Trak1 mutation disrupts GABA(A) receptor homeostasis in hypertonic mice

Nat Genet. 2006 Feb;38(2):245-50. doi: 10.1038/ng1715. Epub 2005 Dec 25.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport
  • Animals
  • Anterior Horn Cells / pathology
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism*
  • Chromosomes, Mammalian / genetics
  • Diazepam / pharmacology
  • Electromyography
  • Gene Expression
  • Homeostasis*
  • Homozygote
  • Humans
  • Inclusion Bodies / pathology
  • Inclusion Bodies / ultrastructure
  • Mice
  • Molecular Sequence Data
  • Muscle Hypertonia / genetics
  • Muscle Hypertonia / metabolism*
  • Muscle Hypertonia / pathology
  • Muscle, Skeletal / drug effects
  • Mutation / genetics*
  • Physical Chromosome Mapping
  • Pons / pathology
  • Pons / ultrastructure
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, GABA-A / metabolism*


  • Adaptor Proteins, Vesicular Transport
  • Carrier Proteins
  • RNA, Messenger
  • Receptors, GABA-A
  • Trak1 protein, mouse
  • Diazepam

Associated data

  • GENBANK/AB028965
  • GENBANK/BC058971