ClinVar Genomic variation as it relates to human health

This variant, formerly titled PARKINSON DISEASE 5, RESISTANCE TO, has been reclassified based on the following conflicting evidence. Lincoln et al. (1999) identified a ser18-to-tyr (S18Y) polymorphism in exon 3 of the UCHL1 gene. The S18Y allele was found in approximately 20% of chromosomes in a Caucasian population, and the authors suggested that it is unlikely to be pathogenic. Liu et al. (2002) found that the S18Y variant had reduced ubiquityl ligase activity compared with the wildtype enzyme, but it had comparable hydrolase activity. Maraganore et al. (2004) performed a collaborative pooled analysis of data from 11 published studies of the UCHL1 S18Y variant and Parkinson disease (613643): 3 studies had reported no association for the variant and PD, 4 reported associations in PD subgroups only, and 4 reported an inverse association of S18Y and PD. From a total of 1,970 cases and 2,224 controls, Maraganore et al. (2004) found an overall inverse association of S18Y with PD. Carriers of the variant allele (Y/Y plus Y/S compared to S/S) had an odds ratio (OR) of 0.84, and homozygotes for the variant allele (Y/Y compared to S/S plus Y/S) had an OR of 0.71. There was a linear trend in the log OR consistent with a gene dosage effect. The inverse association was most apparent for young cases compared with young controls. Among 3,023 white individuals, Healy et al. (2006) found that the S18Y variant was not protective against PD under any genetic mode of inheritance. Furthermore, no association was observed in an updated metaanalysis including 6,594 individuals. A cumulative metaanalysis showed a trend toward a null effect. Kyratzi et al. (2008) found that the S18Y variant of the UCHL1 gene, but not wildtype, conferred a specific antioxidant protective function when expressed at physiologic levels in human neuroblastoma cells and primary cortical neurons. The effect appeared to result from a decrease in reactive oxygen species in response to insult. The results provided indirect evidence for the importance of oxidative stress as a pathogenetic factor in certain forms of sporadic PD. Overexpression of wildtype or the S18Y variant did not appear to directly impact the proteasome, although they both led to stabilization of free ubiquitin. Rudolph et al. (2011) examined the possible effects of the S18Y polymorphism on cataract formation. Using dynamic allele-specific hybridization, they analyzed 493 patients with cataract and 142 controls for the S18Y polymorphism. Significant differences were observed in allele and genotype frequencies between controls and cataract patients with a positive UCHL1 allele A carrier status associated with the cataract diagnosis. Rudolph et al. (2011) concluded that their study did not support a protective role for the S18Y polymorphism in cataract development. Instead, their findings suggested that this polymorphism might have a disease-promoting effect. (less)