Fujian Key Laboratory of Molecular Neurology

Fuzhou, China

Fujian Key Laboratory of Molecular Neurology

Fuzhou, China
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Wang D.-N.,Fujian Medical University | Wang Z.-Q.,Fujian Medical University | Wang Z.-Q.,Fujian Key Laboratory of Molecular Neurology | Yan L.,Fujian Medical University | And 7 more authors.
Neuromuscular Disorders | Year: 2017

The development of clinical trials for Duchenne muscular dystrophy (DMD) in China faces many challenges due to limited information about epidemiological data, natural history and clinical management. To provide these detailed data, we developed a comprehensive database based on registered DMD patients from South China and analysed their clinical and mutational characteristics. The database included DMD registrants confirmed by clinical presentation, family history, genetic detection, prognostic outcome, and/or muscle biopsy. Clinical data were collected by a registry form. Mutations of dystrophin were detected by multiplex ligation-dependent probe amplification (MLPA) and Sanger sequencing. Currently, 132 DMD patients from 128 families in South China have been registered, and 91.7% of them were below 10 years old. In mutational detection, large deletions were the most frequent type (57.8%), followed by small deletion/insertion mutations (14.1%), nonsense mutations (13.3%), large duplications (10.9%), and splice site mutations (3.1%). Clinical analysis revealed that most patients reported initial symptoms between 1 and 3 years of age, but the diagnostic age was more frequently between 6 and 8 years. 81.4% of patients were ambulatory. Baseline cardiac assessments at diagnosis were conducted in 39.4% and 29.5% of patients by echocardiograms and electrocardiograms, respectively. Only 22.7% of registrants performed baseline respiratory assessments. A small numbers of patients (20.5%) were treated with glucocorticoids. 13.3% of patients were eligible for stop codon read-through therapy, and 48.4% of patients would potentially benefit from exon skipping. The top five exon skips applicable to the largest group of registrants were skipping of exons 51 (14.8% of total mutations), 53 (12.5%), 45 (7.0%), 55 (4.7%), and 44 (3.9%). In conclusion, our database provided information on the natural history, diagnosis and management status of DMD in South China, as well as potential molecular therapies suitable for these patients. This comprehensive database will promote future experimental therapies in China. © 2017 Elsevier B.V.

Wang C.,Fujian Medical University | Yao X.-P.,Fujian Medical University | Chen H.-T.,Fujian Medical University | Lai J.-H.,Fujian Medical University | And 7 more authors.
Journal of Human Genetics | Year: 2017

Four causative genes, including solute carrier family 20 member 2 (SLC20A2), platelet-derived growth factor receptor b (PDGFRB), platelet-derived growth factor b (PDGFB)and xenotropic and polytropic retrovirus receptor 1 (XPR1), have been identified to cause primary familial brain calcification (PFBC). However, PDGFRB mutations seem to be quite rare and no PDGFRB mutations have been reported in Chinese PFBC patients. A total of 146 PFBC patients including 12 families and 134 sporadic patients were recruited in this study. All of them were previously tested negative for the SLC20A2. Mutational analyses of the entire exons and exon-intron boundaries of PDGFRB were carried out by direct gene sequencing. In silico analyses of the identified variants were conducted using Mutation Taster, PolyPhen-2 and Sorts Intolerant From Tolerant. Two heterozygous variants, c.3G>A and c.2209G>A, of the PDGFRB gene were revealed in two PFBC families, respectively. These two variants were not observed in 200 healthy controls. The variant c.3G>A was located in exon 2 and affected the initiation codon of the PDGFRB gene. The variant c.2209G>A resulted in amino-Acid substitutions of aspartic acid to asparagine at position 737. Both of these two variants co-segregated with the disease phenotype (variant carriers in Family 1: I1, II2 and II3; variant carriers in Family 2: I2 and II8), suggesting a pathogenic impact of these variants. The prevalence of PDGFRB mutations in Chinese PFBC patients seems to be quite low, indicating that PDGFRB is not a major causative gene of PFBC in Chinese population. © 2017 The Japan Society of Human Genetics All rights reserved.

