TY - JOUR
T1 - Reduced expression of the G209A α-synuclein allele in familial parkinsonism
AU - Markopoulou, Katerina
AU - Wszolek, Zbigniew K.
AU - Pfeiffer, Ronald F.
AU - Chase, Bruce A.
PY - 1999
Y1 - 1999
N2 - Missense mutations at the α-synuclein gene have been associated with familial parkinsonism. We report that the phenotype of a kindred (Family H) with autosomal dominant, levodopa-responsive parkinsonism maps to chromosomal region 4q21-23 and that affected members of this kindred harbor a previously reported mutation (G209A) in exon 4 of the α-synuclein gene. We assessed the expression of the G209A allele in lymphoblastoid cell lines established from 12 individuals heterozygous for the G209A allele. The expression of this allele is either absent or significantly reduced in 7 affected heterozygotes and in 3 asymptomatic heterozygotes who are older than the mean age at disease diagnosis for their generation. In contrast, it is expressed in 1 affected and 1 unaffected heterozygote. The unaffected heterozygote is younger than the mean age at disease diagnosis for their generation. The lack of or significantly reduced expression of the G209A allele in affected heterozygotes suggests that the timing of reduced expression may be critical for disease onset. If so, the parkinsonian phenotype may arise from haploinsufficiency at the α-synuclein gene at a time point before symptom onset. In conclusion, reduced α-synuclein gene expression may be important in the pathogenesis of parkinsonism.
AB - Missense mutations at the α-synuclein gene have been associated with familial parkinsonism. We report that the phenotype of a kindred (Family H) with autosomal dominant, levodopa-responsive parkinsonism maps to chromosomal region 4q21-23 and that affected members of this kindred harbor a previously reported mutation (G209A) in exon 4 of the α-synuclein gene. We assessed the expression of the G209A allele in lymphoblastoid cell lines established from 12 individuals heterozygous for the G209A allele. The expression of this allele is either absent or significantly reduced in 7 affected heterozygotes and in 3 asymptomatic heterozygotes who are older than the mean age at disease diagnosis for their generation. In contrast, it is expressed in 1 affected and 1 unaffected heterozygote. The unaffected heterozygote is younger than the mean age at disease diagnosis for their generation. The lack of or significantly reduced expression of the G209A allele in affected heterozygotes suggests that the timing of reduced expression may be critical for disease onset. If so, the parkinsonian phenotype may arise from haploinsufficiency at the α-synuclein gene at a time point before symptom onset. In conclusion, reduced α-synuclein gene expression may be important in the pathogenesis of parkinsonism.
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U2 - 10.1002/1531-8249(199909)46:3<374::AID-ANA13>3.0.CO;2-9
DO - 10.1002/1531-8249(199909)46:3<374::AID-ANA13>3.0.CO;2-9
M3 - Article
C2 - 10482268
AN - SCOPUS:0032835781
SN - 0364-5134
VL - 46
SP - 374
EP - 381
JO - Annals of Neurology
JF - Annals of Neurology
IS - 3
ER -