Publications by authors named "Cheng-Yuan Mao"

26 Publications

  • Page 1 of 1

Generation of an induced pluripotent stem cell line (ZZUi020-A) from a patient with Parkinson's disease harboring the intermediate-length GGC repeat expansions in the NOTCH2NLC gene.

Stem Cell Res 2021 04 18;52:102257. Epub 2021 Feb 18.

Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China. Electronic address:

Here, we describe the generation of an induced pluripotent stem cell (iPSC) line, from a female patient diagnosed with Parkinson's disease (PD). The patient carries a heterozygous intermediate-length GGC repeat expansions mutation in the NOTCH2NLC gene. Skin fibroblasts were reprogrammed using the non-integrating Sendai virus technology to deliver Klf4, OCT3/4, SOX2 and c-MYC factors. The generated iPSC line (ZZUi020-A) presented with expression of common pluripotency markers, showed potential of differentiating into derivatives of the three germ layers, and displayed a normal karyotype. The clone ZZUi020-A is presented thereafter, it can be used to study the mechanisms underlying NOTCH2NLC-PD pathogenesis.
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http://dx.doi.org/10.1016/j.scr.2021.102257DOI Listing
April 2021

NOTCH2NLC Intermediate-Length Repeat Expansions Are Associated with Parkinson Disease.

Ann Neurol 2021 01 19;89(1):182-187. Epub 2020 Oct 19.

Department of Neurology, First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.

NOTCH2NLC GGC repeat expansions were recently identified in neuronal intranuclear inclusion disease (NIID); however, it remains unclear whether they occur in other neurodegenerative disorders. This study aimed to investigate the role of intermediate-length NOTCH2NLC GGC repeat expansions in Parkinson disease (PD). We screened for GGC repeat expansions in a cohort of 1,011 PD patients and identified 11 patients with intermediate-length repeat expansions ranging from 41 to 52 repeats, with no repeat expansions in 1,134 controls. Skin biopsy revealed phospho-alpha-synuclein deposition, confirming the PD diagnosis in 2 patients harboring intermediate-length repeat expansions instead of NIID or essential tremor. Fibroblasts from PD patients harboring intermediate-length repeat expansions revealed NOTCH2NLC upregulation and autophagic dysfunction. Our results suggest that intermediate-length repeat expansions in NOTCH2NLC are potentially associated with PD. ANN NEUROL 2021;89:182-187.
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http://dx.doi.org/10.1002/ana.25925DOI Listing
January 2021

CHIP as a therapeutic target for neurological diseases.

Cell Death Dis 2020 09 9;11(9):727. Epub 2020 Sep 9.

Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, 450000, Zhengzhou, Henan, China.

Carboxy-terminus of Hsc70-interacting protein (CHIP) functions both as a molecular co-chaperone and ubiquitin E3 ligase playing a critical role in modulating the degradation of numerous chaperone-bound proteins. To date, it has been implicated in the regulation of numerous biological functions, including misfolded-protein refolding, autophagy, immunity, and necroptosis. Moreover, the ubiquitous expression of CHIP in the central nervous system suggests that it may be implicated in a wide range of functions in neurological diseases. Several recent studies of our laboratory and other groups have highlighted the beneficial role of CHIP in the pathogenesis of several neurological diseases. The objective of this review is to discuss the possible molecular mechanisms that contribute to the pathogenesis of neurological diseases in which CHIP has a pivotal role, such as stroke, intracerebral hemorrhage, Alzheimer's disease, Parkinson's disease, and polyglutamine diseases; furthermore, CHIP mutations could also cause neurodegenerative diseases. Based on the available literature, CHIP overexpression could serve as a promising therapeutic target for several neurological diseases.
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http://dx.doi.org/10.1038/s41419-020-02953-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481199PMC
September 2020

ARSA gene variants and Parkinson's disease.

Brain 2020 06;143(6):e47

Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450000, Henan, China.

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http://dx.doi.org/10.1093/brain/awaa134DOI Listing
June 2020

No biallelic intronic AAGGG repeat expansion in RFC1 was found in patients with late-onset ataxia and MSA.

Parkinsonism Relat Disord 2020 04 26;73:1-2. Epub 2020 Feb 26.

Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450000, Henan, China. Electronic address:

We screened the RFC1 intronic AAGGG repeat expansions in late-onset ataxia cases, MSA patients and controls. The data suggested that no biallelic repeat expansion carrier was found in our cohort and the heterozygous intronic AAGGG repeat expansions may not lead to an increased risk of late-onset ataxia or MSA.
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http://dx.doi.org/10.1016/j.parkreldis.2020.02.017DOI Listing
April 2020

Carboxyl Terminus of Hsp70-Interacting Protein Is Increased in Serum and Cerebrospinal Fluid of Patients With Spinocerebellar Ataxia Type 3.

Front Neurol 2019 15;10:1094. Epub 2019 Oct 15.

Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.

Spinocerebellar ataxia type 3 (SCA3)/Machado-Joseph disease (MJD) is the most common type of autosomal dominant ataxia. Like other neurodegenerative diseases, is characterized by the dysfunction of the protein quality control (PQC) system. The carboxyl terminus of the Hsp70-interacting protein (CHIP), an important component of PQC, participates in the clearance of misfolded proteins to maintain cellular homeostasis. While no cure for SCA3 exists, the disease progresses slowly. Thus, the identification of biomarkers that indicate the severity and prognosis of this disease would be valuable. In this exploratory case-control study, we quantitatively evaluated the concentrations of CHIP in the sera of 80 patients with SCA3 and 80 age and sex-matched controls, using the enzyme-linked immunosorbent assay (ELISA). CHIP levels in the cerebrospinal fluid (CSF) donated by six patients and six healthy volunteers, who were matched for sex and age were also measured. All the baseline data were collected, and the patients underwent clinical evaluation. The correlations between CHIP levels and several clinical measurements were analyzed. The serum CHIP level in the SCA3 group was (80.93 ± 28.68) ng/mL, which was significantly higher than those in the control group [(40.37 ± 18.55) ng/mL]. Similar results were observed for the CSF [(164.59 ± 42.99) ng/mL and (37.47 ± 7.85) ng/mL, respectively]. CSF CHIP levels were significantly higher than the serum CHIP levels in the SCA3 group but not in the control group. The Dunn-Bonferroni for Kruskal-Wallis test revealed no significant difference between the serum and CSF of the patients and the control group. Multivariate linear regression showed that serum CHIP levels correlated positively with disease severity, as measured by the Scale for the Assessment and Rating of Ataxia (SARA) and the International Cooperative Ataxia Rating Scale (ICARS). Moreover, we found that serum CHIP levels were moderately correlated with age in healthy controls. The present study determined that CHIP levels increased significantly in the serum and CSF of patients with SCA3 and that serum CHIP levels were corelated with disease severity. Thus, CHIP is a promising biomarker for SCA3.
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http://dx.doi.org/10.3389/fneur.2019.01094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6843056PMC
October 2019

AAV/BBB-Mediated Gene Transfer of CHIP Attenuates Brain Injury Following Experimental Intracerebral Hemorrhage.

Transl Stroke Res 2020 04 19;11(2):296-309. Epub 2019 Jul 19.

Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450000, Henan, China.

Cell death is a hallmark of secondary brain injury following intracerebral hemorrhage (ICH). The E3 ligase CHIP has been reported to play a key role in mediating necroptosis-an important mechanism of cell death after ICH. However, there is currently no evidence supporting a function of CHIP in ICH. In the present study, we aimed to determine whether CHIP plays an essential role in brain injury after ICH. Our findings indicated that CHIP expression was increased in the peri-hematomal area in rat models of ICH. The AAV/BBB viral platform enables non-invasive, widespread, and long-lasting global neural expression of target genes. Treatment with AAV/BBB-CHIP ameliorated brain injury and inhibited neuronal necroptosis and inflammation in wild type (WT) rats following ICH. Furthermore, rats with CHIP deficiency experienced severe brain injury and increased levels of neuronal necroptosis and inflammation relative to their WT counterparts. However, treatment with AAV/BBB-CHIP attenuated the effects of CHIP deficiency after ICH. Collectively, our results demonstrate that CHIP inhibits necroptosis and pathological inflammation following ICH, and that overexpression of CHIP may represent a therapeutic intervention for ICH. Moreover, the AAV/BBB viral platform may provide a novel avenue for the treatment of brain injury.
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http://dx.doi.org/10.1007/s12975-019-00715-wDOI Listing
April 2020

Metabolic Profiling Reveals Biochemical Pathways and Potential Biomarkers of Spinocerebellar Ataxia 3.

Front Mol Neurosci 2019 27;12:159. Epub 2019 Jun 27.

Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.

Spinocerebellar ataxia 3, also known as Machado-Joseph disease (SCA3/MJD), is a rare autosomal-dominant neurodegenerative disease caused by an abnormal expansion of CAG repeats in the gene. In the present study, we performed a global metabolomic analysis to identify pathogenic biochemical pathways and novel biomarkers implicated in SCA3 patients. Metabolic profiling of serum samples from 13 preclinical SCA3 patients, 13 symptomatic SCA3 patients, and 15 healthy controls were mapped using ultra-high-performance liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry techniques. The symptomatic SCA3 patients showed a metabolic profile significantly distinct from those of the preclinical SCA3 patients and healthy controls. The principal differential metabolites were involved in the amino acid (AA) metabolism and fatty acid metabolism pathways. In addition, four candidate serum biomarkers, FFA 16:1 (palmitoleic acid), FFA 18:3 (linolenic acid), L-Proline and L-Tryptophan, were selected to discriminate between symptomatic SCA3 patients and healthy controls by receiver operator curve analysis with an area under the curve of 0.979. Our study demonstrates that symptomatic SCA3 patients present distinct metabolic profiles with perturbed AA metabolism and fatty acid metabolism, and FFA 16:1, FFA 18:3, L-Proline and L-Tryptophan are identified as potential disease biomarkers.
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http://dx.doi.org/10.3389/fnmol.2019.00159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611058PMC
June 2019

Novel compound heterozygous GFPT1 mutations in a family with limb-girdle myasthenia with tubular aggregates.

Neuromuscul Disord 2019 07 28;29(7):549-553. Epub 2019 May 28.

Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, 1 Jian-she East Road, Zhengzhou 450000, Henan, China; Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China. Electronic address:

Limb-girdle myasthenia with tubular aggregates, a subtype of congenital myasthenic syndrome, is an extremely rare autosomal recessive genetic disease characterized by prominent limb-girdle weakness and good response to acetylcholinesterase inhibitor therapy. Herein, we reported two novel mutations of GFPT1 gene in a Chinese pedigree. Two siblings presented with fatigue, weakness of limb-girdle and decrement of the muscle action potential with repetitive nerve stimulation. Thus, myasthenia gravis was initially suspected, but anti-AChR antibodies were negative. Two novel missense mutations (p.Lys154Asn and p.Asn363Ser) in GFPT1 were identified through genetic testing conducted on 167 well-established genes associated with muscular diseases by targeted high throughput sequencing. Both mutations have not been recorded in the dsSNP database, Exome Aggregation Consortium database and 1000 Genomes Project database. The mutation sites were co-segregated with the phenotype and conserved between the different species. The mutations were not found in the 200 unrelated normal controls. Muscle biopsies revealed tubular aggregates, in accordance with previous reports with GFPT1 mutations. Subsequently, dramatic improvement in strength occurred following anti-cholinesterase therapy. Our study will be helpful for the diagnosis and treatment for Limb-girdle myasthenia with tubular aggregates.
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http://dx.doi.org/10.1016/j.nmd.2019.05.008DOI Listing
July 2019

SNCA but not DNM3 and GAK modifies age at onset of LRRK2-related Parkinson's disease in Chinese population.

J Neurol 2019 Jul 30;266(7):1796-1800. Epub 2019 Apr 30.

Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, 1 Jian-she east road, Zhengzhou, 450000, Henan, China.

Background: Recently, rs2421947 in DNM3 (dynamin 3) was reported as a genetic modifier of age at onset (AAO) of LRRK2 G2019S-related Parkinson's disease (PD) in a genome-wide association study in Arab-Berber population. Rs356219 in SNCA (α-synuclein) was also reported to regulate the AAO of LRRK2-related PD in European populations, and GAK (Cyclin G-associated kinase) rs1524282 was reported to be associated with an increased PD risk with an interaction with SNCA rs356219. G2019S variant is rare in Asian populations, whereas two other Asian-specific LRRK2 variants, G2385R and R1628P, are more frequent with a twofold increased risk of PD.

Methods: In this study, we investigated whether rs2421947, rs356219 and rs1524282 modified AAO in LRRK2-related PD patients in Han Chinese population. We screened LRRK2 G2385R and R1628P variants in 732 PD patients and 1992 healthy controls, and genotyped DNM3 rs2421947, SNCA rs356219 and GAK rs1524282 among the LRRK2 carriers.

Results: The SNCA rs356219-G allele was found to increase the risk of PD in LRRK2 carriers (OR 1.50, 95%CI 1.08-2.01, P = 0.016), and the AAO of AG + GG genotypes was 4 years earlier than AA genotype (P = 0.006). Nonetheless, no similar association was found in DNM3 rs2421947 and GAK rs1524282.

Conclusions: Our results show that SNCA but not DNM3 or GAK is associated with AAO of LRRK2-PD patients in Chinese population.
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http://dx.doi.org/10.1007/s00415-019-09336-7DOI Listing
July 2019

Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16.

PLoS Genet 2018 09 17;14(9):e1007664. Epub 2018 Sep 17.

McAllister Heart Institute at The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.

CHIP (carboxyl terminus of heat shock 70-interacting protein) has long been recognized as an active member of the cellular protein quality control system given the ability of CHIP to function as both a co-chaperone and ubiquitin ligase. We discovered a genetic disease, now known as spinocerebellar autosomal recessive 16 (SCAR16), resulting from a coding mutation that caused a loss of CHIP ubiquitin ligase function. The initial mutation describing SCAR16 was a missense mutation in the ubiquitin ligase domain of CHIP (p.T246M). Using multiple biophysical and cellular approaches, we demonstrated that T246M mutation results in structural disorganization and misfolding of the CHIP U-box domain, promoting oligomerization, and increased proteasome-dependent turnover. CHIP-T246M has no ligase activity, but maintains interactions with chaperones and chaperone-related functions. To establish preclinical models of SCAR16, we engineered T246M at the endogenous locus in both mice and rats. Animals homozygous for T246M had both cognitive and motor cerebellar dysfunction distinct from those observed in the CHIP null animal model, as well as deficits in learning and memory, reflective of the cognitive deficits reported in SCAR16 patients. We conclude that the T246M mutation is not equivalent to the total loss of CHIP, supporting the concept that disease-causing CHIP mutations have different biophysical and functional repercussions on CHIP function that may directly correlate to the spectrum of clinical phenotypes observed in SCAR16 patients. Our findings both further expand our basic understanding of CHIP biology and provide meaningful mechanistic insight underlying the molecular drivers of SCAR16 disease pathology, which may be used to inform the development of novel therapeutics for this devastating disease.
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http://dx.doi.org/10.1371/journal.pgen.1007664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160236PMC
September 2018

Anisomycin prevents OGD-induced necroptosis by regulating the E3 ligase CHIP.

Sci Rep 2018 04 23;8(1):6379. Epub 2018 Apr 23.

Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450000, Henan, China.

Necroptosis is an essential pathophysiological process in cerebral ischemia-related diseases. Therefore, targeting necroptosis may prevent cell death and provide a much-needed therapy. Ansiomycin is an inhibitor of protein synthesis which can also activate c-Jun N-terminal kinases. The present study demonstrated that anisomycin attenuated necroptosis by upregulating CHIP (carboxyl terminus of Hsc70-interacting protein) leading to the reduced levels of receptor-interacting protein kinase 1 (RIPK1) and receptor-interacting protein kinase 3 (RIPK3) proteins in two in vitro models of cerebral ischemia. Further exploration in this research revealed that losing neither the co-chaperone nor the ubiquitin E3 ligase function of CHIP could abolish its ability to reduce necroptosis. Collectively, this study identifies a novel means of preventing necroptosis in two in vitro models of cerebral ischemia injury through activating the expression of CHIP, and it may provide a potential target for the further study of the disease.
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http://dx.doi.org/10.1038/s41598-018-24414-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5913227PMC
April 2018

Analysis of variant rs3794087 in SLC1A2 and Parkinson's disease in a Chinese Han population: A case-control study and meta-analysis.

Neurosci Lett 2018 02 21;666:165-168. Epub 2017 Dec 21.

Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450000, Henan, China. Electronic address:

Recently, a genome-wide association study of a Caucasian population identified variant rs3794087 in intron 4 of the SLC1A2 gene, which may increase the risk of essential tremor (ET). Considering the overlap in the pathological features and clinical manifestations of ET and Parkinson's disease (PD), several studies on the association between rs3794087 and PD were later performed in other populations. However, results about the role of SLC1A2 rs3794087 in PD were inconsistent. We thus performed a case-control study in a Chinese Han population to investigate the role of SLC1A2 rs3794087 in Chinese patients with PD. Overall, 1096 subjects comprising 546 patients with PD and 550 control subjects were genotyped. A meta-analysis of the data obtained from the current sample-set and those available from prior studies was performed. Taking all patients and controls into consideration, rs3794087 was found to have no significant effect on PD susceptibility in analyses using allelic (p = .486), genotype (p = .736), additive (p = .764), dominant (p = .438), and recessive (p = .878) genetic models. The results of the meta-analysis were in agreement with our findings (the pooled OR was 0.97 and 95% CI = 0.85, 1.10). Our study suggested that rs3794087 does not lead to an increased risk of PD in the Chinese Han population. The role of single nucleotide polymorphism rs3794087 in the development of PD remains to be further studied.
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http://dx.doi.org/10.1016/j.neulet.2017.12.045DOI Listing
February 2018

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

Sci Rep 2017 04 26;7(1):1190. Epub 2017 Apr 26.

Department of Neurology, The first affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450000, Henan, China.

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 (p  = 0.136, p  > 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.
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http://dx.doi.org/10.1038/s41598-017-01398-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5430725PMC
April 2017

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

Mov Disord 2016 12;31(12):1905-1909

Department of Neurology, The First affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China.

Objectives: Mutations in RAB39B have been reported as a potential cause of X-linked Parkinson's 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.

Methods: In this study, 2 patients from an X-linked juvenile parkinsonism pedigree were clinically characterized and underwent whole-exome sequencing. A comprehensive screening for RAB39B mutations in 505 sporadic patients with PD and 510 healthy controls in a Chinese population was also performed.

Results: A novel mutation, c. 536dupA (p.E179fsX48), in RAB39B was identified in the juvenile parkinsonism pedigree. Brain MRI and CT scans in the 2 patients revealed calcification within the bilateral globus pallidus. No other potentially disease-causing RAB39B mutations were found in sporadic PD patients and controls.

Conclusions: X-linked juvenile parkinsonism could be caused by a RAB39B mutation, and basal ganglia calcification may be a novel clinical feature of RAB39B-related parkinsonism. © 2016 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.26828DOI Listing
December 2016

SMPD1 variants in Chinese Han patients with sporadic Parkinson's disease.

Parkinsonism Relat Disord 2017 01 19;34:59-61. Epub 2016 Oct 19.

Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450000, Henan, China. Electronic address:

Introduction: A founder mutation, p.L302P, in sphingomyelin phosphodiesterase 1, acid lysosomal (SMPD1), causing Niemann-Pick disease, a recessive lysosomal storage disorder, was reported to be associated with increased risk of Parkinson's disease (PD) in Ashkenazi Jewish population. Several other studies about the association between SMPD1 variants and PD were performed afterward in other populations. However, the results on the role of SMPD1 mutations for PD have been conflicting. This study aimed to investigate the role of mutations in SMPD1 in Chinese PD patients.

Methods: We sequenced all the exons of this gene in 512 Chinese Han cases with sporadic Parkinson's disease and 495 matched healthy control subjects.

Results: We identified Leu-Ala (Val) repeat variants and six known single nucleotide variants (p.A36V, p.D212D, p.P332R, p.G508R, p.P533L, p.T544T) in SMPD1 in both patients and normal controls. Case-control analysis showed the association between Leu-Ala (Val) repeat variants in SMPD1and Chinese Han patients with PD (χ = 8.771, p = 0.012), and the allele with less than seven LeuAla (Val) repeats may increase the risk of PD (p = 0.010).

Conclusion: We identified association between Leu-Ala (Val) repeat variants in SMPD1 and Chinese Han patients with sporadic Parkinson's disease. Our results provide further support for the role of lysosomal pathways in PD development.
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http://dx.doi.org/10.1016/j.parkreldis.2016.10.014DOI Listing
January 2017

Brain glucose metabolism changes in Parkinson's disease patients with CHCHD2 mutation based on (18)F-FDG PET imaging.

J Neurol Sci 2016 Oct 21;369:303-305. Epub 2016 Aug 21.

Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450000, Henan, China; Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450000, Henan, China. Electronic address:

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http://dx.doi.org/10.1016/j.jns.2016.08.042DOI Listing
October 2016

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

Neurobiol Aging 2016 06 3;42:217.e5-6. Epub 2016 Mar 3.

Department of Neurology, The first affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China. Electronic address:

Recently, a variant p.R160W in the MC1R gene was identified that increased the risk of Parkinson's 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.
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http://dx.doi.org/10.1016/j.neurobiolaging.2016.02.026DOI Listing
June 2016

CHCHD2 gene mutations in familial and sporadic Parkinson's disease.

Neurobiol Aging 2016 Feb 6;38:217.e9-217.e13. Epub 2015 Nov 6.

Department of Neurology, The first affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China. Electronic address:

Mutations in CHCHD2 gene have been reported in autosomal dominant Parkinson's 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.
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http://dx.doi.org/10.1016/j.neurobiolaging.2015.10.040DOI Listing
February 2016

Exome capture sequencing identifies a novel CCM1 mutation in a Chinese family with multiple cerebral cavernous malformations.

Int J Neurosci 2016 Dec 7;126(12):1071-6. Epub 2015 Dec 7.

a 1 Department of Neurology , The First Affiliated Hospital of Zhengzhou University, Zhengzhou University , Zhengzhou , China.

Purpose: Cerebral cavernous malformations (CCMs) are vascular anomalies predominantly in the central nervous system but may include lesions in other tissues, such as the retina, skin and liver. The main clinical manifestations include seizures, hemorrhage, recurrent headaches and focal neurological deficits. Previous studies of familial CCMs (FCCMs) have mainly reported in Hispanic and Caucasian cases. Here, we report on FCCMs in a Chinese family further characterized by a novel CCM1 gene mutation.

Materials And Methods: We investigated clinical and neuroradiological features of a Chinese family of 30 members. Furthermore, we used exome capture sequencing to identify the causing gene. The CCM1 mRNA expression level in three patients of the family and 10 wild-type healthy individuals were detected by real-time quantitative polymerase chain reaction (real-time RT-PCR).

Results: Brain magnetic resonance imaging demonstrated multiple intracranial lesions in seven members. The clinical manifestation of CCM was found in five of these cases, including recurrent headaches, weakness, hemorrhage and seizures. Moreover, we identified a novel nonsense mutation c.1159G>T (p. E387*) in the CCM1 gene in the pedigree. Based on real-time RT-PCR results, we have found that the CCM1 mRNA expression level in three patients was reduced by 35% than that in wild-type healthy individuals.

Conclusions: Our finding suggests that the novel nonsense mutation c.1159G>T in CCM1 gene is associated with FCCM, and that CCM1 haploinsufficiency may be the underlying mechanism of CCMs. Furthermore, it also demonstrates that exome capture sequencing is an efficient and direct diagnostic tool to identify causes of genetically heterogeneous diseases.
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http://dx.doi.org/10.3109/00207454.2015.1118628DOI Listing
December 2016

Recessive hereditary motor and sensory neuropathy caused by IGHMBP2 gene mutation.

Neurology 2015 Jul 1;85(4):383-4. Epub 2015 Jul 1.

From the Department of Neurology (C-h.S., B.S., H-y.L., C-y.M., D-d.S., Y.C., S-l.S., J.W., Y-m.X.), The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China; and Surgical Neurology Branch (Z-p.Z.), National Institute of Neurological Disorders and Stroke, Bethesda, MD.

