Genetic variations and neuropathologic features of patients with PARK2.
Genetic variations and neuropathologic features of patients with PARK2.
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PARK2 患者的遗传变异和神经病理学特征。
DOI：
10.1002/mds.28521
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Kakita A.
中科院分区：
文献类型：
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作者：
Seike N;Yokoseki A;Takeuchi R;Saito K;Miyahara H;Miyashita A;Ikeda T;Aida I;Nakajima T;Kanazawa M;Wakabayashi M;Toyoshima Y;Takahashi H;Matumoro R;Toda T;Onodera O;Ishikawa A;Ikeuchi T;Kakita A.
背景PRKN基因突变是常染色体隐性遗传性青少年帕金森综合征最常见的病因。本研究的目的是探讨基因型和病理学的患者与PRKN突变之间的关联。MethodsWe进行了序列和拷贝数变异分析的PRKN，mRNA转录，帕金蛋白表达，和神经病理学8尸检patients.ResultsAll患者harbored biallelicPRKN突变。2例患者分别为错义突变p.C431F的纯合子和杂合子。7例患者有外显子重排，包括2例来自单个家族的患者，其携带外显子4的纯合缺失，3例患者携带外显子6-7的纯合重复，外显子10-11的纯合重复和外显子2-4的杂合重复。在另外2例患者中，我们发现了外显子2的复合杂合重复，外显子3的缺失和外显子2的杂合重复。然而，从mRNA制备的cDNA的测序揭示了源自外显子2的三倍化和外显子2-3的缺失以及源自外显子2-4的重复和外显子3-4的缺失的2种不同的转录物。Western blotting和免疫组化显示，Parkin在他们的大脑中微弱或无表达。在黑质延髓部，神经元丢失和轻度神经胶质增生的亚区特异性模式明显。Lewy小体3例。外周感觉神经元病是一个特点。结论需要基因组和mRNA分析来确定PRKN突变。可变突变可能导致不产生或产生很少的成熟帕金，组织病理学特征可能相似。 © 2021国际帕金森和运动障碍协会
BackgroundMutations inPRKNare the most common cause of autosomal recessive juvenile parkinsonism. The objective of this study was to investigate the association between genotype and pathology in patients withPRKNmutations.MethodsWe performed a sequence and copy number variation analysis ofPRKN, mRNA transcripts, Parkin protein expression, and neuropathology in 8 autopsied patients.ResultsAll the patients harbored biallelicPRKNmutations. Two patients were homozygous and heterozygous, respectively, for the missense mutation p.C431F. Seven patients had exon rearrangements, including 2 patients from a single family who harbored a homozygous deletion of exon 4, and 3 patients who carried a homozygous duplication of exons 6–7, a homozygous duplication of exons 10–11, and a heterozygous duplication of exons 2–4. In the other 2 patients, we found a compound heterozygous duplication of exon 2, deletion of exon 3, and a heterozygous duplication of exon 2. However, sequencing of cDNA prepared from mRNA revealed 2 different transcripts derived from triplication of exon 2 and deletion of exons 2–3 and from duplication of exons 2–4 and deletion of exons 3–4. Western blotting and immunohistochemistry revealed faint or no expression of Parkin in their brains. In the substantia nigra pars compacta, a subfield‐specific pattern of neuronal loss and mild gliosis were evident. Lewy bodies were found in 3 patients. Peripheral sensory neuronopathy was a feature.ConclusionsGenomic and mRNA analysis is needed to identify thePRKNmutations. Variable mutations may result in no or little production of mature Parkin and the histopathologic features may be similar. © 2021 International Parkinson and Movement Disorder Society