RESUMEN
Using exome sequencing and linkage analysis in a three-generation family with a unique dominant myoclonus-dystonia-like syndrome with cardiac arrhythmias, we identified a mutation in the CACNA1B gene, coding for neuronal voltage-gated calcium channels CaV2.2. This mutation (c.4166G>A;p.Arg1389His) is a disruptive missense mutation in the outer region of the ion pore. The functional consequences of the identified mutation were studied using whole-cell and single-channel patch recordings. High-resolution analyses at the single-channel level showed that, when open, R1389H CaV2.2 channels carried less current compared with WT channels. Other biophysical channel properties were unaltered in R1389H channels including ion selectivity, voltage-dependent activation or voltage-dependent inactivation. CaV2.2 channels regulate transmitter release at inhibitory and excitatory synapses. Functional changes could be consistent with a gain-of-function causing the observed hyperexcitability characteristic of this unique myoclonus-dystonia-like syndrome associated with cardiac arrhythmias.
Asunto(s)
Canales de Calcio Tipo N/genética , Trastornos Distónicos/genética , Estudios de Asociación Genética , Mutación , Potenciales de Acción , Canales de Calcio Tipo N/metabolismo , Señalización del Calcio , Trastornos Distónicos/diagnóstico , Exoma , Femenino , Ligamiento Genético , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Técnicas de Placa-Clamp , Linaje , FenotipoRESUMEN
Primrose syndrome and 3q13.31 microdeletion syndrome are clinically related disorders characterized by tall stature, macrocephaly, intellectual disability, disturbed behavior and unusual facial features, with diabetes, deafness, progressive muscle wasting and ectopic calcifications specifically occurring in the former. We report that missense mutations in ZBTB20, residing within the 3q13.31 microdeletion syndrome critical region, underlie Primrose syndrome. This finding establishes a genetic link between these disorders and delineates the impact of ZBTB20 dysregulation on development, growth and metabolism.
Asunto(s)
Anomalías Múltiples/genética , Calcinosis/genética , Enfermedades del Oído/genética , Discapacidad Intelectual/genética , Atrofia Muscular/genética , Mutación Missense , Proteínas del Tejido Nervioso/genética , Factores de Transcripción/genética , Secuencia de Aminoácidos , Secuencia de Bases , Línea Celular , Deleción Cromosómica , Cromosomas Humanos Par 3 , Discapacidades del Desarrollo/genética , Femenino , Predisposición Genética a la Enfermedad , Células HEK293 , Humanos , Masculino , Modelos Moleculares , Datos de Secuencia Molecular , Homología de Secuencia de AminoácidoRESUMEN
Growth factors, such as ciliary neurotrophic factor (CNTF), have been implicated in neuronal survival and proliferation. About 2% of the human population is homozygous for a polymorphism that induces truncated and biologically inactive CNTF but does not obviously change the phenotype. In a population of patients with hereditary neuropathy, a higher rate of the CNTF null mutation would indicate greater susceptibility for clinically significant disease, and a recent report attributes early onset and rapid deterioration in a case of familial ALS (FALS) to this mutation. We have, therefore, genotyped the CNTF polymorphism in a large group of patients with CMT 1a, HNPP, sporadic ALS, in one pedigree with FALS, and controls. All groups exhibited a similar distribution of the polymorphism. We conclude that absence of CNTF does not increase susceptibility for these disorders and confirm that it does not affect onset and course of familial and sporadic ALS.
