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.

Figure 1.

Group differences. A, Warmth detection thresholds were significantly lower in the carriers than in the controls (p < 0.001); N_carriers = 22 (11 females), N_{wild types} = 34 (17 females). B, Carriers displayed lower cool detection threshold than the wild types (p < 0.03); N_carriers = 21 (10 female), N_{wild types} = 34 (16 females). C, Carriers tended to display lower cold detection thresholds than the wild types (p = 0.095); N_carriers = 22 (11 females), N_{wild types} = 35 (17 females). Raw data are displayed for each group. Circles, Carriers (white: c.918–919insA; black: c.934C→T); diamonds, wild types. Bars represent mean ± SD.

Figure 2.

Correlations with age. A, In the wild types (right), the correlation between WD thresholds and age was positive but not statistically significant (r = 0.16, p = 0.37). In the carriers (left), this correlation displayed a trend in the opposite direction (r = −0.39, p = 0.08). These two correlations were statistically different, p = 0.054. B, Cool detection thresholds increased with age in the wild types (r = 0.34, p = 0.05; right), but not in the carriers (r = 0.27, p = 0.24; left). However, these correlations were not statistically different (p = 0.82). See the Figure 1 legend for more information. C, The matched-pair analysis showed that the differences between the WD thresholds of the carriers and those of gender- and sex-matched wild types significantly increased with age (Spearman r = 0.76, p = 0.02). Squares, Male; triangles, female.