Zhi-hua Yang

CHCHD2 gene mutations in familial and sporadic Parkinson's disease

Mutations in CHCHD2 gene have been reported in autosomal dominant Parkinsons disease (ADPD). However, there is still lack of evidence supported CHCHD2 mutations lead to ADPD in other populations. We performed whole exome sequencing, positron emission tomography (PET), and haplotype analyses in an ADPD pedigree and then comprehensively screened for CHCHD2 gene mutations in additional 18 familial parkinsonism pedigrees, 364 sporadic PD patients, and 384 healthy controls to assess the frequencies of known and novel rare nonsynonymous CHCHD2 mutations. We identified a heterozygous variant (c.182C>T; p.Thr61Ile) in the CHCHD2 gene in the ADPD pedigree. PET revealed a significant reduction in dopamine transporter binding in the putamen and caudate nucleus of the proband, similar to idiopathic PD. The single nucleotide variant 5C>T (Pro2Leu) in CHCHD2 was confirmed to have a significantly higher frequency among sporadic PD patients than controls. Our results confirm that ADPD can be caused by CHCHD2 mutations and show that the Pro2Leu variant in CHCHD2 may be a risk factor for sporadic PD in Chinese populations.

A novel RAB39B gene mutation in X-linked juvenile parkinsonism with basal ganglia calcification.

Mutations in RAB39B have been reported as a potential cause of X‐linked Parkinsons disease (PD), a rare form of familial PD. We conducted a genetic analysis on RAB39B to evaluate whether RAB39B mutations are related to PD in the Chinese population.

MC1R variants in Chinese Han patients with sporadic Parkinson's disease

Recently, a variant p.R160W in the MC1R gene was identified that increased the risk of Parkinsons disease (PD) in Spanish population. To explore whether the MC1R gene variants are associated with sporadic PD in Chinese population, we performed a case-control comparison study for comprehensive MC1R variant screening in 510 Chinese Han patients and 495 healthy controls as ethnically matched controls. We identify 5 nonsynonymous variants, including rs34090186 (p.R67Q), rs2228479 (p.V92M), rs33932559 (p.I120T), rs885479 (p.R163Q), and rs372152373 (p.R223W). However, variants mentioned previously did not show association with PD. Our results suggest that variants in MC1R do not play a major role in PD in the Chinese population.

Genetic analysis of the TMEM230 gene in Chinese Han patients with Parkinson’s disease

TMEM230 mutations have been recently reported to cause autosomal dominant Parkinson’s disease (PD). However, there are limited studies from different ethnic populations to support the role of TMEM230 in sporadic PD. In this study, we performed a comprehensive TMEM230 mutation screening in 550 sporadic PD patients and 560 controls to elaborate the genetic contribution of TMEM230 to sporadic PD. Overall, we did not find any pathogenic mutations in the coding sequence, while we identified four variants (c.68 + 182G > A, c.78A > G, c.552 + 11A > G and c.174 + 11C > T) both in the patients and controls, and c.68 + 182G > A appeared to be associated with an increased risk of PD (odds ratio 1.782, 95% confidence interval 1.035–3.067, p < 0.05). After Bonferroni correction, however, c. 68 + 182G > A had no significant association with sporadic PD (pc = 0.136, pc > 0.05). Thus our results suggest that TMEM230 gene mutations may be rare in Chinese populations, and the variability of TMEM230 gene may not be a main factor for sporadic PD patients in Chinese Han populations. More evidence is still needed to clarify this question.

AQP4 Association with Amyloid Deposition and Astrocyte Pathology in the Tg-ArcSwe Mouse Model of Alzheimer’s Disease

Amyloid-β deposition in senile plaques is one of the main pathological changes in Alzheimers disease (AD). We previously reported that aquaporin-4 (AQP4) is redistributed within the astrocytes in cerebral amyloid angiopathy in the tg-ArcSwe mouse model of AD, suggesting that AQP4 may participate in amyloid-β deposition. However, the role of AQP4 in plaque formation is not currently clear. The objective of the current study was to explore the AQP4 distribution within plaques in the tg-ArcSwe mice in more depth by the combined application of immunofluorescence cytochemistry and immunogold electron microscopy. In addition, the astrocyte marker, glial fibrillary acidic protein (GFAP), was studied in association with AQP4. We demonstrated a robust upregulation of AQP4 expression in areas of plaques. Compared to GFAP, AQP4 appeared predominantly at later stages of plaque formation, in older mice, and within the processes of astrocytes. In combination with GFAP, AQP4 differentiated plaques into three progression stages under light microscopy. This suggests that AQP4 expression was associated with amyloid deposition and astrocyte pathology in the Tg-ArcSwe mouse model of AD. This provides novel proof for the involvement of AQP4 in the process of amyloid deposition in AD.

