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Polymeropoulos et al described the genetic linkage of a large Italian Parkinson’s disease pedigree (Contursi) to chromosome 4q21-q231; more recently the sequence of the α-synuclein gene located in this chromosomal region in affected patients from this kindred disclosed that most of the affected members were heterozygous for a missense mutation (alanine→threonine) at position 53 of the protein.2 This same missense mutation was also found in three additional unrelated families of Greek origin with Parkinson’s disease.
The mutation was found by DNA sequence analysis of the fourth exon of the α-synuclein gene, disclosing a single base pair change at position 209 from G to A (G209A), and creating a novelTsp45I restriction site. Using a polymerase chain reaction (PCR) assay and Tsp45I restriction, we have found some French patients with Parkinson’s disease. Genomic DNA was amplified with primers 3 and 13 of the DNA sequence (GenBank ID U46898) in a 50 μl reaction volume (10 mM Tris-HCl, pH=8.3; 50 mM KCl; 1.5 mM MgCl2; 200 μM of each dNTP and 1 U Taqpolymerase); cycling parameters were: one initial step of hybridisation at 94°C during 5 minutes, 35 cycles of PCR (hybridisation at 60°C, 40 seconds, extension at 72°C, 40 seconds; denaturation at 94°C, 40 seconds) and a final extension step (5 minutes at 74°C). A 20 μl aliquot of the 216 base pair (bp) product was restricted with theTsp45I enzyme at 65°C for 5 hours ; the efficiency of the Tsp45I restriction was verificated by monitoring for the pUC19 plasmid restriction (four fragments at 1588, 576, 31, and 211 bp). The digested PCR products were separated by electrophoresis on a 3% agarose gel and visualised by ethidium bromide staining.
Fourteen French families3 4 with at least two members in each family meeting clinical criteria for idiopathic Parkinson’s disease were tested. Affected members in all families exhibited at least two of the three cardinal signs of Parkinson’s disease (bradykinesia, rigidity, and resting tremor), as well as marked improvement with levodopa treatment. The G209A mutation was not found in 27 patients with Parkinson’s disease belonging to these 14 French pedigrees. The Tsp45I restriction site was also absent in the genomic amplifiate of 79 patients of French origin with sporadic Parkinson’s disease.
We conclude that the G209A mutation is rare, or absent, in French patients with familial and sporadic Parkinson’s disease, and similar results were obtained recently from American patients.5The main age at onset of disease in our patients with Parkinson’s disease, both familial and sporadic, was 64.5 (range 25–88) years. The major kindred published1 2 in which the G209A mutation was found originates in Contursi (southern Italy) and has fairly typical Parkinson’s disease, albeit with relatively early onset of symptoms and rapid subsequent progression; little has been reported until now about the three Greek families with Parkinson’s disease with the G209A mutation, except that they too have relatively early onset. Probably the G209A mutation concerns a small set of families with Parkinson’s disease, originating from some focal localities on the Mediterranean coast.