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http://dx.doi.org/10.1212/WNL.0000000000001747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4520818PMC
July 2015

Calcium intake and the risk of stroke: an up-dated meta-analysis of prospective studies.

Asia Pac J Clin Nutr 2015 ;24(2):245-52

Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Henan, China. Email:

Background And Purpose: Calcium intake has been associated with stroke risk in a prior meta-analysis, however, newly published results are inconsistent. Dairy food benefits on stroke incidence may involve a calcium-related mechanism. We have therefore updated this meta-analysis with particular references to any possibility of a calcium-mediated dairy food risk reduction of stroke risk.

Methods: We searched multiple databases and bibliographies for prospective cohort studies. Reports with multivariate-adjusted relative risk (RR) and corresponding 95% confidence intervals (CI) for the association of calcium intake with stroke incidence were considered.

Results: Ten studies with 371,495 participants and 10,408 stroke events were analyzed. The pooled analysis showed no statistically significant association of the risk of total stroke (RR=0.96; 95% CI: 0.89-1.04) and stroke subtypes with the highest and lowest calcium intake quantiles. Nevertheless, high dairy calcium intake was significantly associated with an approximately 24% reduction of stroke risk. (RR=0.76; 95% CI: 0.66-0.86). Furthermore, a long-term follow-up (>=14 years) was helpful to reduce the risk of stroke (RR=0.67; 95% CI: 0.51-0.88). Additionally, a non-linear dose-response relationship was predicted between calcium intake and stroke risk.

Conclusions: Dairy calcium intake is inversely associated with stroke incidence. There is a non-linear dose-response relationship between calcium intake and stroke risk. However, when the follow-up time is long enough, the inverse relationship is independent of dose. Additional large cohort studies are required to illustrate this relationship in detail.
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http://dx.doi.org/10.6133/apjcn.2015.24.2.22DOI Listing
August 2015

Exome sequencing reveals novel SPG11 mutation in hereditary spastic paraplegia with complicated phenotypes.

J Clin Neurosci 2015 Jul 21;22(7):1150-4. Epub 2015 May 21.

Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, 1 Jian-she East Road, Zhengzhou 450000, Henan, China; Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China. Electronic address:

We used a combined approach of whole-exome sequencing and candidate mutation validation to identify the disease-causing gene in a hereditary spastic paraplegia (HSP) patient with lower motor neuron involvement, mild cerebellar signs and dysgenesis of the corpus callosum. HSP is a clinically and genetically heterogeneous neurodegenerative disorder characterized by degeneration of the corticospinal tract motor neurons and resulting in progressive lower limb spasticity, often with a complicated phenotype. We identified novel compound heterozygous mutations in the SPG11 gene in this patient as follows: a mutation in exon 32, c.6194C > G transition (p.S2056X) and a novel c.5121+1C > T splicing mutation. Our finding suggests that these novel compound heterozygous mutations in SPG11 are associated with HSP and lower motor neuron involvement, mild cerebellar signs and dysgenesis of the corpus callosum. This study also demonstrates that exome sequencing is an efficient and rapid diagnostic tool for identifying the causes of some complex and genetically heterogeneous neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.jocn.2015.01.014DOI Listing
July 2015

Nerve growth factor for the treatment of spinocerebellar ataxia type 3: an open-label study.

Chin Med J (Engl) 2015 Feb;128(3):291-4

Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.

Background: Spinocerebellar ataxia type 3 (SCA3) is the most common subtype of SCA worldwide, and runs a slowly progressive and unremitting disease course. There is currently no curable treatment available. Growing evidence has suggested that nerve growth factor (NGF) may have therapeutic effects in neurodegenerative diseases, and possibly also in SCA3. The objective of this study was to test the efficacy of NGF in SCA3 patients.

Methods: We performed an open-label prospective study in genetically confirmed adult (>18 years old) SCA3 patients. NGF was administered by intramuscular injection (18 μg once daily) for 28 days consecutively. All the patients were evaluated at baseline and 2 and 4 weeks after treatment using the Chinese version of the scale for assessment and rating of ataxia (SARA).

Results: Twenty-one SCA3 patients (10 men and 11 women, mean age 39.14 ± 7.81 years, mean disease duration 4.14 ± 1.90 years, mean CAG repeats number 77.57 ± 2.27) were enrolled. After 28 days of NGF treatment, the mean total SARA score decreased significantly from a baseline of 8.48 ± 2.40 to 6.30 ± 1.87 (P < 0.001). Subsections SARA scores also showed significant improvements in stance (P = 0.003), speech (P = 0.023), finger chase (P = 0.015), fast alternating hand movements (P = 0.009), and heel-shin slide (P = 0.001).

Conclusions: Our preliminary data suggest that NGF may be effective in treating patients with SCA3.
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http://dx.doi.org/10.4103/0366-6999.150087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4837856PMC
February 2015

Genotype-phenotype correlation in a cohort of paroxysmal kinesigenic dyskinesia cases.

J Neurol Sci 2014 May 3;340(1-2):91-3. Epub 2014 Mar 3.

Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450000 Henan, People's Republic of China. Electronic address:

Background: Recently, PRRT2 gene mutations have been identified as a causative factor of paroxysmal kinesigenic dyskinesia (PKD). However, evidence is still lacking with respect to the genotype to phenotype correlation in PKD patients.

Methods: We recruited a cohort of PKD patients with or without PRRT2 mutations for the study, and followed them for 6 months to observe the response to carbamazepine treatment.

Results: Thirty-four participants were included in this study; 16 patients were positive for a hot-spot p.R217Pfs 8 heterozygous PRRT2 gene mutation, while the other 18 patients were negative for PRRT2 gene mutations. PRRT2 mutations were found to be associated with a younger age of onset, bilateral presence and a higher frequency of attacks. Furthermore, the follow-up study revealed that p.R217Pfs 8-positive patients showed dramatic improvement with complete abolition of dyskinetic episodes with carbamazepine treatment, while only 7 of the 18 patients without PRRT2 mutations showed a response to the antiepileptic drug.

Conclusions: Our study indicated that positivity for PRRT2 mutation is a predictor of younger age of onset and more frequent of attacks in PKD patients. Interestingly, the presence of PRRT2 mutations also predicted a good response to carbamazepine therapy, especially at low dose. Therefore, genetic testing shows potential clinical significance for guiding the choice of medication for individual PKD cases.
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http://dx.doi.org/10.1016/j.jns.2014.02.034DOI Listing
May 2014

Ataxia and hypogonadism caused by the loss of ubiquitin ligase activity of the U box protein CHIP.

Hum Mol Genet 2014 Feb 9;23(4):1013-24. Epub 2013 Oct 9.

Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China.

Gordon Holmes syndrome (GHS) is a rare Mendelian neurodegenerative disorder characterized by ataxia and hypogonadism. Recently, it was suggested that disordered ubiquitination underlies GHS though the discovery of exome mutations in the E3 ligase RNF216 and deubiquitinase OTUD4. We performed exome sequencing in a family with two of three siblings afflicted with ataxia and hypogonadism and identified a homozygous mutation in STUB1 (NM_005861) c.737C→T, p.Thr246Met, a gene that encodes the protein CHIP (C-terminus of HSC70-interacting protein). CHIP plays a central role in regulating protein quality control, in part through its ability to function as an E3 ligase. Loss of CHIP function has long been associated with protein misfolding and aggregation in several genetic mouse models of neurodegenerative disorders; however, a role for CHIP in human neurological disease has yet to be identified. Introduction of the Thr246Met mutation into CHIP results in a loss of ubiquitin ligase activity measured directly using recombinant proteins as well as in cell culture models. Loss of CHIP function in mice resulted in behavioral and reproductive impairments that mimic human ataxia and hypogonadism. We conclude that GHS can be caused by a loss-of-function mutation in CHIP. Our findings further highlight the role of disordered ubiquitination and protein quality control in the pathogenesis of neurodegenerative disease and demonstrate the utility of combining whole-exome sequencing with molecular analyses and animal models to define causal disease polymorphisms.
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http://dx.doi.org/10.1093/hmg/ddt497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3900109PMC
February 2014
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