Human Molecular Genetics, 2001, Vol. 10, No. 22 2515-2523
© 2001 Oxford University Press
The HD mutation causes progressive lethal neurological disease in mice expressing reduced levels of huntingtin
1Skirball Institute of Biomolecular Medicine and 2Howard Hughes Medical Institute, 3Departments of Radiology and Pathology and 4Departments of Cell Biology and Physiology and Neuroscience, New York University School of Medicine, 540 First Avenue, New York, NY 10016, USA and 5Molecular Neurogenetics Unit, Massachusetts General Hospital East, Charlestown, MA 02129, USA
Huntingtin is an essential protein that with mutant polyglutamine tracts initiates dominant striatal neurodegeneration in Huntington’s disease (HD). To assess the consequences of mutant protein when huntingtin is limiting, we have studied three lines of compound heterozygous mice in which both copies of the HD gene homolog (Hdh) were altered, resulting in greatly reduced levels of huntingtin with a normal human polyglutamine length (Q20) and/or an expanded disease-associated segment (Q111): HdhneoQ20/HdhneoQ20, HdhneoQ20/Hdhnull and HdhneoQ20/HdhneoQ111. All surviving mice in each of the three lines were small from birth, and had variable movement abnormalities. Magnetic resonance micro-imaging and histological evaluation showed enlarged ventricles in 
50% of the HdhneoQ20/HdhneoQ111 and HdhneoQ20/Hdhnull mice, revealing a developmental defect that does not worsen with age. Only HdhneoQ20/HdhneoQ111 mice exhibited a rapidly progressive movement disorder that, in the absence of striatal pathology, begins with hind-limb clasping during tail suspension and tail stiffness during walking by 3–4 months of age, and then progresses to paralysis of the limbs and tail, hypokinesis and premature death, usually by 12 months of age. Thus, dramatically reduced huntingtin levels fail to support normal development in mice, resulting in reduced body size, movement abnormalities and a variable increase in ventricle volume. On this sensitized background, mutant huntingtin causes a rapid neurological disease, distinct from the HD-pathogenic process. These results raise the possibility that therapeutic elimination of huntingtin in HD patients could lead to unintended neurological, as well as developmental side-effects.
+ To whom correspondence should be addressed at: Skirball Institute of Biomolecular Medicine, New York University School of Medicine, 540 First Avenue, New York, NY 10016, USA. Tel: +1 212 263 7262; Fax: +1 212 263 8214; Email: turnbull@saturn.med.nyu.edu The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors
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