Carriers of recessive WNK1/HSN2 mutations for hereditary sensory and autonomic neuropathy type 2 (HSAN2) are more sensitive to thermal stimuli.
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.
Loggia
Marco L
ML
Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec, Canada H3A 2B2. marco@nmr.mgh.harvard.edu
Bushnell
M Catherine
MC
Tétreault
Martine
M
Thiffault
Isabelle
I
Bhérer
Claude
C
Mohammed
Nazma K
NK
Kuchinad
Anil A
AA
Laferrière
Audrey
A
Dicaire
Marie-Josée
MJ
Loisel
Lina
L
Mogil
Jeffrey S
JS
Brais
Bernard
B
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
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