Markopoulou K, Wszolek Z K, Pfeiffer R F, Chase B A
Department of Biology, University of Nebraska at Omaha, USA.
Ann Neurol. 1999 Sep;46(3):374-81. doi: 10.1002/1531-8249(199909)46:3<374::aid-ana13>3.0.co;2-9.
Missense mutations at the alpha-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 alpha-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 alpha-synuclein gene at a time point before symptom onset. In conclusion, reduced alpha-synuclein gene expression may be important in the pathogenesis of parkinsonism.
α-突触核蛋白基因的错义突变与家族性帕金森病有关。我们报告，一个患常染色体显性遗传、左旋多巴反应性帕金森病的家族（家族H）的表型定位于染色体区域4q21 - 23，且该家族的患病成员在α-突触核蛋白基因第4外显子中携带一个先前报道的突变（G209A）。我们评估了从12名G209A等位基因杂合子个体建立的淋巴母细胞系中G209A等位基因的表达情况。在7名患病杂合子以及3名年龄大于其同代疾病诊断平均年龄的无症状杂合子中，该等位基因的表达缺失或显著降低。相比之下，在1名患病杂合子和1名未患病杂合子中该等位基因有表达。未患病杂合子的年龄小于其同代疾病诊断平均年龄。患病杂合子中G209A等位基因表达的缺失或显著降低表明，表达降低的时间点可能对疾病发病至关重要。如果是这样，帕金森病表型可能在症状出现前的某个时间点由α-突触核蛋白基因的单倍剂量不足引起。总之，α-突触核蛋白基因表达降低可能在帕金森病发病机制中起重要作用。
