title: Trak1 mutation disrupts GABA(A) receptor homeostasis in hypertonic mice.
abstract: 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.
authors.affiliation: Howard Hughes Medical Institute and Department of Human Genetics, University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Gilbert
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Michele L
authors.initials: ML
authors.lastname: Forster
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Anderson
authors.forename: Tamaki
authors.initials: T
authors.lastname: Iwase
authors.forename: Betty
authors.initials: B
authors.lastname: Soliven
authors.forename: Leah Rae
authors.initials: LR
authors.lastname: Donahue
authors.forename: Hope O
authors.initials: HO
authors.lastname: Sweet
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.forename: Muriel T
authors.initials: MT
authors.lastname: Davisson
authors.forename: Robert L
authors.initials: RL
authors.lastname: Wollmann
authors.forename: Bruce T
authors.initials: BT
authors.lastname: Lahn
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D000870:Anterior Horn Cells / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D033481:Chromosomes, Mammalian / Q000235:genetics; D003975:Diazepam / Q000494:pharmacology; D004576:Electromyography; D015870:Gene Expression; D006706:Homeostasis; D006720:Homozygote; D006801:Humans; D002479:Inclusion Bodies / Q000473:pathology / Q000648:ultrastructure; D051379:Mice; D008969:Molecular Sequence Data; D009122:Muscle Hypertonia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018482:Muscle, Skeletal / Q000187:drug effects; D009154:Mutation / Q000235:genetics*; D020161:Physical Chromosome Mapping; D011149:Pons / Q000473:pathology / Q000648:ultrastructure; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D002352:Carrier Proteins; D012333:RNA, Messenger; D011963:Receptors, GABA-A; C509169:Trak1 protein, mouse; D003975:Diazepam