title: Carriers of recessive WNK1/HSN2 mutations for hereditary sensory and autonomic neuropathy type 2 (HSAN2) are more sensitive to thermal stimuli.
abstract: Hereditary sensory and autonomic neuropathy type 2 (HSAN2) is a rare recessive genetic disorder characterized by severe sensory loss affecting the tactile, thermal and nociceptive modalities. Although heterozygous carriers of nonsense mutations in the HSN2 gene, called with-no-lysine(K)-1 (WNK1), do not develop the disease, historical and experimental evidence suggests that these individuals might perceive somatosensory stimuli differently from others. Using the method-of-limits, we assessed the thresholds for warmth detection, cool detection, heat pain and cold pain in 25 mutation carriers and 35 controls. In group analyses, carriers displayed significantly lower warmth (p<0.001) and cool (p<0.05) difference thresholds, and also tended to report cold pain at higher temperatures (p=0.095), than controls. Similarly, matched-pair analyses showed that carriers are significantly more sensitive to warm stimuli (p<0.01) and cold pain stimuli (p<0.05), and tend to be more sensitive to cool stimuli (p=0.11). Furthermore, the differences between the warmth detection thresholds of the carriers and those of gender- and sex-matched wild types significantly increased with age (r=0.76, p=0.02), and in carriers cool detection thresholds did not increase with age (r=0.27, p=0.24) as expected and observed in controls (r=0.34, p=0.05). This study demonstrates that the carriers of a recessive mutation for HSAN2 display greater sensitivity to innocuous thermal stimuli, as well as for cold pain, suggesting a possible environmental adaptive advantage of the heterozygous state.
authors.affiliation: Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec, Canada H3A 2B2. marco@nmr.mgh.harvard.edu
authors.forename: Marco L
authors.initials: ML
authors.lastname: Loggia
authors.forename: M Catherine
authors.initials: MC
authors.lastname: Bushnell
authors.forename: Martine
authors.initials: M
authors.lastname: Tétreault
authors.forename: Isabelle
authors.initials: I
authors.lastname: Thiffault
authors.forename: Claude
authors.initials: C
authors.lastname: Bhérer
authors.forename: Nazma K
authors.initials: NK
authors.lastname: Mohammed
authors.forename: Anil A
authors.initials: AA
authors.lastname: Kuchinad
authors.forename: Audrey
authors.initials: A
authors.lastname: Laferrière
authors.forename: Marie-Josée
authors.initials: MJ
authors.lastname: Dicaire
authors.forename: Lina
authors.initials: L
authors.lastname: Loisel
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Mogil
authors.forename: Bernard
authors.initials: B
authors.lastname: Brais
mesh_terms: D000328:Adult; D000368:Aged; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D005808:Genes, Recessive / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D009477:Hereditary Sensory and Autonomic Neuropathies / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006930:Hyperalgesia / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics; D017288:Pain Threshold / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011792:Quebec / Q000208:ethnology; D000076204:WNK Lysine-Deficient Protein Kinase 1
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D015778:Minor Histocompatibility Antigens; D009419:Nerve Tissue Proteins; D017346:Protein Serine-Threonine Kinases; D000076204:WNK Lysine-Deficient Protein Kinase 1; C498743:WNK1 protein, human