by Gordon [87]. Mutations in the WNK1 gene have been shown to be causative of the hereditary sensory neuropathy in a French family with PHA2 and defects in peripheral sensory perception; the authors demonstrated that WNK1 is highly expressed in the sensory components of peripheral nervous system and is associated with relaying sensory and nociceptive signals in sensory neurons [86] [88]. "
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    • "Previous work has cited exon 11 and exon 12 to be crucial exons in the regulation of WNK1 function and there splicing to be tightly regulated.34 Shekarabi et al.9 probedneuronal specific HSN2 exon with the “anti-WNK1/HSN2” antibody. One possible explanation why Shekarabi et al.9 did not observe an HSN2 detected WNK1 isoform above 230 kDa in spinal cord is that this novel 250 kDa WNK1 isoform is only induced in injury or stressed situations (e.g. "
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    • "The Wnk1 template spans from the 39 end of exon one to the 39 end of exon 6 of Wnk1 (accession number: NM_001199083.1, 1693–2497 bp) (Shekarabi et al., 2008) and the Wnk1/Hsn2 template was amplified from the 59 end of the Hsn2 exon to a Bgl I site in its ORF (4192–4626 bp). cRNAs were then produced in vitro from the DNA templates after linearization with Xba I or Sal I in the presence of T7 or SP6 Figure 1. "
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