Association of variants in microRNA with Parkinson’s disease in Chinese Han population

MicroRNAs (miRNAs) are short RNAs regulating gene expression and may participate in pathogenesis of various diseases. Recently, rs897984:T > C in miR-4519 and rs11651671:A > G in miR-548at-5p have been reported that associate with Parkinson’s disease (PD). However, to our knowledge, there is no further evidence regarding this finding. Herein, we performed a case-control study of 546 PD patients and 550 healthy controls to genotype the two single-nucleotide polymorphisms (SNPs) to assess their associations with PD. The results showed that rs897984 (OR value for C allele = 0.851, 95% CI 0.603–1.201, P = 0.358) in miR-4519 and rs11651671 (OR value for G allele = 1.405, 95% CI 0.927–2.131, P = 0.107) in miR-548at-5p were not associated to PD, which suggest they may not contribute to the gene susceptibility of PD at least in Chinese Han population. More evidences from larger sample size and other ethnic populations are still needed to illustrate the association between miRNAs and PD.

Generation of induced pluripotent stem cell line (ZZUi005-A) from a 21-year-old patient with a novel RAB39B gene mutation in X-linked juvenile parkinsonism

Ras-related protein 39B (RAB39B) mutation has been reported as a potential cause of X-linked Parkinsons disease (PD), a rare form of familial PD. Recently, a novel RAB39B mutation was identified in an X-linked juvenile parkinsonism family and the dermal fibroblasts of the patient were obtained and successfully induced to induced pluripotent stem cells (iPSCs) by the human OSKM transcription factors using the Sendai-virus delivery system. Our model may offer a good platform for further research of the pathomechanism, drug testing, and gene therapy of this disease.

Generation of induced pluripotent stem cell line (ZZUi004-A) from urine sample of a patient with spinocerebellar ataxia type 3

Spinocerebellar ataxia type 3 (SCA3) is a dominantly inherited neurodegenerative disease caused by a CAG repeat expansion in the region of the ATXN3 gene. The main feature of SCA3 is progressive ataxia, which affects balance, gait, and speech. Urine cells (UCs) of a SCA3 patient were successfully translated to induced pluripotent stem cells (iPSCs) by using the Sendai virus delivery system. ZZUi004-A cell line may provide a robust platform for further study of SCA3 pathogenesis as well as drug testing and gene therapy research.

DNAJC12 mutation is rare in Chinese Han population with Parkinson's disease

Recently, mutations of DNAJC12 gene were reported to be associated with early-onset parkinsonism, progressive neurodevelopmental delay, and dystonia in several unrelated pedigrees. This study aimed to evaluate DNAJC12 coding mutations in sporadic Chinese Han patients with Parkinsons disease (PD) and test whether an age-of-onset effect exists. Seven hundred two Chinese Han sporadic PD patients, including 181 early-onset PD and 521 late-onset PD, and 728 healthy controls were recruited. No documented disease-causing mutation of DNAJC12 was identified, but we found 7 single-nucleotide polymorphisms. Allele frequencies did not differ between all the PD patients and controls or between any 2 subgroups for all these single-nucleotide polymorphisms. Our study suggests that DNAJC12 mutation is not a risk factor of PD in Chinese Han population, and no age-of-onset effect was verified.

Novel compound heterozygous PANK2 gene mutations in a Chinese patient with atypical pantothenate kinase-associated neurodegeneration

Abstract Aim: Pantothenate-kinase-associated neurodegeneration (PKAN), which is characterised by iron accumulation in the basal ganglia, is a rare autosomal recessive neurodegenerative disorder caused by pantothenate kinase 2 (PANK2) gene mutations. The PANK2 gene is located on chromosome 20p13 and encodes pantothenate kinase. Herein, we identified one patient with PKAN who had mutations in the PANK2 gene. Materials and methods: We performed clinical and radiographic investigations, and diagnosed this disease at the clinical and genetic levels. Results: It is worth mentioning that the patient displayed an eye-of-the-tiger sign. Through scanning the exons and flanking intronic sequences of PANK2 in patient and control subjects, we report a compound heterozygote c. 260A > G (NM_001324191) and c.405dupC (NM_153638) for PANK2 mutations in a Chinese patient with clinical manifestation of progressive prosopospasm, dysarthria and gait disturbance. Bioinformatics analysis showed that two variants exhibited highly conserved residues across species. Conclusion: we reported a patient presenting with atypical PKAN, and identified novel compound heterozygous PANK2 gene mutations..