Genetic Variations and Neuropathologic Features of Patients with PRKN Mutations

• Published in: Movement disorders Vol. 36; no. 7; pp. 1634 - 1643
• Main Authors: Seike, Naohiko, Yokoseki, Akio, Takeuchi, Ryoko, Saito, Kento, Miyahara, Hiroaki, Miyashita, Akinori, Ikeda, Tetsuhiko, Aida, Izumi, Nakajima, Takashi, Kanazawa, Masato, Wakabayashi, Masatoshi, Toyoshima, Yasuko, Takahashi, Hitoshi, Matsumoto, Riki, Toda, Tatsushi, Onodera, Osamu, Ishikawa, Atsushi, Ikeuchi, Takeshi, Kakita, Akiyoshi
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.07.2021; Wiley Subscription Services, Inc
• Subjects: autosomal‐recessive juvenile parkinsonism; Basal ganglia; Brain diseases; Central nervous system diseases; Copy number; DNA Copy Number Variations - genetics; Exons; Gene deletion; Gene expression; Genetic diversity; Genotypes; Gliosis; Homozygote; Humans; Immunohistochemistry; Lewy bodies; Missense mutation; Movement disorders; Mutation; Mutation - genetics; PARK2; Parkin; Parkin protein; pathology; PRKN; Sequence Deletion; Substantia nigra; Ubiquitin-Protein Ligases - genetics; Western blotting; PRKN; autosomal-recessive juvenile parkinsonism; pathology; PARK2; Parkin
• ISSN: 0885-3185; 1531-8257
• DOI: 10.1002/mds.28521

Background 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. Methods We performed a sequence and copy number variation analysis of PRKN, mRNA transcripts, Parkin protein expression, and neuropathology in 8 autopsied patients. Results 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. Conclusions 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 The predicted abnormal mRNA structures because of the biallelic PRKN mutations in patients with autosomal recessive juvenile parkinsonism. Patients harbor variable mutations that result in no production of mature Parkin and exhibit similar histopathologic features.