Document Detail

Huntingtin-associated protein-1 is a modifier of the age-at-onset of Huntington's disease.
MedLine Citation:
PMID:  18192679     Owner:  NLM     Status:  MEDLINE    
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 (AAO), 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 AAO of HD. We hypothezised that htt interacting proteins might contribute to this variation in the AAO and investigated human htt-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 soluble htt degraded products and protects against htt-mediated toxicity. We thus provide genetic and functional evidence that the M441-HAP1 polymorphism modifies the AAO of HD.
Silke Metzger; Juan Rong; Huu-Phuc Nguyen; Austin Cape; Juergen Tomiuk; Anne S Soehn; Peter Propping; Yun Freudenberg-Hua; Jan Freudenberg; Liang Tong; Shi-Hua Li; Xiao-Jiang Li; Olaf Riess
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-01-11
Journal Detail:
Title:  Human molecular genetics     Volume:  17     ISSN:  1460-2083     ISO Abbreviation:  Hum. Mol. Genet.     Publication Date:  2008 Apr 
Date Detail:
Created Date:  2008-04-02     Completed Date:  2008-04-21     Revised Date:  2010-05-28    
Medline Journal Info:
Nlm Unique ID:  9208958     Medline TA:  Hum Mol Genet     Country:  England    
Other Details:
Languages:  eng     Pagination:  1137-46     Citation Subset:  IM    
Department of Medical Genetics, University of Tuebingen, 72076 Tuebingen, Germany.
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MeSH Terms
Age of Onset
Aged, 80 and over
Amino Acid Substitution
Child, Preschool
Huntington Disease / epidemiology*,  genetics*
Middle Aged
Mutation, Missense
Nerve Tissue Proteins / genetics*
Polymorphism, Genetic*
Serotonin Plasma Membrane Transport Proteins / metabolism
Trinucleotide Repeats
Grant Support
Reg. No./Substance:
0/HAP1 protein, human; 0/Nerve Tissue Proteins; 0/SLC6A4 protein, human; 0/Serotonin Plasma Membrane Transport Proteins

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