Department of Pathology, Brain Research Institute, Niigata University, Niigata, Japan.
Division of Neurology, Kobe University Graduate School of Medicine, Kobe, Japan.
Mov Disord. 2021 Jul;36(7):1634-1643. doi: 10.1002/mds.28521. Epub 2021 Feb 11.
Mutations in PRKN are 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 with PRKN mutations.
We performed a sequence and copy number variation analysis of PRKN, mRNA transcripts, Parkin protein expression, and neuropathology in 8 autopsied patients.
All the patients harbored biallelic PRKN mutations. 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.
Genomic and mRNA analysis is needed to identify the PRKN mutations. 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.
PRKN 基因突变是常染色体隐性遗传少年型帕金森病的最常见病因。本研究旨在探讨 PRKN 基因突变患者的基因型与病理学之间的关系。
我们对 8 例尸检患者进行了 PRKN 序列和拷贝数变异分析、mRNA 转录本、Parkin 蛋白表达和神经病理学检查。
所有患者均携带双等位基因 PRKN 突变。2 例患者分别为错义突变 p.C431F 的纯合子和杂合子。7 例患者存在外显子重排，包括来自单个家族的 2 例纯合子缺失外显子 4，和 3 例患者携带外显子 6-7、10-11 的纯合子重复，以及外显子 2-4 的杂合子重复。在另外 2 例患者中，我们发现了外显子 2 的复合杂合子重复、外显子 3 的缺失以及外显子 2-4 的杂合子重复。然而，从 mRNA 制备的 cDNA 测序显示有 2 种不同的转录本，分别来自外显子 2 的三倍体和外显子 2-3 的缺失，以及外显子 2-4 的重复和外显子 3-4 的缺失。Western blot 和免疫组化显示他们的大脑中 Parkin 表达微弱或缺失。在黑质致密部，存在神经元丢失和轻度神经胶质增生的亚区特异性模式。在 3 例患者中发现了 Lewy 体。周围感觉神经元病是一个特征。
需要进行基因组和 mRNA 分析以鉴定 PRKN 突变。不同的突变可能导致成熟 Parkin 的产生减少或缺失，且组织病理学特征可能相似。© 2021 国际帕金森病和运动障碍学会。
