Background-Recent studies indicate an increased frequency of mutations in the gene for Gaucher disease, glucocerebrosidase (GBA), among patients with Parkinson disease. An international collaborative study was conducted to ascertain the frequency of GBA mutations in ethnically diverse patients with Parkinson disease.

Common genetic variants that increase the risk for Parkinson's disease may differentiate patient subgroups and influence future individualized therapeutic strategies. Herein we show evidence for leucine-rich repeat kinase 2 (LRRK2) c.4883G>C (R1628P) as a risk factor in ethnic Chinese populations. A study of 1,986 individuals from 3 independent centers in Taiwan and Singapore demonstrates that Lrrk2 R1628P increases risk for Parkinson's disease (odds ratio, 1.84; 95% confidence interval, 1.20-2.83; p = 0.006). Haplotype analysis suggests an ancestral founder for carriers approximately 2,500 years ago. These findings support the importance of LRRK2 variants in sporadic Parkinson's disease. Ann Neurol 2008.

The efficiency of simian virus 40 (SV40) DNA replication is dependent on the structural organization of the regulatory region. The enhancing effect of the G+C-rich 21-base-pair (bp) repeats on SV40 DNA replication is position and dose dependent and to some extent orientation dependent. The inverted orientation is about 50% as effective as the normal orientation of the 21-bp repeat region. Movement of the 21-bp The double-stranded circular genome of simian virus 40 (SV40) represents a simple model system for studying mechanisms involved in eucaryotic DNA replication (for a review, see reference 8). Replication of the 5,243-base-pair (bp) genome of SV40 begins at a unique site, and the elongation of nascent DNA chains proceeds bidirectionally (9, 14). Viral DNA replication depends mainly on cellular mechanisms. The analysis of naturally arising evolutionary variants and deletion mutants has narrowed the limits of the origin signal for SV40 DNA replication (core ori) to a segment of approximately 65 bp from 0.653 to 0.666 map units including a 27-bp palindrome and an A+T-rich sequence (5,11,12,22,32,42,48). Single nucleotide changes or small deletions within this segment abolish or alter replication (20,42,46). The in vivo initiation sites for DNA synthesis have been mapped within the ori segment in the 27-bp palindrome as well as within the three 21-bp, G+C-rich tandem repeats (25). The 21-bp repeat has an enhancing effect on SV40 DNA replication (5,15,28) and is a bidirectional promoter element for SV40 transcription (3,13,18,40,54). The 72-bp repeat is a position-and orientationindependent enhancer for transcription (2,4,15,16,21,41,55).We examined the effects of the orientation, location, and number of copies of the 21-bp repeat on SV40 DNA replication. The role(s) of the 72-bp repeat in SV40 DNA replication was also investigated. Fragments containing the SV40 ori sequence plus various portions of the normal or relocated regulatory sequences were cloned into bacterial plasmids. By mixed transfection of monkey cells and Southern blot analysis of newly replicated DNAs, we compared the effects of various structural rearrangements of the 21-or 72-bp repeat or both on the replication efficiency of the SV40 ori region. MATERIALS AND METHODSCells and plasmid vector. The BSC-1 line of African green monkey kidney cells was grown in 8% calf serum plus 2% * Corresponding author.fetal calf serum and Eagle minimal essential medium (MEM-10). The COS-1 line of African green monkey kidney cells (19) was grown in 5% fetal calf serum (MEM-5).The plasmid vector pKP45 (kindly provided by K. Peden, The Johns Hopkins University, School of Medicine) is derived from pBR322 by deletion of nucleotides 676 to 2364 which removes the sequence that is "poisonous" for plasmid replication in mammalian cells (23,36,43).Restriction endonuclease digestion and DNA fragment purification. Restriction endonucleases were purchased from New England BioLabs, Inc. (Beverly, Mass.) or Boehringer Mannheim Biochemicals (Indianapolis, Ind.) and used as su...

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