RESUMEN
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.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Neuropatías Hereditarias Sensoriales y Autónomas/genética , Hiperalgesia/genética , Mutación/genética , Proteínas Serina-Treonina Quinasas/genética , Adulto , Anciano , Análisis Mutacional de ADN , Femenino , Frecuencia de los Genes/genética , Genes Recesivos/genética , Pruebas Genéticas , Genotipo , Neuropatías Hereditarias Sensoriales y Autónomas/etnología , Neuropatías Hereditarias Sensoriales y Autónomas/metabolismo , Humanos , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatología , Péptidos y Proteínas de Señalización Intracelular , Masculino , Persona de Mediana Edad , Antígenos de Histocompatibilidad Menor , Proteínas del Tejido Nervioso/genética , Umbral del Dolor/fisiología , Quebec/etnología , Proteína Quinasa Deficiente en Lisina WNK 1RESUMEN
Charcot-Marie-Tooth polyneuropathies (CMT) are clinically and genetically heterogeneous. We describe a French-Canadian cluster of 17 recessive CMT cases belonging to 10 families with variable early-onset CMT and scoliosis. The patients demonstrate great intra- and inter-familial variability. Linkage analysis confirmed that all families are linked to CMT4C locus on chromosome 5q32 (multipoint LOD score of 9.06). Haplotype analysis suggests that two SH3TC2 mutations are present in this cohort. The majority of carrier chromosomes, 26 of 34 (76%), carry the c.2860C-->T mutation. Despite extensive sequencing, the other mutation is not yet uncovered. This study demonstrates that the clinical variability observed in CMT4C is due to other factors than the nature of the mutation and that further work is needed to better define the SH3TC2 gene to ensure the identification of all CMT4C mutations.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Predisposición Genética a la Enfermedad , Mutación/genética , Proteínas/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Canadá/epidemiología , Canadá/etnología , Enfermedad de Charcot-Marie-Tooth/epidemiología , Enfermedad de Charcot-Marie-Tooth/patología , Niño , Cromosomas Humanos Par 5 , Análisis por Conglomerados , Salud de la Familia , Femenino , Humanos , Péptidos y Proteínas de Señalización Intracelular , Masculino , Persona de Mediana Edad , Población BlancaRESUMEN
Senataxin recently was identified as the mutated gene in ataxia-oculomotor apraxia 2, which is characterized by ataxia, oculomotor apraxia, and increased alpha-fetoprotein levels. In this study, we evaluated 24 ataxic patients from 10 French-Canadian families. All cases have a homogeneous phenotype consisting of a progressive ataxia appearing between 2 and 20 (mean age, 14.8) years of age with associated dysarthria, saccadic ocular pursuit, distal amyotrophy, sensory and motor neuropathy, and increased alpha-fetoprotein levels but absence of oculomotor apraxia. Linkage disequilibrium was observed with markers in the ataxia-oculomotor apraxia 2 locus on chromosome 9q34. We have identified four mutations in senataxin in the French-Canadian population including two novel missense mutations: the 5927T-->G mutation changes the leucine encoded by codon 1976 to an arginine in the helicase domain (L1976R), and the 193G-->A mutation changes a glutamic acid encoded by codon 65 into a lysine in the N-terminal domain of the protein (E65K). The common L1976R mutation is shared by 17 of 20 (85%) carrier chromosomes. The study of this large French-Canadian cohort better defines the phenotype of this ataxia and presents two novel mutations in senataxin including the more common founder mutation in the French-Canadian population.