Mutation analysis and association studies of the ubiquitin carboxy- terminal hydrolase L1 gene in Huntington’s disease Peggy Naze ´ a , Isabelle Vuillaume a , Alain Deste ´e b , Florence Pasquier b , Bernard Sablonnie ` re a, * a Laboratoire de Biochimie et de Biologie Mole ´culaire, Unite ´ Fonctionnelle de Neurobiologie, Ho ˆpital R. Salengro, Centre Hospitalier Re ´gional et Universitaire de Lille, 59037 Lille Cedex, France b Clinique Neurologique, Ho ˆpital R. Salengro, Centre Hospitalier Re ´gional et Universitaire de Lille, 59037 Lille, France Received 1 August 2001; received in revised form 28 February 2002; accepted 28 February 2002 Abstract Huntington’s disease (HD) 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 HD with the I93M mutation and S18Y polymorphism in 138 HD patients and 136 control subjects, but we did not identify the I93M mutation. The S18Y polymorphism was present in 17% of HD 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 HD 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 HD. q 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Huntington’s disease; Ubiquitin carboxy-terminal hydrolase L1; Modifying genes; Mutations Huntington’s disease (HD) is a progressive, neurodegen- erative disorder that presents with motor disturbances, psychiatric symptoms, and cognitive decline [5]. The gene responsible for HD contains an expanded and unstable CAG trinucleotide repeat [16]. An inverse correlation between the size of the expanded allele and the age-at-onset is consis- tently observed in HD: a number of studies have shown that the CAG repeat number on HD chromosomes account for 60–73% of the variance of the age of onset [1,2,15]. The contribution of the CAG repeat number to age-at-onset is less marked at the lower end of the disease range and differ- ent possible genotype–age-at-onset association effects have been studied [3,10,12,14]. Among them, a TAA repeat poly- morphism in close linkage to the kainate receptor, GluR6, was reported to be associated with younger onset age of HD, suggesting that it could be in linkage disequilibrium with a variant of the GluR6 gene. This gene or another in this region may represent modifying genes in HD. Proteasome function and dysfunction in triplet repeat expansion diseases have been the focus of work in several laboratories [6,19]. Among numerous components of the proteasome pathway, ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) is an abundant neuron-specific deubiquitinat- ing enzyme in the human brain thought to hydrolyse poly- meric ubiquitin and ubiquitin conjugates into monomeric ubiquitin [9]. Recently, an I93M mutation in the UCH-L1 gene has been described in a German family with Parkin- son’s disease that may lead to a loss of enzyme function and subsequent abnormal protein aggregation [7]. Further studies failed to reveal the I93M, or other pathogenic muta- tions in the coding region of the UCH-L1 gene in Parkin- son’s disease [8,4,20]. A total of 138 unrelated HD-diagnosed patients were studied. All of these were confirmed by molecular analysis showing CAG expansion of 38 or more. Age-at-onset was estimated as the age at which initial either neurological, psychiatric or cognitive symptoms were first noted. Each medical report was screened through a questionnaire record- ing a list of clinical features at onset [17]. The CAG repeat sizes were determined by denaturing polyacrylamide gel electrophoresis and silver nitrate staining as previously reported [18]. One hundred and thirty-six controls matched Neuroscience Letters 328 (2002) 1–4 0304-3940/02/$ - see front matter q 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S0304-3940(02)00231-8 www.elsevier.com/locate/neulet * Corresponding author. Tel.: 133-320446173; fax: 133- 320446919. E-mail address: b-sablonniere@chru-lille.fr (B. Sablonnie ` re).