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Science 21 July 1995:
Vol. 269. no. 5222, pp. 407 - 410
DOI: 10.1126/science.7618107
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Articles

Science, Vol 269, Issue 5222, 407-410
Copyright © 1995 by American Association for the Advancement of Science

articles

Inactivation of the mouse Huntington's disease gene homolog Hdh

MP Duyao, AB Auerbach, A Ryan, F Persichetti, GT Barnes, SM McNeil, P Ge, JP Vonsattel, JF Gusella, AL Joyner, and al. et

Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown 02129, USA.

Huntington's disease (HD) is a dominant neurodegenerative disorder caused by expansion of a CAG repeat in the gene encoding huntingtin, a protein of unknown function. To distinguish between "loss of function" and "gain of function" models of HD, the murine HD homolog Hdh was inactivated by gene targeting. Mice heterozygous for Hdh inactivation were phenotypically normal, whereas homozygosity resulted in embryonic death. Homozygotes displayed abnormal gastrulation at embryonic day 7.5 and were resorbing by day 8.5. Thus, huntingtin is critical early in embryonic development, before the emergence of the nervous system. That Hdh inactivation does not mimic adult HD neuropathology suggests that the human disease involves a gain of function.


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Expanded polyglutamine peptides alone are intrinsically cytotoxic and cause neurodegeneration in Drosophila.
J. L. Marsh, H. Walker, H. Theisen, Y.-Z. Zhu, T. Fielder, J. Purcell, and L. M. Thompson (2000)
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   Abstract »    Full Text »    PDF »
A molecular investigation of true dominance in Huntington's disease.
Y. Narain, A. Wyttenbach, J. Rankin, R. A Furlong, and D. C Rubinsztein (1999)
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   Abstract »    Full Text »
Intracellular inclusions, pathological markers in diseases caused by expanded polyglutamine tracts?.
D C Rubinsztein, A Wyttenbach, and J Rankin (1999)
J. Med. Genet. 36, 265-270
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Generation of Neuronal Intranuclear Inclusions by Polyglutamine-GFP: Analysis of Inclusion Clearance and Toxicity as a Function of Polyglutamine Length.
K. L. Moulder, O. Onodera, J. R. Burke, W. J. Strittmatter, and E. M. Johnson Jr (1999)
J. Neurosci. 19, 705-715
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Molecular Chaperones: Biology and Prospects for Pharmacological Intervention.
D. F. Smith, L. Whitesell, and E. Katsanis (1998)
Pharmacol. Rev. 50, 493-514
   Abstract »    Full Text »    PDF »
A Human HAP1 Homologue. CLONING, EXPRESSION, AND INTERACTION WITH HUNTINGTIN.
S.-H. Li, S. H. Hosseini, C.-A. Gutekunst, S. M. Hersch, R. J. Ferrante, and X.-J. Li (1998)
J. Biol. Chem. 273, 19220-19227
   Abstract »    Full Text »    PDF »
Mouse mutant embryos lacking huntingtin are rescued from lethality by wild-type extraembryonic tissues.
I Dragatsis, A Efstratiadis, and S Zeitlin (1998)
Development 125, 1529-1539
   Abstract »    PDF »
Heterogeneous Topographic and Cellular Distribution of Huntingtin Expression in the Normal Human Neostriatum.
R. J. Ferrante, C.-A. Gutekunst, F. Persichetti, S. M. McNeil, N. W. Kowall, J. F. Gusella, M. E. MacDonald, M. F. Beal, and S. M. Hersch (1997)
J. Neurosci. 17, 3052-3063
   Abstract »    Full Text »    PDF »
The bZIP transcription factor LCR-F1 is essential for mesoderm formation in mouse development..
S C Farmer, C W Sun, G E Winnier, B L Hogan, and T M Townes (1997)
Genes & Dev. 11, 786-798
   Abstract »    PDF »
Mouse models of human disease. Part II: recent progress and future directions..
M A Bedell, D A Largaespada, N A Jenkins, and N G Copeland (1997)
Genes & Dev. 11, 11-43
   PDF »
Expression of Normal and Mutant Huntingtin in the Developing Brain.
P. G. Bhide, M. Day, E. Sapp, C. Schwarz, A. Sheth, J. Kim, A. B. Young, J. Penney, J. Golden, N. Aronin, et al. (1996)
J. Neurosci. 16, 5523-5535
   Abstract »    Full Text »    PDF »
Protein:Protein Interactions in Alzheimer's Disease and the CAG Triplet Repeat Diseases.
W.J. Strittmatter, J.R. Burke, V.S. DeSerrano, D.Y. Huang, W. Matthew, A.M. Saunders, B.L. Scott, J.M. Vance, K.H. Weisgraber, and A.D. Roses (1996)
Cold Spring Harb Symp Quant Biol 61, 597-605
   Abstract »    PDF »
Targeted Inactivation of the Mouse Huntington's Disease Gene Homolog Hdh.
M.E. MacDonald, M. Duyao, T. Calzonetti, A. Auerbach, A. Ryan, G. Barnes, J.K. White, W. Auerbach, J.-P. Vonsattel, J.F. Gusella, et al. (1996)
Cold Spring Harb Symp Quant Biol 61, 627-638
   Abstract »    PDF »
Loss of Huntingtin-Mediated BDNF Gene Transcription in Huntington's Disease.
C. Zuccato, A. Ciammola, D. Rigamonti, B. R. Leavitt, D. Goffredo, L. Conti, M. E. MacDonald, R. M. Friedlander, V. Silani, M. R. Hayden, et al. (2001)
Science 293, 493-498
   Abstract »    Full Text »    PDF »
Huntingtin's Neuroprotective Activity Occurs via Inhibition of Procaspase-9 Processing.
D. Rigamonti, S. Sipione, D. Goffredo, C. Zuccato, E. Fossale, and E. Cattaneo (2001)
J. Biol. Chem. 276, 14545-14548
   Abstract »    Full Text »    PDF »
Isolation of a 40-kDa Huntingtin-associated Protein.
M. F. Peters and C. A. Ross (2001)
J. Biol. Chem. 276, 3188-3194
   Abstract »    Full Text »    PDF »


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