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Trak1 mutation disrupts GABAA receptor homeostasis in hypertonic mice

Nature Genetics volume 38, pages 245–250 (2006)Cite this article

A Corrigendum to this article was published on 01 March 2006

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 γ-aminobutyric acid type A (GABAA) 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 GABAA receptors. Our data implicate Trak1 as a crucial regulator of GABAA receptor homeostasis and underscore the importance of hyrt mice as a model for studying the molecular etiology of hypertonia associated with human neurological diseases.

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Figure 1: Resting-state EMG activity in mouse gastrocnemius muscle.
Figure 2: Inclusion bodies in homozygous hyrt mutants.
Figure 3: Positional cloning of the Trak1 (KIAA1042) gene on mouse chromosome 9.
Figure 4: Tissue expression of mouse Trak1 mRNA in wild-type animals.
Figure 5: Marked reduction in the steady-state levels of GABAA receptors in homozygous hyrt mutants, as revealed by immunofluorescence and protein blotting.
Figure 6: Association between TRAK1 and GABAA receptors.

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Acknowledgements

We thank J. Estes for initial discovery of the mutant; W.B. Dobyns, F. Elsen, G. Ghadge, H.A. Jinnah, U. Kang, O. Lazarov, K. Millen, B. Popko, J.M. Ramirez, R. Roos, K. Sharma, S. Sisodia and M. Utset for observations of mutant mice and insightful discussions; and J. Brainer, Y.M. Chen, E. Chettiath, A. Lindgren, H. Macdonald, L. Moran, S. Rokosik, R. Tai and R. Samples for technical assistance. This work was supported in part by a center grant from the National Institutes of Health's National Center for Research Resources (to M.T.D.) and a Searle Scholarship and Burroughs Wellcome Career Award (to B.T.L.).

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Authors and Affiliations

  1. Howard Hughes Medical Institute and Department of Human Genetics, University of Chicago, Chicago, 60637, Illinois, USA

    Sandra L Gilbert, Li Zhang, Michele L Forster & Bruce T Lahn

  2. Department of Neurology, University of Chicago, Chicago, 60637, Illinois, USA

    Tamaki Iwase & Betty Soliven

  3. Department of Pathology, University of Chicago, Chicago, 60637, Illinois, USA

    Robert L Wollmann

  4. The Jackson Laboratory, Bar Harbor, 04609, Maine, USA

    Leah Rae Donahue, Hope O Sweet, Roderick T Bronson & Muriel T Davisson

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Correspondence to Bruce T Lahn.

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Supplementary information

Supplementary Fig. 1

cDNA sequence of mouse Trak1 (also known as KIAA1042). (PDF 16 kb)

Supplementary Table 1

Primer sequences. (PDF 9 kb)

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Gilbert, S., Zhang, L., Forster, M. et al. Trak1 mutation disrupts GABAA receptor homeostasis in hypertonic mice. Nat Genet 38, 245–250 (2006). https://doi.org/10.1038/ng1715

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