Origin of the mutations in the parkin gene in Europe: exon rearrangements are independent recurrent events, whereas point mutations may result from Founder effects

Abstract

A wide variety of mutations in the parkin gene, including exon deletions and duplications, as well as point mutations, result in autosomal recessive early-onset parkinsonism. Interestingly, several of these anomalies were found repeatedly in unrelated patients and may therefore result from recurrent, de novo mutational events or from founder effects. In the present study, haplotype analysis, using 10 microsatellite markers covering a 4.7-cM region known to contain the parkin gene, was performed in 48 families, mostly from European countries, with early-onset autosomal recessive parkinsonism. The patients carried 14 distinct mutations in the parkin gene, and each mutation was detected in more than one family. Our results support the hypothesis that exon rearrangements occurred independently, whereas some point mutations, found in families from different geographic origins, may have been transmitted by a common founder.

Figure 1

Recurrent mutations in the parkin gene and localization of the intragenic microsatellites, showing genetic map of the 10 microsatellites studied (A), exon rearrangements (B, top), and point mutations (B, bottom) that were detected more than once. Exon rearrangements are represented as bars corresponding to their size and position, and they are divided into deletions (del) and duplications (dup). The positions of point mutations are indicated by arrows. The ATG of the initiator methionine codon begins at nucleotide 102 of the published cDNA (Kitada et al. 1998). The number of index patients with the same mutation is indicated in parentheses. The positions of the microsatellites in the parkin gene are indicated by dotted arrows. Note the difference, arising from recent results of chromosome 6 sequencing, between the genetic map and physical map.