α-synuclein locus triplication causes Parkinson's disease
α-synuclein locus triplication causes Parkinson's disease
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DOI：
10.1126/science.1090278
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发表时间：
2003-10-31
期刊：
影响因子：
56.9
通讯作者：
Gwinn-Hardy, K
中科院分区：
文献类型：
--
作者：
Singleton, AB;Farrer, M;Gwinn-Hardy, K
我们检查了一个常染色体显性PD大家族（平均发病年龄34岁），临床上从路易体痴呆到典型PD（3）。神经病理学检查发现，受影响的成员深刻的病理，包括广泛的路易体和一些胶质细胞胞浆包涵体。对这个家族进行SNCA突变或与SNCA连锁的筛查是阴性的。连锁分析显示，染色体4p 15单倍型与帕金森综合征和特发性震颤分离，提示与PARK 4连锁的证据[D4 S1609的多点比值对数（LOD）2.64]（4）。然而，一个没有共享4p 15单倍型的未受影响的个体患病。这促使在更高分辨率下进行第二次全基因组搜索，其揭示了与疾病共分离的单倍型超过26 cM（D4 S2367-D4 S1560），在D4 S2460处的多点LOD为3.50。SNCA基因型与以前的数据不一致，导致最初的排除;重新评估原始连锁发现一个样本交换。SNCA基因重测序未能发现致病性突变，SNCA基因启动子和内含子5的杂合单核苷酸多态性表明该区域不可能缺失。逆转录-聚合酶链反应（RT-PCR）扩增SNCA显示，只有正常的长度和序列在受影响的家庭成员的成绩单。在SNCA基因座的基因内标记MG 4S 2和MG 4S 5的分析显示了明显的非孟德尔遗传的例子，这可以解释为多等位基因。SNCA外显子的定量实时PCR扩增产生的结果与全基因三重化一致（图1）。为了证实SNCA三倍体，我们对来自受影响家族成员的EB病毒（EBV）永生化淋巴细胞的染色体进行荧光原位杂交（FISH）（9-77）。SNCA三倍体在这个家庭中分离，
We examined a large family with autosomal dominant PD (average age of onset, 34 years), ranging clinically from dementia with Lewy bodies to typical PD (3). Neuropathological examination of affected members revealed profound pathology including extensive Lewy bodies and some glial cell cytoplasmic inclusions. Screening this family for mutations in, or linkage to, SNCA was negative. Linkage analysis revealed a chromosome 4p15 haplotype segregating with parkinsonism and essential tremor, with suggestive evidence for linkage to PARK4 [multipoint logarithm of odds (LOD) 2.64 at D4S1609](4). However, an unaffected individual who did not share the 4p15 haplotype became ill. This prompted a second genome-wide search at higher resolution, which revealed a haplotype co-segregating with disease over 26 cM (D4S2367–D4S1560), with a multipoint LOD of 3.50 at D4S2460. The SNCA genotypes were inconsistent with previous data, leading to initial exclusion; re-evaluation of the original linkage revealed a sample swap. Resequencing of SNCA failed to reveal pathogenic mutations.The heterozygous single nucleotide polymorphisms in the SNCA promoter and in intron 5 suggested that deletion of this region was unlikely. Reverse transcriptase–polymerase chain reaction (RT-PCR) amplification of SNCA revealed only transcripts of normal length and sequence in affected family members. Analysis of intragenic markers MG4S2 and MG4S5 at the SNCA locus showed apparent examples of non-mendelian inheritance, which could be interpreted as multiple alleles. Quantitative real-time PCR amplification of SNCA exons yielded results consistent with whole gene triplication (Fig. 1). To confirm SNCA triplication, we performed fluorescent in situ hybridization (FISH) of chromosomes from Epstein-Barr virus (EBV)-immortalized lymphocytes from an affected family member (9-77). SNCA triplication in this family segregates with