Yao X.-P.,Fujian Medical University | Zhao M.,Fujian Medical University | Wang C.,Fujian Medical University | Guo X.-X.,Fujian Medical University | And 8 more authors.
Cell and Tissue Research | Year: 2017

Primary familial brain calcification (PFBC) is a neuropsychiatric disorder characterized by bilateral cerebral calcification with diverse neurologic or psychiatric symptoms. Recently, XPR1 variation has accounted for PFBC as another new causative gene. However, little is known about the distribution and basic function of XPR1 and its interaction with the other three pathogenic genes for PFBC (SLC20A2, PDGFRB and PDGFB). The aim of this study was to further clarify the role of XPR1 in PFBC brain pathology. As a result, gene expression profiles showed that XPR1 mRNA was widely expressed throughout the mouse brain. Cerebellum and striatum, most commonly affected in PFBC, contained a higher level of XPR1 protein than other brain regions. Additionally, XPR1 deficiency seriously affected Pi efflux and XPR1 mutations seemed to have an effect through haploinsufficiency mechanism. The immunoprecipitation and immunohistochemical studies demonstrated that XPR1 could interact with PDGFRB and might form a complex on the cell membrane. These results suggested that XPR1 played a fundamental role in the maintenance of cellular phosphate balance in the brain. This provided us with a novel perspective on understanding the pathophysiology of PFBC. The expression networks and interaction with the known pathogenic genes could shed new light on additional candidate genes for PFBC. © 2017 Springer-Verlag GmbH Germany

Zhang Q.-J.,Fujian Medical University | Li J.-J.,Fujian Medical University | Lin X.,Fujian Medical University | Lu Y.-Q.,Fujian Medical University | And 8 more authors.
Oncotarget | Year: 2017

Spinal muscular atrophy (SMA) is a lethal autosomal recessive neurological disease characterized by selective degeneration of motor neurons in the spinal cord. In recent years, the development of cellular reprogramming technology has provided an alternative and effective method for obtaining patient-specific neurons in vitro. In the present study, we applied this technology to the field of SMA to acquire patientspecific induced motor neurons that were directly converted from fibroblasts via the forced expression of 8 defined transcription factors. The infected fibroblasts began to grow in a dipolar manner, and the nuclei gradually enlarged. Typical Tuj1-positive neurons were generated at day 23. After day 35, induced neurons with multiple neurites were observed, and these neurons also expressed the hallmarks of Tuj1, HB9, ISL1 and CHAT. The conversion efficiencies were approximately 5.8% and 5.5% in the SMA and control groups, respectively. Additionally, the SMA-induced neurons exhibited a significantly reduced neurite outgrowth rate compared with the control neurons. After day 60, the SMA-induced neurons also exhibited a liability of neuronal degeneration and remarkable fracturing of the neurites was observed. By directly reprogramming fibroblasts, we established a feeder-free conversion system to acquire SMA patient-specific induced motor neurons that partially modeled the phenotype of SMA in vitro.

Chen Y.-F.,Fujian Medical University | Wang D.-N.,Fujian Medical University | Chen Z.-T.,Fujian Medical University | Zhao Z.-H.,Fujian Provincial Hospital | And 5 more authors.
Journal of the Neurological Sciences | Year: 2016

Objective To explore the risk factors associated with acute/subacute cerebral infarction (ASCI) in HIV-negative patients with cryptococcal meningitis (CM). Methods This case-control study included 10 HIV-negative CM patients with ASCI and 30 age- and sex-matched HIV-negative control (1:3) CM patients without ASCI. The clinical manifestations and neuroimaging findings were collected. Risk factors for ASCI in the HIV-negative CM patients were confirmed by conditional logistic regression analysis. Results Among the 10 HIV-negative CM patients with ASCI, all cases had lacunar infarctions. Single infarctions were found in 6 patients, and multiple infarctions in 4. Hydrocephalus (p = 0.020, OR = 23.77, 95% CI, 1.67-339.33) and smoking (p = 0.039, OR = 11.63, 95% CI, 1.14-118.96) were found to be independently associated with the occurrence of ASCI. Conclusions Hydrocephalus and smoking may increase the risk of ASCI in HIV-negative CM patients. In the clinical course, cerebral infarction should be strongly suspected in CM patients with hydrocephalus or smoking histories. © 2016 Elsevier B.V. V. All rights reserved.

Wang R.,Fudan University | Wang R.,Guangdong Academy of Medical science | He J.,Fujian Medical University | He J.,Fujian Key Laboratory of Molecular Neurology | And 7 more authors.
Clinica Chimica Acta | Year: 2015

The aim of this study was to determine the clinical features and frequencies of genetic subtypes in a series of patients with Charcot-Marie-Tooth (CMT) disease from Eastern China. Patients were divided into three subtypes, CMT1, CMT2 and hereditary neuropathy with liability to pressure palsy (HNPP), according to their electrophysiological manifestations. Multiplex ligation-dependent probe analysis (MLPA) was performed to detect duplications/deletions in the PMP22 gene. The coding regions and splice sites of the GJB1, MPZ, MFN2 and GDAP-1 genes were determined by direct sequencing. Among the 148 patients in the study, 37.2% of the cases had mutations in genes assessed. The mutation detection rate was higher in patients with family histories than in spontaneous cases. PMP22 duplication (13.5%) was predominant in this group of patients, followed by PMP22 deletion (11.5%), and point mutations in GJB1 (8.8%), MPZ (2.0%) and MFN2 (0.7%). Three novel mutations (c.151T > C and c.310 A > G in GJB1 and c.1516 C > G in MFN2) were detected. A small deletion in PMP22 exon 4 was detected in a patient with severe CMT1. Genetic tests have great value in CMT patients with family histories. The frequency of PMP22 duplications was lower in Asian patients than in others. We suggest that genetic testing strategies in CMT patients should be primarily based on electromyography data. © 2015 Elsevier B.V.

Liu X.-Y.,Fujian Medical University | Jin M.,Fujian Medical University | Wang Z.-Q.,Fujian Medical University | Wang Z.-Q.,Fujian Key Laboratory of Molecular Neurology | And 6 more authors.
Chinese Medical Journal | Year: 2016

Background: Lipid storage myopathy (LSM) is a genetically heterogeneous group with variable clinical phenotypes. Late-onset multiple acyl-coenzyme A dehydrogenation deficiency (MADD) is a rather common form of LSM in China. Diagnosis and clinical management of it remain challenging, especially without robust muscle biopsy result and genetic detection. As the noninvasion and convenience, muscle magnetic resonance imaging (MRI) is a helpful assistant, diagnostic tool for neuromuscular disorders. However, the disease-specific MRI patterns of muscle involved and its diagnostic value in late-onset MADD have not been systematic analyzed. Methods: We assessed the MRI pattern and fat infiltration degree of the lower limb muscles in 28 late-onset MADD patients, combined with detailed clinical features and gene spectrum. Fat infiltration degree of the thigh muscle was scored while that of gluteus was described as obvious or not. Associated muscular atrophy was defined as obvious muscle bulk reduction. Results: The mean scores were significantly different among the anterior, medial, and posterior thigh muscle groups. The mean of fat infiltration scores on posterior thigh muscle group was significantly higher than either anterior or medial thigh muscle group (P < 0.001). Moreover, the mean score on medial thigh muscle group was significantly higher than that of anterior thigh muscle group (P < 0.01). About half of the patients displayed fat infiltration and atrophy in gluteus muscles. Of 28 patients, 12 exhibited atrophy in medial and/or posterior thigh muscle groups, especially in posterior thigh muscle group. Muscle edema pattern was not found in all the patients. Conclusions: Late-onset MADD patients show a typical muscular imaging pattern of fat infiltration and atrophy on anterior, posterior, and medial thigh muscle groups, with major involvement of posterior thigh muscle group and gluteus muscles and a sparing involvement of anterior thigh compartment. Our findings also suggest that muscle MRI of lower limbs is a helpful tool in guiding clinical evaluation on late-onset MADD. © 2016 Chinese Medical Journal.

Fu H.-X.,Fujian Medical University | Liu X.-Y.,Fujian Medical University | Wang Z.-Q.,Fujian Medical University | Wang Z.-Q.,Fujian Key Laboratory of Molecular Neurology | And 6 more authors.
Neurological Sciences | Year: 2016

Late-onset multiple acyl-CoA dehydrogenase deficiency (MADD) with electron transfer flavoprotein dehydrogenase (ETFDH) gene mutations is the most common lipid storage myopathy (LSM) in China. Its clinical features vary widely and pose a challenge for diagnosis. We presented the significant clinical heterogeneity among three Chinese late-onset MADD patients with similar ETFDH genotype by collecting clinical information, muscle histology, and genetic analysis. Three novel compound heterozygous variants of ETFDH gene were identified: c.892C > T (p.Pro298Ser), c.453delA (p.Glu152ArgfsTer15), and c.449_453delTAACA (p.Leu150Ter). Moreover, all patients carried a hotspot mutation c.250G > A (p.Ala84Thr). Western blot analysis of the patients’ muscular tissue showed a significantly reduced ETFDH expression, and normal electron transfer flavoprotein A (ETFA) and electron transfer flavoprotein B (ETFB) expression. Two patients with similar genotypes (c.453delA and c.449_453delTAACA) presented a significant clinical heterogeneity. Among them, one exhibited muscle weakness and exercise intolerance as initial and major symptoms, and the other showed episodic recurrent gastrointestinal symptoms before a serious muscle weakness appeared in later life. The novel variants in ETFDH and the corresponding clinical features enrich the variant spectrum of late-onset MADD and provide a new insight into the genotype-phenotype relationship. Late-onset MADD should be included in differential diagnosis for adult myopathy along with chronic digestive disease. © 2016, Springer-Verlag Italia.

Wang D.-N.,Fujian Medical University | Hou X.-W.,China Medical University at Heping | Yang B.-W.,China Medical University at Heping | Lin Y.,Fujian Medical University | And 3 more authors.
Journal of Stroke and Cerebrovascular Diseases | Year: 2015

Background and purpose: Cerebral microbleeds (CMBs) increase future intracerebral hemorrhage (ICH) risk after ischemic stroke (IS) or transient ischemic attack (TIA). However, whether CMB-related ICH risk depends on CMB quantity, CMB location, or antithrombotic agents is unclear. We performed a systematic review and meta-analysis to investigate CMB-related ICH risk, stratifying patients according to the quantity of CMB, the location of CMB, and the type of antithrombotic therapy used. Methods: Literature databases were searched for prospective cohorts reporting ICH outcomes in patients with IS or TIA with baseline CMB evaluation. We calculated pooled relative ratios (RRs) for ICH among patients with and without CMBs. Pooled RRs of CMB-related ICH were further calculated in subgroups stratified by CMB quantity, CMB location, and antithrombotic therapy. Results: Among the 10 included studies, the pooled RR of future ICH was 7.73 (95% confidence interval [CI], 4.07-14.70; P <.001) in CMB versus non-CMB patients. Subgroup analysis revealed that compared with non-CMB patients, multiple-CMB patients were at an increased risk for future ICH (RR = 8.02; 95% CI, 3.21-20.01; P <.001), whereas single-CMB patients did not incur this risk (RR = 2.33; 95% CI,.63-8.63; P =.205). A strong association was found between CMB presence and subsequent ICH in antiplatelet users (RR = 16.56; 95% CI, 3.68-74.42; P <.001). Studies on CMB-related ICH according to CMB locations and in anticoagulant users are lacking for subgroup analysis. Conclusion: Our study revealed that patients with IS or TIA with multiple CMBs may incur a higher risk of future ICH, and the presence of CMBs in patients with IS or TIA using antiplatelet agents may significantly increase the subsequent ICH risk. © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Chen Y.-F.,Fujian Medical University | Chen W.-J.,Fujian Key Laboratory of Molecular Neurology | Lin X.-Z.,Fujian Medical University | Zhang Q.-J.,Fujian Medical University | And 4 more authors.
Chinese Medical Journal | Year: 2015

Background: Mitochondrial dysfunction is linked to the pathogenesis of Parkinson’s disease (PD). However, the precise role of mitochondrial DNA (mtDNA) variations is obscure. On the other hand, mtDNA haplogroups have been inconsistently reported to modify the risk of PD among different population. Here, we try to explore the relationship between mtDNA haplogroups and sporadic PD in a Han Chinese population. Methods: Nine single‑nucleotide polymorphisms, which define the major Asian mtDNA haplogroups (A, B, C, D, F, G), were detected via polymerase chain reaction‑restriction fragment length polymorphism or denaturing polyacrylamide gel electrophoresis in 279 sporadic PD patients and 510 matched controls of Han population. Results: Overall, the distribution of mtDNA haplogroups did not show any significant differences between patients and controls. However, after stratification by age at onset, the frequency of haplogroup B was significantly lower in patients with early‑onset PD (EOPD) compared to the controls (odds ratio [OR] =0.225, 95% confidence interval [CI]: 0.082–0.619, P = 0.004), while other haplogroups did not show significant differences. After stratification by age at examination, among subjects younger than 50 years of age: Haplogroup B also showed a lower frequency in PD cases (OR = 0.146, 95% CI: 0.030–0.715, P = 0.018) while haplogroup D presented a higher risk of PD (OR = 3.579, 95% CI: 1.112–11.523, P = 0.033), other haplogroups also did not show significant differences in the group. Conclusions: Our study indicates that haplogroup B might confer a lower risk for EOPD and people younger than 50 years in Han Chinese, while haplogroup D probably lead a higher risk of PD in people younger than 50 years of age. In brief, particular Asian mtDNA haplogroups likely play a role in the pathogenesis of PD among Han Chinese. © 2015, Chinese Medical Association. All rights reserved.

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