Haploinsufficiency at the α-synuclein gene underlies phenotypic severity in familial Parkinson's disease

被引:35
作者
Kobayashi, H
Krüger, R
Markopoulou, K
Wszolek, Z
Chase, B
Taka, H
Mineki, R
Murayama, K
Riess, O
Mizuno, Y
Hattori, N
机构
[1] Juntendo Univ, Sch Med, Dept Neurol, Tokyo 1138421, Japan
[2] Juntendo Univ, Sch Med, Div Biochem Anal, Tokyo 1138421, Japan
[3] Univ Tubingen, Dept Neurol, D-7400 Tubingen, Germany
[4] Univ Tubingen, Dept Med Genet, Tubingen, Germany
[5] Univ Nebraska, Dept Neurol Sci, Med Ctr, Lincoln, NE 68583 USA
[6] Univ Nebraska, Dept Biol, Omaha, NE 68182 USA
[7] Mayo Clin, Dept Neurol, Jacksonville, FL USA
基金
美国国家卫生研究院;
关键词
alpha-synuclein; haploinsufficiency; familial Parkinson's disease; G88C and G209A mutations;
D O I
10.1093/brain/awg010
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
To date, two point mutations, G209A and G88C, have been reported in the coding region of the alpha-synuclein gene in autosomal dominant familial Parkinson's disease. When translated, these lead to the missense mutations Ala53Thr and Ala30Pro, respectively. Reduced mRNA expression of the G209A allele was reported recently in a Greek-American family. Here, we show that alpha-synuclein mRNA is normally expressed in blood cells and report the results of an analysis of alpha-synuclein mRNA and protein expression in lymphoblastoid cell lines established from kindreds with the G209A and G88C mutations. mRNA expression was characterized using a TaqMan real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) assay. We assessed five affected and three unaffected members of a German family with the G88C mutation and two affected members in different, unrelated Greek families with the G209A mutation. The ratio of wild-type to mutant alpha-synuclein allele expression ranged from 2.2 to 9.2 in the affected individuals with a severe clinical phenotype. The ratios of the expression levels of the wild-type to mutant alleles were only slightly decreased in mild cases and were less than 1.0 in two asymptomatic heterozygotes. Sequence analysis of the RT-PCR products showed only the presence of G in position 88 and G in position 209 in severely affected heterozygotes of the German and Greek families, respectively. High performance liquid chromatography/mass spectrometry demonstrated that, relative to wild-type alpha-synuclein, there is a reduction of Ala30Pro alpha-synuclein in lymphoblastoid cell lines originating from severely affected, but not mildly affected G88C/+ heterozygotes. Taken together, these data indicate that there is haploinsufficiency at the alpha-synuclein gene and that the ratio of expression of the wild-type to mutant alleles correlates with the severity of the clinical phenotype. Furthermore, these findings suggest that haploinsufficiency of alpha-synuclein mutations may contribute to disease progression in these forms of familial Parkinson's disease.
引用
收藏
页码:32 / 42
页数:11
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