Ceruloplasmin gene variations and substantia nigra hyperechogenicity in Parkinson disease
Ceruloplasmin gene variations and substantia nigra hyperechogenicity in Parkinson disease
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DOI：
10.1212/01.wnl.0000144276.29988.c3
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发表时间：
2004-11-23
期刊：
影响因子：
9.9
通讯作者：
Berg, D
中科院分区：
文献类型：
--
作者：
Hochstrasser, H;Bauer, P;Berg, D
背景：经颅超声可用于检测帕金森病（PD）患者和对照组黑质（SN）铁水平升高。目前尚不清楚PD中的铁积累是原发性还是继发性现象。然而，参与铁代谢的基因序列变异与基底神经节疾病有关。其中之一是铜蓝蛋白（Cp），它在铁的跨细胞膜运输中起着至关重要的作用。方法：符合英国脑库标准的176例PD患者和180例种族匹配的对照组，先前通过经颅超声检查SN铁信号变化，使用变性高效液相色谱法检查Cp基因突变，随后测序以验证明确的信号。采用PD中脑免疫组化检测路易小体中Cp的存在。结果：检测到5种新的错义变异。其中之一（I63T）在单个PD患者中发现。已知的变异（D554E）与PD和SN铁水平升高的超声标记物显著相关。此外，发现第三个序列变异（R793H）与患者和对照组中铁水平升高的超声标记物分离。免疫组化显示PD中Cp与路易小体共定位。结论：在单个帕金森病（PD）患者中检测到序列变异或与黑质铁水平升高的超声标记物和路易小体中铜蓝蛋白（Cp）免疫反应性的存在相关，强调了Cp在PD发病机制中的可疑作用。进一步的功能分析是有必要的，以调查这些变异是否与PD的复杂发病机制有因果关系。
Background: Transcranial ultrasound may be used to detect increased iron levels of the substantia nigra (SN) in patients with Parkinson disease (PD) and in control subjects. It is not known whether iron accumulation in PD is a primary or secondary phenomenon. However, sequence variations in genes involved in iron metabolism have been linked to basal ganglia disorders. One of these is ceruloplasmin (Cp), which is vitally involved in iron transport across the cell membrane. Methods: One hundred seventy-six patients with PD according to the UK Brain Bank criteria and 180 ethnically matched control subjects, who were previously examined for SN iron signal changes by transcranial ultrasound, were examined for mutations in the Cp gene using denaturing high-performance liquid chromatography and subsequent sequencing for verification of unequivocal signals. Immunohistochemistry of PD midbrains was performed to examine the presence of Cp in Lewy bodies. Results: Five novel missense variations were detected. One of these (I63T) was found in a single PD patient. A known variation ( D554E) was significantly associated with PD and the ultrasound marker for increased SN iron levels. Moreover, a third sequence variation (R793H) was found to segregate with the ultrasound marker for increased iron levels in patients and control subjects. Immunohistochemistry demonstrated that Cp co-localizes with Lewy bodies in PD. Conclusions: Detection of sequence variations in a single Parkinson disease ( PD) patient or associated with the ultrasound marker for increased substantia nigra iron levels and the presence of ceruloplasmin ( Cp) immunoreactivity in Lewy bodies underline a suspected role for Cp in the pathogenesis of PD. Further functional analyses are warranted to investigate whether these variations are causally linked to the complex pathogenesis of PD in a subset of cases.