Carriers of recessive WNK1/HSN2 mutations for hereditary sensory and autonomic neuropathy type 2 (HSAN2) are more sensitive to thermal stimuli

J Neurosci. 2009 Feb 18;29(7):2162-6. doi: 10.1523/JNEUROSCI.4633-08.2009.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • DNA Mutational Analysis
  • Female
  • Gene Frequency / genetics
  • Genes, Recessive / genetics
  • Genetic Predisposition to Disease / genetics*
  • Genetic Testing
  • Genotype
  • Hereditary Sensory and Autonomic Neuropathies / ethnology
  • Hereditary Sensory and Autonomic Neuropathies / genetics*
  • Hereditary Sensory and Autonomic Neuropathies / metabolism
  • Humans
  • Hyperalgesia / genetics*
  • Hyperalgesia / metabolism
  • Hyperalgesia / physiopathology
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Middle Aged
  • Minor Histocompatibility Antigens
  • Mutation / genetics*
  • Nerve Tissue Proteins / genetics
  • Pain Threshold / physiology
  • Protein-Serine-Threonine Kinases / genetics*
  • Quebec / ethnology
  • WNK Lysine-Deficient Protein Kinase 1

Substances

  • Intracellular Signaling Peptides and Proteins
  • Minor Histocompatibility Antigens
  • Nerve Tissue Proteins
  • Protein-Serine-Threonine Kinases
  • WNK Lysine-Deficient Protein Kinase 1
  • WNK1 protein, human