Molecular genetic analysis of a novel Parkin gene in Japanese families with autosomal recessive juvenile parkinsonism: evidence for variable homozygous deletions in the Parkin gene in affected individuals.
Autosomal recessive juvenile parkinsonism (AR-JP) is a distinct clinical and genetic entity characterized by selective degeneration of nigral dopaminergic neurons and young-onset parkinsonism with remarkable response to levodopa. Recently, we mapped the gene locus for AR-JP to chromosome 6q25.2-q27 by linkage analysis and we identified a novel large gene, Parkin, consisting of 12 exons from this region; mutations of this gene were found to be the cause of AR-JP in two families. Now we report results of extensive molecular analysis on 34 affected individuals from 18 unrelated families with AR-JP. We found four different homozygous intragenic deletional mutations, involving exons 3 to 4, exon 3, exon 4, and exon 5 in 10 families (17 affected individuals). In addition to the exonic deletions, we identified a novel one-base deletion involving exon 5 in two families (2 affected individuals). All mutations so far found were deletional types in which large exonic deletion accounted for 50% (17 of 34) and the one-base deletion accounted for 6% (2/34); in the remaining, no homozygous mutations were found in the coding regions. Our findings indicate that loss of function of the Parkin protein results in the clinical phenotype of AR-JP and that subregions between introns 2 and 5 of the Parkin gene are mutational hot spots.
Hattori
N
N
Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.
Kitada
T
T
Matsumine
H
H
Asakawa
S
S
Yamamura
Y
Y
Yoshino
H
H
Kobayashi
T
T
Yokochi
M
M
Wang
M
M
Yoritaka
A
A
Kondo
T
T
Kuzuhara
S
S
Nakamura
S
S
Shimizu
N
N
Mizuno
Y
Y
D000595:Amino Acid Sequence; D001483:Base Sequence; D005091:Exons / Q000235:genetics; D017353:Gene Deletion; D005808:Genes, Recessive; D006720:Homozygote; D006801:Humans; D007564:Japan; D008025:Ligases; D008967:Molecular Biology; D008969:Molecular Sequence Data; D010300:Parkinson Disease / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases
D011506:Proteins; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D008025:Ligases