Mutation analysis and association studies of the ubiquitin carboxyterminal hydrolase L1 gene in Huntington's disease

Huntington's disease (HID) is attributed to a triplet CAG repeat mutation, and about 70% of the variance in age-at-onset can be explained by the size of the repeat expansion. Among potential candidates as modifier genes, we investigated the role of ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) gene. We examined the association of HID with the I93M mutation and S18Y polymorphism in 138 HID patients and 136 control subjects, but we did not identify the 193M mutation. The S18Y polymorphism was present in 17% of HID patients. Of the variance in the age-at-onset that was not accounted for by the CAG repeat, 13% could be attributed to S18Y polymorphism. We sequenced the entire coding region of the UCH-L1 gene in seven HID patients with unexplained older or younger onset age. The S18Y polymorphism was found in three out of the four patients presenting with a later age-at-onset. We conclude that the UCH-L1 gene may be a genetic factor that influences the variability in age-at-onset of HID. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.