Human Molecular Genetics Advance Access published online on January 11, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn003
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Huntingtin-associated protein-1 is a modifier of the age-at-onset of Huntington's disease
1 Department of Medical Genetics, University of Tuebingen, 72076 Tuebingen, Germany 2 Department of Human Genetics, Emory University, Atlanta, GA 30322, USA 3 Institute of Human Genetics, University of Bonn, 52111 Bonn, Germany 4 Department of Neurology, Institute of Human Genetics, University of California, San Francisco, CA 94143-2922, USA 5 Department of Biological Sciences, Columbia University, New York, NY 10027, USA
* To whom correspondence should be addressed: X.-J. Li: Department of Human Genetics, Emory University School of Medicine, 615 Michael St Room 347, Atlanta, GA 30322, USA; Tel: +1 404-727-3290; Fax: +1 404-727-3949; Email: xiaoli{at}genetics.emory.edu
* O. Riess: Department of Medical Genetics, University of Tuebingen, Calwerstr. 7, 72076 Tuebingen, Germany; Tel: +49 7071 2976458; Fax: +49 7071 295171; Email: olaf.riess{at}med.uni-tuebingen.de
Received November 20, 2007; Revised December 21, 2007; Accepted January 5, 2008
A polyglutamine repeat expansion of more than 36 units in a protein called huntingtin (htt) is the only known cause of Huntington's disease (HD). The expanded repeat length is inversely correlated with the age-at-onset, however, the onset age among HD patients with CAG repeats below 60 units varies considerably. In addition to environmental factors, genetic factors different from the expanded CAG repeat length can modify the age-at-onset (AAO) of HD. We hypothezised that htt interacting proteins might contribute to this variation in the AAO and investigated human huntingtin-associated protein-1 (HAP1) using genetic and functional assays. We identified six polymorphisms in the HAP1 gene including one that substitutes methionine (M441) for threonine (T441) at amino acid 441. Analyzing 980 European HD patients, we found that patients homozygous for the M441 genotype show an 8-year delay in the AAO. Functional assays demonstrated that human M441-HAP1 interacts with mutant htt more tightly than does human T441-HAP1, reduces huntingtin degradation, and protects against huntingtin-mediated toxicity. We thus provide genetic and functional evidence that the M441-HAP1 polymorphism modifies the AAO of HD.
6 These authors contributed equally to this work.