Huntingtin-associated protein-1 is a modifier of the age-at-onset of Huntington's disease.
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.
Metzger
Silke
S
Department of Medical Genetics, University of Tuebingen, 72076 Tuebingen, Germany.
Rong
Juan
J
Nguyen
Huu-Phuc
HP
Cape
Austin
A
Tomiuk
Juergen
J
Soehn
Anne S
AS
Propping
Peter
P
Freudenberg-Hua
Yun
Y
Freudenberg
Jan
J
Tong
Liang
L
Li
Shi-Hua
SH
Li
Xiao-Jiang
XJ
Riess
Olaf
O
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
C096896:HAP1 protein, human; D009419:Nerve Tissue Proteins; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins