Mutations in the nervous system–specific HSN2 exon of WNK1 cause hereditary sensory neuropathy type II
Masoud Shekarabi, … , Mark Samuels, Guy A. Rouleau
Masoud Shekarabi, … , Mark Samuels, Guy A. Rouleau
Published June 2, 2008
Citation Information: J Clin Invest. 2008;118(7):2496-2505. https://doi.org/10.1172/JCI34088.
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Research Article Neuroscience

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

Abstract

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.

Authors

Masoud Shekarabi, Nathalie Girard, Jean-Baptiste Rivière, Patrick Dion, Martin Houle, André Toulouse, Ronald G. Lafrenière, Freya Vercauteren, Pascale Hince, Janet Laganiere, Daniel Rochefort, Laurence Faivre, Mark Samuels, Guy A. Rouleau

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Figure 3

Flanking junction sites of the novel alternatively spliced WNK1/HSN2 isoforms.

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Flanking junction sites of the novel alternatively spliced WNK1/HSN2 iso...
(A) RACE revealed that exon 8B was specifically spliced in some transcripts from mouse brain and spinal cord and the amino acids encoded by this mouse putative exon 8B of the longer Wnk1/Hsn2 isoform are highly conserved across species. A comparison of the amino acids encoded by the exon 8B ORF in the mouse was made with different species/taxa (chicken, Xenopus, and zebrafish), and greater than 95% residues are fully or highly conserved (an asterisk below the residues indicates those that are fully conserved across the different taxa/species). (B) The amino acid sequences of the splice acceptor and splice donor sites that flank the HSN2 exon are highly conserved across species. The regions in blue represent the sequence flanking HSN2, whereas the regions indicated in black are spliced out during mRNA maturation. Splice acceptor and donor sites are in bold characters. The sequences presented were obtained from the UCSC Genome Bioinformatics Browser ( http://genome.ucsc.edu).