Ruxu Zhang
Central South University
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Featured researches published by Ruxu Zhang.
Human Genetics | 2005
Beisha Tang; Guohua Zhao; Wei Luo; Kun Xia; Fang Cai; Qian Pan; Ruxu Zhang; Fufeng Zhang; Xiaomin Liu; Biao Chen; Cheng Zhang; Lu Shen; Hong Jiang; Zhigao Long; Heping Dai
Charcot-Marie-Tooth (CMT) disease is the most common inherited motor and sensory neuropathy. We have previously described a large Chinese CMT family and assigned the locus underlying the disease (CMT2L; OMIM 608673) to chromosome 12q24. Here, we report a novel c.423G→T (Lys141Asn) missense mutation of small heat-shock protein 22-kDa protein 8 (encoded by HSPB8), which is also responsible for distal hereditary motor neuropathy type (dHMN) II. No disease-causing mutations have been identified in another 114 CMT families.
JAMA Neurology | 2005
Beisha Tang; Xiaomin Liu; Guohua Zhao; Wei Luo; Kun Xia; Qian Pan; Fang Cai; Zhengmao Hu; Cheng Zhang; Biao Chen; Fufeng Zhang; Lu Shen; Ruxu Zhang; Hong Jiang
BACKGROUND Charcot-Marie-Tooth (CMT) disease, the most common hereditary peripheral neuropathy, is highly clinically and genetically heterogeneous, and mutations in at least 18 genes have been identified. Recently, mutations in small heat shock protein 27 (Hsp27) were reported to cause CMT disease type 2F and distal hereditary motor neuropathy. OBJECTIVE To investigate the frequency and phenotypic features of an Hsp27 mutation in Chinese patients with CMT disease. DESIGN DNA samples from 114 unrelated patients with CMT disease were screened for mutations in Hsp27 by polymerase chain reaction and direct sequencing. A cosegregated study was performed using the MbiI restriction endonuclease, and 50 healthy control subjects were analyzed. Haplotype analysis was performed using 5 short tandem repeat markers to analyze whether the families with the same mutation probably had a common ancestor. RESULTS One missense mutation, C379T, was detected in 4 autosomal dominant families with CMT disease type 2, and haplotype analysis indicated that the 4 families probably had a common founder. The frequency of the Hsp27 mutation is 0.9% (1/111) in Chinese patients with CMT disease in our study, and the phenotypes were characterized by later onset (age, 35-60 years) and mild sensory impairments. Electrophysiological findings showed moderately to severely slowed nerve conduction velocities in lower limb nerves but normal or mildly reduced velocities in upper limb nerves. CONCLUSIONS To our knowledge, this is the first report of an Hsp27 mutation in the Peoples Republic of China. The C379T mutation in Hsp27 also causes CMT disease type 2, except for distal hereditary motor neuropathy, and the phenotypes are distinct from the family with CMT disease type 2F described previously. A mutation of Hsp27 may be uncommon in Chinese patients with CMT disease.
Neurology | 2015
Xiaobo Li; Zhengmao Hu; Lei Liu; Yongzhi Xie; Yajing Zhan; Xiaohong Zi; Junling Wang; Lixiang Wu; Kun Xia; Beisha Tang; Ruxu Zhang
Objective: To identify the underlying genetic cause in a consanguineous Chinese family segregating distal hereditary motor neuropathy (dHMN) in an autosomal recessive pattern. Methods: We used whole-exome sequencing and homozygosity mapping to detect the genetic variant in 2 affected individuals of the consanguineous Chinese family with dHMN. RNA analysis of peripheral blood leukocytes and immunofluorescence and immunoblotting of stable cell lines were performed to support the pathogenicity of the identified mutation. Results: We identified 3 shared novel homozygous variants in 3 shared homozygous regions of the affected individuals. Sequencing of these 3 variants in family members revealed the c.151+1G>T mutation in SIGMAR1 gene, which located in homozygous region spanning approximately 5.3 Mb at chromosome 9p13.1-p13.3, segregated with the dHMN phenotype. The mutation causes an alternative splicing event and generates a transcript variant with an in-frame deletion of 60 base pairs in exon 1 (c.92_151del), and results in an internally shortened protein σ1R31_50del. The proteasomal inhibitor treatment increased the intracellular amount of σ1R31_50del and led to the formation of nuclear aggregates. Stable expressing σ1R31_50del induced endoplasmic reticulum stress and enhanced apoptosis. Conclusion: The homozygous c.151+1G>T mutation in SIGMAR1 caused a novel form of autosomal recessive dHMN in a Chinese consanguineous family. Endoplasmic reticulum stress may have a role in the pathogenesis of dHMN.
