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The Journal of Neuroscience, February 18, 2009, 29(7):2162-2166; doi:10.1523/JNEUROSCI.4633-08.2009

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Brief Communications
Carriers of Recessive WNK1/HSN2 Mutations for Hereditary Sensory and Autonomic Neuropathy Type 2 (HSAN2) Are More Sensitive to Thermal Stimuli

Marco L. Loggia,^1,2 M. Catherine Bushnell,^1,3,4 Martine Tétreault,⁶ Isabelle Thiffault,⁶ Claude Bhérer,⁶ Nazma K. Mohammed,¹ Anil A. Kuchinad,¹ Audrey Laferrière,¹ Marie-Josée Dicaire,⁶ Lina Loisel,⁶ Jeffrey S. Mogil,^1,5 and Bernard Brais⁶

¹Alan Edwards Centre for Research on Pain and Departments of ²Neurology and Neurosurgery, ³Anesthesia, ⁴Dentistry, and ⁵Psychology, McGill University, Montreal, Quebec, Canada H3A 2B2, and ⁶Laboratoire de neurogénétique de la motricité, Centre d'Excellence en Neuromique de l'Université de Montréal, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada H2L 4M1

Correspondence should be addressed to Dr. Marco L. Loggia at his present address: Athinoula A. Martinos Center for Biomedical Imaging, Building 149, 13th Street, Room 2663, Charlestown, MA 02129-2000. Email: marco{at}nmr.mgh.harvard.edu

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.

Key words: genetics; phenotype; human; psychophysics; heat; cold; pain

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Received Sept. 26, 2008; revised Dec. 17, 2008; accepted Dec. 30, 2008.

Correspondence should be addressed to Dr. Marco L. Loggia at his present address: Athinoula A. Martinos Center for Biomedical Imaging, Building 149, 13th Street, Room 2663, Charlestown, MA 02129-2000. Email: marco{at}nmr.mgh.harvard.edu

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