RESUMEN
Hypertonia, which results from motor pathway defects in the central nervous system (CNS), is observed in numerous neurological conditions, including cerebral palsy, stroke, spinal cord injury, stiff-person syndrome, spastic paraplegia, dystonia and Parkinson disease. Mice with mutation in the hypertonic (hyrt) gene exhibit severe hypertonia as their primary symptom. Here we show that hyrt mutant mice have much lower levels of gamma-aminobutyric acid type A (GABA(A)) receptors in their CNS, particularly the lower motor neurons, than do wild-type mice, indicating that the hypertonicity of the mutants is likely to be caused by deficits in GABA-mediated motor neuron inhibition. We cloned the responsible gene, trafficking protein, kinesin binding 1 (Trak1), and showed that its protein product interacts with GABA(A) receptors. Our data implicate Trak1 as a crucial regulator of GABA(A) receptor homeostasis and underscore the importance of hyrt mice as a model for studying the molecular etiology of hypertonia associated with human neurological diseases.
Asunto(s)
Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Homeostasis , Hipertonía Muscular/metabolismo , Mutación/genética , Receptores de GABA-A/metabolismo , Proteínas Adaptadoras del Transporte Vesicular , Animales , Células del Asta Anterior/patología , Cromosomas de los Mamíferos/genética , Diazepam/farmacología , Electromiografía , Expresión Génica , Homocigoto , Humanos , Cuerpos de Inclusión/patología , Cuerpos de Inclusión/ultraestructura , Ratones , Datos de Secuencia Molecular , Hipertonía Muscular/genética , Hipertonía Muscular/patología , Músculo Esquelético/efectos de los fármacos , Mapeo Físico de Cromosoma , Puente/patología , Puente/ultraestructura , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
Mice that are homozygous for the autosomal recessive hydrocephaly with hop gait (hyh) mutation on Chromosome (Chr) 7 have congenital hydrocephalus characterized by an interhemispheric cyst arising from the third ventricle and agenesis of the corpus callosum. Analysis of more than 500 backcross and intercross progeny maps the hyh locus to proximal Chr 7, approximately 13 cM centromeric to its originally reported map position. Analysis of recombinants at several MIT microsatellite markers localized the hyh locus between D7Mit75 and D7Mit56. Development of several new SSLP markers allowed us to refine the hyh candidate interval to a region defined by the cone-rod homeobox ( Crx) gene proximally and D7Mit56 distally. A contig of yeast artificial chromosome (YAC) clones and bacterial artificial chromosome (BAC) clones spanning this entire region has been developed, and a number of potential candidate genes for hyh within this interval have been identified. Gene content is conserved between this region of mouse Chr 7 and human Chr 19q13.3. Physical mapping of the regions around D7Mit75 and D7Mit56 has also determined the order of a number of MIT markers that remain unresolved on the Mouse Genome Database (MGD) map. Our physical map and transcript map may be useful for positional cloning of genes in this unusually gene-rich region of the genome.
