RESUMEN
Although many genes that predispose for epilepsy in humans have been determined, those that underlie the classical syndromes of idiopathic generalized epilepsy (IGE) have yet to be identified. We report that an Ala322Asp mutation in GABRA1, encoding the alpha1 subunit of the gamma-aminobutyric acid receptor subtype A (GABA(A)), is found in affected individuals of a large French Canadian family with juvenile myoclonic epilepsy. Compared with wildtype receptors, GABA(A) receptors that contain the mutant subunit show a lesser amplitude of GABA-activated currents in vitro, indicating that seizures may result from loss of function of this inhibitory ligand-gated channel. Our results confirm that mutation of GABRA1 predisposes towards a common idiopathic generalized epilepsy syndrome in humans.
Asunto(s)
Mutación Missense , Epilepsia Mioclónica Juvenil/genética , Receptores de GABA-A/genética , Adolescente , Adulto , Secuencia de Aminoácidos , Sustitución de Aminoácidos/genética , Niño , Preescolar , Epilepsia Generalizada/etiología , Epilepsia Generalizada/genética , Genes Dominantes , Predisposición Genética a la Enfermedad , Humanos , Datos de Secuencia Molecular , Mutación Missense/genética , Epilepsia Mioclónica Juvenil/etiología , LinajeRESUMEN
BACKGROUND: Genes are involved in the etiology of restless legs syndrome, a common sensorimotor disorder. OBJECTIVES: To replicate and to further characterize our previously reported chromosome 12q linkage results. DESIGN: Family linkage study. SETTING AND PARTICIPANTS: A total of 276 individuals from 19 families have been examined using a selection of markers spanning the identified candidate interval on chromosome 12q. RESULTS: Two-point analyses of individual pedigrees indicated that 5 kindreds were consistent with linkage to chromosome 12q. When considering these 5 pedigrees along with the family in which linkage was originally reported, we observed a maximum 2-point logarithm-of-odds score of 5.67 (at theta = 0.10; for marker D12S1636; autosomal recessive) and a maximum multipoint logarithm-of-odds score of 8.84 between the interval defined by markers D12S326 and D12S304. Furthermore, our results also suggest the presence of heterogeneity in restless legs syndrome as linkage was formally excluded across the region in 6 pedigrees. Interestingly, significantly higher periodic leg movements during sleep indices were observed for all probands with restless legs syndrome from linked families. CONCLUSIONS: These results support the presence of a major restless legs syndrome-susceptibility locus on chromosome 12q, which has been designated as RLS1, and also suggest that at least one additional locus may be involved in the origin of this prevalent condition.
Asunto(s)
Cromosomas Humanos Par 12/genética , Ligamiento Genético/genética , Marcadores Genéticos/genética , Predisposición Genética a la Enfermedad/genética , Síndrome de las Piernas Inquietas/genética , Mapeo Cromosómico , Análisis Mutacional de ADN , Femenino , Pruebas Genéticas , Humanos , Escala de Lod , Masculino , Linaje , Síndrome de las Piernas Inquietas/fisiopatología , Trastornos del Sueño-Vigilia/genética , Trastornos del Sueño-Vigilia/fisiopatologíaRESUMEN
STUDY OBJECTIVES: A relatively high prevalence of restless legs syndrome symptoms has been recently reported in a substantial proportion of patients affected with spinocerebellar ataxia type 3. Our aim was to investigate whether there is a common genetic etiology between restless legs syndrome and spinocerebellar ataxia type 3. DESIGN: Systematic differences in the number of spinocerebellar ataxia type 3 trinucleotide repeat were investigated by means of an association study. The relationship between the size of the expanded alleles and several clinical features was also considered. PARTICIPANTS AND SETTING: 125 extensively characterized restless legs syndrome patients compared with 188 healthy controls matched for ethnic background. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: No CAG repeat expansions in the pathologic or intermediate range were detected in any of the examined subjects, including patients and controls. A similar allelic distribution was observed in both groups (Mann-Whitney U test = 78406; P = 0.99). Moreover, stratification analyses of the patients' samples according to different clinical and polysomnographic variables disclosed no significant differences. CONCLUSIONS: These results do not provide evidence toward an involvement of large CAG trinucleotide expansions at the spinocerebellar ataxia type 3 locus in idiopathic restless legs syndrome.