Inactivation of the Mouse Huntington's Disease Gene Homolog Hdh
Abstract
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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References
CELL 72: 971 (1993).
CELL 78: 23 (1994).
AMBROSE, C.M., STRUCTURE AND EXPRESSION OF THE HUNTINGTONS-DISEASE GENE - EVIDENCE AGAINST SIMPLE INACTIVATION DUE TO AN EXPANDED CAG REPEAT, SOMATIC CELL AND MOLECULAR GENETICS 20: 27 (1994).
BARNES, G.T., MOUSE HUNTINGTONS-DISEASE GENE HOMOLOG (HDH), SOMATIC CELL AND MOLECULAR GENETICS 20: 87 (1994).
BLUM, M, GASTRULATION IN THE MOUSE - THE ROLE OF THE HOMEOBOX GENE GOOSECOID, CELL 69: 1097 (1992).
CONLON, R.A., DETECTION OF MESSENGER-RNA BY IN-SITU HYBRIDIZATION TO POSTIMPLANTATION EMBRYO WHOLE MOUNTS, GUIDE TO TECHNIQUES IN MOUSE DEVELOPMENT 225: 373 (1993).
COPP, A.J., DEATH BEFORE BIRTH - CLUES FROM GENE KNOCKOUTS AND MUTATIONS, TRENDS IN GENETICS 11: 87 (1995).
DIFIGLIA, M, HUNTINGTIN IS A CYTOPLASMIC PROTEIN ASSOCIATED WITH VESICLES IN HUMAN AND RAT-BRAIN NEURONS, NEURON 14: 1075 (1995).
Folstein, S. E., Huntington's Disease. A Disorder of Families (1989).
GUSELLA, J.F., MOLECULAR-GENETICS OF HUNTINGTONS-DISEASE, ARCHIVES OF NEUROLOGY 50: 1157 (1993).
GUSELLA, J.F., HUNTINGTONS-DISEASE, SEMINARS IN CELL BIOLOGY 6: 21 (1995).
HERRMANN, B.G., EXPRESSION PATTERN OF THE BRACHYURY GENE IN WHOLE-MOUNT TWIS/TWIS MUTANT EMBRYOS, DEVELOPMENT 113: 913 (1991).
JOU, Y.S., EVIDENCE FROM ANTIBODY STUDIES THAT THE CAG REPEAT IN THE HUNTINGTON DISEASE GENE IS EXPRESSED IN THE PROTEIN, HUMAN MOLECULAR GENETICS 4: 465 (1995).
Joyner, A. L., Gene Targeting: A Practical Approach (1993).
LIN, B, SEQUENCE OF THE MURINE HUNTINGTON DISEASE GENE - EVIDENCE FOR CONSERVATION, AND POLYMORPHISM IN A TRIPLET (CCG) REPEAT ALTERNATE SPLICING, HUMAN MOLECULAR GENETICS 3: 85 (1994).
MARTIN, J.B., HUNTINGTONS-DISEASE - PATHOGENESIS AND MANAGEMENT, NEW ENGLAND JOURNAL OF MEDICINE 315: 1267 (1986).
MONAGHAN, A.P., POSTIMPLANTATION EXPRESSION PATTERNS INDICATE A ROLE FOR THE MOUSE FORKHEAD/HNF-3 ALPHA,BETA AND GAMMA GENES IN DETERMINATION OF THE DEFINITIVE ENDODERM, CHORDAMESODERM AND NEUROECTODERM, DEVELOPMENT 119: 567 (1993).
MORTENSEN, R.M., PRODUCTION OF HOMOZYGOUS MUTANT ES CELLS WITH A SINGLE TARGETING CONSTRUCT, MOLECULAR AND CELLULAR BIOLOGY 12: 2391 (1992).
Nagy, A., Gene Targeting: A Practical Approach: 147 (1993).
NAGY, A, DERIVATION OF COMPLETELY CELL CULTURE-DERIVED MICE FROM EARLY-PASSAGE EMBRYONIC STEM-CELLS, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 90: 8424 (1993).
NASIR, J, TARGETED DISRUPTION OF THE HUNTINGTONS-DISEASE GENE RESULTS IN EMBRYONIC LETHALITY AND BEHAVIORAL AND MORPHOLOGICAL-CHANGES IN HETEROZYGOTES, CELL 81: 811 (1995).
PERSICHETTI, F, NORMAL AND EXPANDED HUNTINGTONS-DISEASE GENE ALLELES PRODUCE DISTINGUISHABLE PROTEINS DUE TO TRANSLATION ACROSS THE CAG REPEAT, MOLECULAR MEDICINE 1: 374 (1995).
PIERETTI, M, ABSENCE OF EXPRESSION OF THE FMR-1 GENE IN FRAGILE-X SYNDROME, CELL 66: 817 (1991).
SHARP, A.H., WIDESPREAD EXPRESSION OF HUNTINGTONS-DISEASE GENE (IT15) PROTEIN PRODUCT, NEURON 14: 1065 (1995).
SUTCLIFFE, J.S., HUM MOL GENET 1: 397 (1992).
TROTTIER, Y, CELLULAR-LOCALIZATION OF THE HUNTINGTONS-DISEASE PROTEIN AND DISCRIMINATION OF THE NORMAL AND MUTATED FORM, NATURE GENETICS 10: 104 (1995).
TYBULEWICZ, VLJ, NEONATAL LETHALITY AND LYMPHOPENIA IN MICE WITH A HOMOZYGOUS DISRUPTION OF THE C-ABL PROTOONCOGENE, CELL 65: 1153 (1991).
VERKERK, AJMH, IDENTIFICATION OF A GENE (FMR-1) CONTAINING A CGG REPEAT COINCIDENT WITH A BREAKPOINT CLUSTER REGION EXHIBITING LENGTH VARIATION IN FRAGILE-X SYNDROME, CELL 65: 905 (1991).
VONSATTEL, J.P., NEUROPATHOLOGICAL CLASSIFICATION OF HUNTINGTONS-DISEASE, JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY 44: 559 (1985).
WILLEMS, P.J., DYNAMIC MUTATIONS HIT DOUBLE FIGURES, NATURE GENETICS 8: 213 (1994).
Wurst, W., Gene Targeting: A Practical Approach: 31 (1993).
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Science
Volume 269 | Issue 5222
21 July 1995
21 July 1995
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© 1995.
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Published in print: 21 July 1995
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- Mabel P. Duyao et al.
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Cited by
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- Loss of Huntingtin-Mediated BDNF Gene Transcription in Huntington's Disease, Science, 293, 5529, (493-498), (2001)./doi/10.1126/science.1059581
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