Clinical Genetics | 2008
Hy Li; Nan Li; Hong Jiang; Li Shen; Ji-feng Guo; Ruxu Zhang; Kun Xia; Qian Pan; Xiaohong Zi; Beisha Tang
To the Editor: Benign familial infantile seizures (BFIS), formerly named benign familial infantile convulsions, is an autosomal dominant idiopathic epilepsy syndrome characterized by afebrile partial seizures with or without secondary generalized tonic-clonic seizures, age at onset from3 to 10 months, a benign course and normal psychomotor development. Patients affected with BFIS usually have a normal neurological examination and no changes in biochemical and neuroradiological investigations (1, 2). To date, three susceptibility loci of BFIS have been identified, 19q12-q13.1, 16p12-q12 and 2q24. Further investigations have indicated that other loci may exist (3–5). We report here a family of Chinese origin affected with BFIS and mapped to a different causative locus from previously established studies. All patients and unaffected members of the family gave informed consent to the clinical and genetic studies. Eight individuals (four female and four male) of the family were diagnosed as having BFIS. Neurological examination, serum biochemical determination (total protein, electrolytes, glucose, lactic dehydrogenase, uric acid, etc.), electroencephalogram (EEG), brain computed tomography (CT) and/or magnetic resonance imaging (MRI) were performed for all existing familymembers. No demonstrable underlying pathologywas observed.Age at seizure onset ranged from 3 to 10 months of life. The proband (Fig. 1, III:6), 31 years old at the timeof our study, was born at full term after normal pregnancy. At age 6 months, he experienced afebrile seizures, including staring, eye deviation, focal clonus of the face, followed by secondarily generalized phase with hypertonia, extremities clonus, cyanosis and urinary incontinence. The seizures, lasting from 30 s to 2 min in one attack, occurred mainly in clusters with 3–10 episodes per day. Interictal EEG, brain CT and MRI were classified as normal. Serum biochemical determination and chromosome karyotype were normal. Treatment with sodium valproate was effective. His seizures spontaneously remitted by 3 years of age. Blood samples were collected from available family members. Karyotype analysis of peripheral lymphocytes by G-banding was normal. Genomic DNA samples were extracted from peripheral blood leukocytes and tested first with microsatellite markers situated at chromosome 19q12-13.1, 16p12-q12 and 2q24. Linkage analysis showed that two-point logarithm of odds (LOD) scores were negative (Table 1), thereby excluding this BFIS family from linkage to the three known susceptibility loci. Genome-wide scan was subsequently performed using 382 fluorescencelabeled microsatellite markers of the ABI Prism Linkage Mapping Set, version 2 (Applied Biosystems, Foster City, CA). At recombination fraction y 1⁄4 0, a maximum two-point LOD score of 3.14 was obtained at marker D1S2674 (Table 1). Multipoint linkage analyses with markers D1S2702-D1S2674-D1S2830 on the sexaveraged linkage map confirmed the linkage, with a maximum LOD score of 3.27 at D1S2674. A particular single haplotype was identified to cosegregate with the disease phenotype in all affected individuals (Fig. 1). Based on recombination events, the underlying causative gene was mapped to a 12.4-cM interval extending from D1S2864 to D1S2830, corresponding to 1p36.12-p35.1 by referring to NCBI Map Viewer Build 34. In 1996,Auburger et al. (6) reportedanautosomal dominant form of paroxysmal choreo-athetosis/ spasticity,withonset age ranging from2 to15 years, precipitated by factors such as physical exercise and emotional stress. It was alsomapped to 1p, between D1S443 and D1S197, but about 11.07 cM distant to locus 1p36.12-p35.1. Differences in onset age, clinical features and genetic mapping indicate that they are likely to be two different disorders. The Chinese family affected with pure BFIS is identified to map to 1p36.12-p35.1, a novel locus
Journal of The Peripheral Nervous System | 2016
Yongzhi Xie; Xiaobo Li; Lei Liu; Zhengmao Hu; Shunxiang Huang; Yajin Zhan; Xiaohong Zi; Kun Xia; Beisha Tang; Ruxu Zhang
Charcot‐Marie‐Tooth disease 2A (CMT2A), caused by mutations in the mitofusin 2 gene (MFN2), is the most common CMT2 subtype. The aim of our study is to assess the frequency and summarize the genetic and clinical characteristics of Chinese CMT2A patients. A total of 17 coding exons of MFN2 were detected by direct sequencing in 82 unrelated Chinese families diagnosed as CMT2. Clinical evaluations were analyzed among CMT2A patients. We identified 14 missense variants in 9 sporadic and 6 familial cases, including four novel mutations (T129A, S249F, Q367P, and Q674L), 4 known mutations (R94W, R94Q, T105M, C132Y, M376V and Q751X), and 4 rare missense variants (K120E, C217F, K307E and T356S). A total of 23 patients had early‐onset phenotype. Two patients had a CMTNS score of 0 to 10; 16 had a score of 11 to 20; and 7 had a score greater than 20. Five patients were confirmed a de novo origin. Six of 14 variants were located or closed to the GTPase domain. We report four novel mutations and four rare missense variants. MFN2 mutations account for 18% of CMT2 families in mainland China. The common characteristics of Chinese pedigree are early disease onset and moderate phenotypes.
Journal of The Peripheral Nervous System | 2013
Lei Liu; Xiaobo Li; Xiaohong Zi; Shunxiang Huang; Yajing Zhan; Mingming Jiang; Ji-feng Guo; Kun Xia; Beisha Tang; Ruxu Zhang
To investigate the myelin protein zero (MPZ) gene mutation and related clinical features in Chinese Charcot‐Marie‐Tooth (CMT) patients, we screened the coding sequence of MPZ in 70 unrelated CMT index patients after excluding the PMP22 duplication, Cx32 and MFN2 mutations. We found four different missense mutations: c.194C>T, c.242A>T, c.371C>T, and c.419C>G. The frequency of MPZ mutation was approximately 4.35% of the total, 3.08% of CMT1, and 6% of CMT2. Mutations c.242A>T and c.419C>G are novel. The mutation c.242A>T exhibited late onset and rapidly progressive CMT2 phenotype. The mutation c.419C>G exhibited relatively late onset and slowly progressive CMT1 phenotype.
Clinical Genetics | 2017
Lei Liu; Xuning Li; Zhengmao Hu; Xiaohong Zi; Xin Zhao; Yongzhi Xie; Shunxiang Huang; Kun Xia; Beisha Tang; Ruxu Zhang
The aim of this study is to explore the phenotypic and genotypic features of X‐linked Charcot–Marie‐Tooth (CMT) disease in the mainland of China and to study the cellular effects of six novel Gap junction protein beta‐1 variants. We identified 25 missense and 1 non‐sense mutations of GJB1 in 31 unrelated families out of 226 CMT families. The frequency of GJB1 mutations was 13.7% of the total and 65% of intermediate CMT. Six novel GJB1 variants (c.5A>G, c.8G>A, c.242T>C, c.269T>C, c.317T>C and c.434T>G) were detected in six unrelated intermediate CMT families. Fluorescence revealed that HeLa cells transfected with EGFP‐GJB1‐V74M, EGFP‐GJB1‐L81P or EGFP‐GJB1‐L90P had diffuse endoplasmic reticulum staining, HeLa cells transfected with EGFP‐GJB1‐L106P had diffuse intracellular staining, and HeLa cells transfected with EGFP‐GJB1‐N2S had cytoplasmic and nuclear staining. The distribution of Cx32 in HeLa cells transfected with EGFP‐GJB1‐F145C was similar to that of those transfected with wild‐type (WT). These six variants resulted in a higher percentage of apoptosis than did WT as detected by flow cytometry and Hoechst staining. In conclusion, mutation screening should be first performed in intermediate CMT patients, especially those with additional features. The novel GJB1 variants c.5A>G, c.8G>A, c.242T>C and c.269T>C are considered pathogenic, and c.317T>C and c.434T>G are classified as probably pathogenic.
Neural Regeneration Research | 2014
Ruxu Zhang; Fufeng Zhang; Xiaobo Li; Shunxiang Huang; Xiaohong Zi; Ting Liu; Sanmei Liu; Xuning Li; Kun Xia; Qian Pan; Beisha Tang
We previously found that the K141N mutation in heat shock protein B8 (HSPB8) was responsible for Charcot-Marie-Tooth disease type 2L in a large Chinese family. The objective of the present study was to generate a transgenic mouse model bearing the K141N mutation in the human HSPB8 gene, and to determine whether this K141NHSPB8 transgenic mouse model would manifest the clinical phenotype of Charcot-Marie-Tooth disease type 2L, and consequently be suitable for use in studies of disease pathogenesis. Transgenic mice overexpressing K141NHSPB8 were generated using K141N mutant HSPB8 cDNA cloned into a pCAGGS plasmid driven by a human cytomegalovirus expression system. PCR and western blot analysis confirmed integration of the K141NHSPB8 gene and widespread expression in tissues of the transgenic mice. The K141NHSPB8 transgenic mice exhibited decreased muscle strength in the hind limbs and impaired motor coordination, but no obvious sensory disturbance at 6 months of age by behavioral assessment. Electrophysiological analysis showed that the compound motor action potential amplitude in the sciatic nerve was significantly decreased, but motor nerve conduction velocity remained normal at 6 months of age. Pathological analysis of the sciatic nerve showed reduced myelinated fiber density, notable axonal edema and vacuolar degeneration in K141NHSPB8 transgenic mice, suggesting axonal involvement in the peripheral nerve damage in these animals. These findings indicate that the K141NHSPB8 transgenic mouse successfully models Charcot-Marie-Tooth disease type 2L and can be used to study the pathogenesis of the disease.
Muscle & Nerve | 2015
Yajing Zhan; Xiaohong Zi; Zhengmao Hu; Ying Peng; Lingqian Wu; Xiaobo Li; Mingming Jiang; Lei Liu; Yongzhi Xie; Kun Xia; Beisha Tang; Ruxu Zhang
Introduction: Most cases of Charcot‐Marie‐Tooth (CMT) disease are caused by mutations in the peripheral myelin protein 22 gene (PMP22), including heterozygous duplications (CMT1A), deletions (HNPP), and point mutations (CMT1E). Methods: Single‐nucleotide polymorphism (SNP) arrays were used to study PMP22 mutations based on the results of multiplex ligation‐dependent probe amplification (MLPA) and polymerase chain reaction–restriction fragment length polymorphism methods in 77 Chinese Han families with CMT1. PMP22 sequencing was performed in MLPA‐negative probands. Clinical characteristics were collected for all CMT1A/HNPP probands and their family members. Results: Twenty‐one of 77 CMT1 probands (27.3%) carried duplication/deletion (dup/del) copynumber variants. No point mutations were detected. SNP array and MLPA seem to have similar sensitivity. Fifty‐seven patients from 19 CMT1A families had the classical CMT phenotype, except for 1 with concomitant CIDP. Two HNPP probands presented with acute ulnar nerve palsy or recurrent sural nerve palsy, respectively. Conclusions: The SNP array has wide coverage, high sensitivity, and high resolution and can be used as a screening tool to detect PMP22 dup/del as shown in this Chinese Han population. Muscle Nerve 52: 69–75, 2015
Journal of Neurology | 2018
Pukar Singh Pakhrin; Yongzhi Xie; Zhengmao Hu; Xiaobo Li; Lei Liu; Shunxiang Huang; Binghao Wang; Zihan Yang; Jiejun Zhang; Xin Liu; Kun Xia; Beisha Tang; Ruxu Zhang
Mutations in ganglioside-induced differentiation-associated-protein 1 (GDAP1) have been associated with both subtypes of Charcot–Marie–Tooth (CMT) disease, autosomal recessive (CMT4A and AR-CMT2K) and autosomal dominant (AD-CMT2K). Over 80 different mutations have been identified so far. With the use of Sanger sequencing and Next Generation Sequencing (NGS) technologies, we screened a cohort of 306 unrelated Chinese CMT patients and identified 8 variants in the GDAP1 gene in 4 families, 5 of which were novel (R41H, N201Kfs*5, Q38X, V215I and Q38R). Application of Bioinformatics tool and classification according to the American College of Medical Genetics (ACMG) predicted them of being likely pathogenic with the exception of one variant of uncertain significance (VUS). In addition, we detected the presence of a single heterozygous variant of uncertain significance H256R in one additional family from the CMT cohorts. We found a GDAP1 prevalence rate of 1.63% (5/306). Three families (families 1, 2 and 3) were found to have an autosomal recessive (AR) pattern of inheritance while family 4 displayed an autosomal dominant (AD) mode of inheritance. Electro-physiologic studies revealed an axonal type of neuropathy (AR-CMT2K and AD-CMT2K) in all affected individuals. Clinical characteristics and findings in our study demonstrated that the recessive form presented earlier in life and exhibited severe symptoms and rapid evolution compared to the dominant form. We observed a marked intra-familial variability within the AD family in terms of age at disease onset, symptom severity and clinical progression. Our study expands the mutational spectrum of GDAP1-related CMT disease with the identification of new and unreported GDAP1 variants and demonstrates the predominance of the axonal form of neuropathy in CMT disease associated with GDAP1. We highlight the clinical characteristics associated with these genotypes and describe the relative frequency of GDAP1 variants amongst the Chinese population.