title: Huntingtin-associated protein-1 is a modifier of the age-at-onset of Huntington's disease.
abstract: 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.
authors.affiliation: Department of Medical Genetics, University of Tuebingen, 72076 Tuebingen, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Metzger
authors.forename: Juan
authors.initials: J
authors.lastname: Rong
authors.forename: Huu-Phuc
authors.initials: HP
authors.lastname: Nguyen
authors.forename: Austin
authors.initials: A
authors.lastname: Cape
authors.forename: Juergen
authors.initials: J
authors.lastname: Tomiuk
authors.forename: Anne S
authors.initials: AS
authors.lastname: Soehn
authors.forename: Peter
authors.initials: P
authors.lastname: Propping
authors.forename: Yun
authors.initials: Y
authors.lastname: Freudenberg-Hua
authors.forename: Jan
authors.initials: J
authors.lastname: Freudenberg
authors.forename: Liang
authors.initials: L
authors.lastname: Tong
authors.forename: Shi-Hua
authors.initials: SH
authors.lastname: Li
authors.forename: Xiao-Jiang
authors.initials: XJ
authors.lastname: Li
authors.forename: Olaf
authors.initials: O
authors.lastname: Riess
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D019943:Amino Acid Substitution; D002648:Child; D002675:Child, Preschool; D006801:Humans; D006816:Huntington Disease / Q000453:epidemiology* / Q000235:genetics*; D008875:Middle Aged; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics*; D011110:Polymorphism, Genetic; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D018911:Trinucleotide Repeats
chemical_list: C096896:HAP1 protein, human; D009419:Nerve Tissue Proteins; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins