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The MORC2 p.S87L mutation reduces proliferation of pluripotent stem cells derived from a patient with the spinal muscular atrophy-like phenotype by inhibiting proliferation-related signaling pathways

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Neural Regeneration Research 2024年第1期19卷 205-211页

作者： Sen Zeng Honglan Yang Binghao Wang Yongzhi Xie Ke Xu Lei Liu Wanqian Cao Xionghao Liu Beisha Tang Mujun Liu ruxu zhang Department of Neurology The Third Xiangya HospitalCentral South UniversityChangshaHunan ProvinceChina Department of Neurology The First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan ProvinceChina Department of Radiology The Third Xiangya HospitalCentral South UniversityChangshaHunan ProvinceChina Health Management Center The Third Xiangya HospitalCentral South UniversityChangshaHunan ProvinceChina Center for Medical Genetics&Hunan Key Laboratory of Medical Genetics School of Life SciencesCentral South UniversityChangshaHunan ProvinceChina National Clinical Research Center for Geriatric Disorders Central South UniversityChangshaHunan ProvinceChina Department of Cell Biology School of Life SciencesCentral South UniversityChangshaHunan ProvinceChina

Mutations in the microrchidia CW-type zinc finger protein 2(MORC2)gene are the causative agent of Charcot-Marie-Tooth disease type 2Z(CMT2Z),and the hotspot mutation p.S87L is associated with a more seve re spinal muscular atrophy-like clinical *** aims of this study were to determine the mechanism of the severe phenotype caused by the MORC2 p.S87L mutation and to explore potential treatment *** cells were isolated from urine samples from a spinal muscular atrophy(SMA)-like patient[MORC2 p.S87L),a CMT2Z patient[MORC2 p.Q400R),and a healthy control and induced to generate pluripotent stem cells,which were then differentiated into motor neuron precursor ***-generation RNA sequencing followed by KEGG pathway enrichment analysis revealed that differentially expressed genes involved in the PI3K/Akt and MAP K/ERK signaling pathways were enriched in the p.S87L SMA-like patient group and were significantly downregulated in induced pluripotent stem *** proliferation was observed in the induced pluripotent stem cells and motor neuron precursor cells derived from the p.S87L SMA-like patient group compared with the CMT2Z patient group and the healthy control.G0/G1 phase cell cycle arrest was observed in induced pluripotent stem cells derived from the p.S87L SMA-like ***2 p.S87Lspecific antisense oligonucleotides(p.S87L-ASO-targeting)showed significant efficacy in improving cell prolife ration and activating the PI3K/Akt and MAP K/ERK pathways in induced pluripotent stem *** r,p.S87L-ASO-ta rgeting did not rescue prolife ration of motor neuron precursor *** findings suggest that downregulation of the PI3K/Akt and MAP K/ERK signaling pathways leading to reduced cell proliferation and G0/G1 phase cell cycle arrest in induced pluripotent stem cells might be the underlying mechanism of the severe p.S87L SMA-like phenotype.p.S87L-ASO-targeting treatment can alleviate disordered cell proliferation in the early stag

关键词： antisense oligonucleotides cell cycle arrest Charcot-Marie-Tooth disease 2Z induced pluripotent stem cells MAPK/ERK PI3K/Akt proliferation spinal muscular atrophy-like

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Intermediate Charcot-Marie-Tooth disease

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Neuroscience Bulletin 2014年第6期30卷 999-1009页

作者： Lei Liu ruxu zhang Department of Neurology the Third Xiangya HospitalCentral South University

Charcot-Marie-Tooth（CMT） disease is a common neurogenetic disorder and its heterogeneity is a challenge for genetic diagnostics. The genetic diagnostic procedures for a CMT patient can be explored according to the electrophysiological criteria： very slow motor nerve conduction velocity（MNCV）（〈15 m/s）, slow MNCV（15–25 m/s）, intermediate MNCV（25–45 m/s）, and normal MNCV（〉45 m/s）. Based on the inheritance pattern, intermediate CMT can be divided into dominant（DI-CMT） and recessive types（RI-CMT）. GJB1 is currently considered to be associated with X-linked DI-CMT, and MPZ, INF2, DNM2, YARS, GNB4, NEFL, and MFN2 are associated with autosomal DI-CMT. Moreover, GDAP1, KARS, and PLEKHG5 are associated with RI-CMT. Identification of these genes is not only important for patients and families but also provides new information about pathogenesis. It is hoped that this review will lead to a better understanding of intermediate CMT and provide a detailed diagnostic procedure for intermediate CMT.

关键词： Charcot-Marie-Tooth disease intermediate CMT dominant type CMT recessive type CMT diagnostic procedure

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2型糖尿病伴腓骨肌萎缩症1例

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中华糖尿病杂志 2024年第5期16卷 553-555页

作者：万金晶赵立玲曹婉芊张如旭金萍中南大学湘雅三医院内分泌科长沙410013 中南大学湘雅三医院神经内科长沙410013

糖尿病周围神经病变(DPN)是糖尿病最常见的慢性并发症之一,腓骨肌萎缩症(CMT)则是最常见的遗传性周围神经病之一,但糖尿病合并CMT的相关报道较少。该文报道了1例误诊为DPN的2型糖尿病合并腓骨肌萎缩症病例,以提高临床医师对该病的认识... 详细信息

糖尿病周围神经病变(DPN)是糖尿病最常见的慢性并发症之一,腓骨肌萎缩症(CMT)则是最常见的遗传性周围神经病之一,但糖尿病合并CMT的相关报道较少。该文报道了1例误诊为DPN的2型糖尿病合并腓骨肌萎缩症病例,以提高临床医师对该病的认识。先证者为57岁男性,因“发现血糖升高8个月余,四肢麻木疼痛3个月”入院,体格检查有跛行步态,行走时足内翻,高足弓,双下肢肌肉萎缩。基因检测发现先证者存在周围神经髓鞘蛋白22(PMP22)基因杂合重复突变,确诊为2型糖尿病合并CMT1A型。家系验证发现其父亲也存在PMP22基因重复扩增,但无糖尿病,其父CMT1A临床表现不典型。2型糖尿病和CMT1A都会造成周围神经病变,部分CMT患者临床表型与DPN相似,临床医师需对DPN进行仔细的鉴别诊断。

关键词：糖尿病神经病变腓骨肌萎缩症周围神经髓鞘蛋白22

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中国人群MORC2基因相关神经病的基因变异和临床表现分析

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中华神经科杂志 2024年第4期57卷 351-358页

作者：周淋王梦丽曹婉芊黄顺祥赵华栋李陆曾森张如旭中南大学湘雅三医院神经内科长沙410013

目的总结中国人群MORC2基因相关神经病的基因变异谱和临床特点。方法收集2010—2023年就诊于中南大学湘雅三医院并明确基因诊断的MORC2基因相关神经病家系的临床资料和全外显子测序结果,回顾性分析其基因变异和临床特点,并查阅已报道的... 详细信息

目的总结中国人群MORC2基因相关神经病的基因变异谱和临床特点。方法收集2010—2023年就诊于中南大学湘雅三医院并明确基因诊断的MORC2基因相关神经病家系的临床资料和全外显子测序结果,回顾性分析其基因变异和临床特点,并查阅已报道的中国MORC2基因相关神经病家系相关文献,对中国人群该疾病的基因变异和临床表型谱进行总结。结果本中心收集的10个家系共携带6个不同的MORC2基因杂合致病变异,其中c.1330G>C(p.G444R)为新报道的变异。6个家系表现为儿童期或成年期起病的MORC2基因变异所致的轴索型腓骨肌萎缩症(CMT2Z)表型,携带c.754C>T(p.R252W)、c.1199A>G(p.Q400R)、c.1330G>C(p.G444R)或c.1396G>A(p.D466N);3个家系表现为婴幼儿起病、严重的脊髓性肌萎缩(SMA)样表型,均携带c.260C>T(p.S87L);1个家系表现为婴幼儿起病、以智能和运动发育迟缓为主要表现的DIGFAN综合征,携带c.1181A>G(p.Y394C)。文献复习发现8个携带MORC2基因致病变异的中国家系,其中5个家系表现为CMT2Z表型,携带c.754C>T(p.R252W)、c.1079A>G(p.E360G)、c.1220G>A(p.C407Y)或c.1397A>G(p.D466G);1个家系为SMA样表型,携带c.260C>T(p.S87L);2个家系表现为DIGFAN综合征,分别携带c.79G>A(p.E27K)和c.292G>A(p.G98R)。结论本研究报道了CMT2表型相关的MORC2基因新致病变异c.1330G>C(p.G444R)。在中国人群中,迄今共报道11个MORC2基因致病变异,c.754C>T(p.R252W)可能为最常见致病变异。MORC2基因相关神经病具有明显的临床异质性,不同变异可表现为CMT2Z、早发严重的SMA样肌无力或DIGFAN综合征。

关键词：夏科-马里-图斯病肌萎缩,脊髓性基因变异 MORC2基因

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Clinical classification and gene mutation of Chinese probands with Charcot-Marie-Tooth disease Analysis of 57 cases

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Neural Regeneration Research 2011年第9期6卷 706-711页

作者： ruxu zhang Xiaobo Li Xiaohong Zi Shunxiang Huang Fufeng zhang Kun Xia Qian Pan Beisha Tang Department of Neurology the Third Xiangya Hospital Central South University Changsha 410013 Hunan Province China Department of Neurology Xiangya Hospital Central South University Changsha 410008 Hunan Province China National Key Laboratory of Medical Genetics Central South University Changsha 410078 Hunan Province China

Charcot-Marie-Tooth （CMT） disease is the most common inherited peripheral neuropathic disorder. CMT is clinically and genetically heterogeneous. To date, 27 genes associated with the disease have been cloned. The present study carried out clinical classification according to clinical, electrophysiological and pathological features, conducted inheritance classification according to inheritance patterns, and performed mutation analysis of 13 CMT disease genes （PMP22, CX32, HSPB1, MNF2, MPZ, HSPB8, GDAP1, NFL, EGR2, SIMPLE, RAB7, LMNA, MTMR2） in 57 Chinese probands with CMT. Five cases of AD-CMT1 and 13 cases of sporadic CMT1 were diagnosed as CMT1A; five cases of X-CMT1, one case of X-CMT2 and one case of sporadic CMT1 were diagnosed as CMTXl; four cases of AD-CMT2 were diagnosed as CMT2F; one case of AD-CMT2 and one case of sporadic CMT2 were diagnosed as CMT2A2; one case of AD-CMT2 was diagnosed as CMT2L; one case of AD-CMT2 was diagnosed as CMT2J; one case of AR-CMT1 was diagnosed as CMT4A. Among the 57 CMT probands, seven genotypes were determined among 34 patients, with a detection rate of 59.6%. The results indicated that the clinical classification and inheritance classification are indispensable for selecting potential disease genes for mutation detection, and for efficient molecular diagnosis.

关键词： Charcot-Marie-Tooth disease clinical classification gene mutation analysis

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A novel transgenic mouse model of Chinese CharcotMarie-Tooth disease type 2L

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Neural Regeneration Research 2014年第4期9卷 413-419页

作者： ruxu zhang Fufeng zhang Xiaobo Li Shunxiang Huang Xiaohong Zi Ting Liu Sanmei Liu Xuning Li Kun Xia Qian Pan Beisha Tang Department of Neurology Third Xiangya HospitalCentral South University Department of Neurology Xiangya HospitalCentral South University National Key Laboratory of Medical Genetics Central South University

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 K141N HSPB8 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 KI41NHSPB8 gene and widespread expression in tissues of the transgenic mice. The K141N HSPB8 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 K141N HSPB8 transgenic mice, suggesting axonal involvement in the peripheral nerve damage in these animals. These findings indicate that the KI4mHSPB8 transgenic mouse successfully models Charcot-Marie-Tooth disease type 2L and can be used to study the pathogenesis of the disease.

关键词： nerve regeneration peripheral nerve injury axonal injury animal models Charcot-Ma-rie-Tooth disease type 2L gene mutation pronuclear injection transgenic model small heat shockprotein B8 NSFC grant neural regeneration

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Rapid genetic screening of Charcot-Marie-Tooth disease type 1A and hereditary neuropathy with liability to pressure palsies patients

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Neural Regeneration Research 2012年第32期7卷 2522-2527页

作者： Xiaobo Li Xiaohong Zi Lin Li Yajing Zhan Shunxiang Huang Jin Li Xuning Li Xigui Li Zhengmao Hu Kun Xia Beisha Tang ruxu zhang Department of Neurology Third Xiangya Hospital Central South University Changsha 410013 Hunan Province China Department of Ultrastructure School of Basic Medical Science Central South University Changsha 410078 Hunan Province China State Key Laboratory of Medical Genetics Central South University Changsha 410078 Hunan Province China

We used the allele-specific PCR-double digestion method on peripheral myelin protein 22 （PMP22） to determine duplication and deletion mutations in the proband and family members of one family with Charcot-Marie-Tooth disease type 1 and one family with hereditary neuropathy with liability to pressure palsies. The proband and one subclinical family member from the Charcot-Marie-Tooth disease type 1 family had a PMP22 gene duplication; one patient from the hereditary neuropathy with liability to pressure palsies family had a PMP22 gene deletion. Electron microscopic analysis of ultrathin sections of the superficial peroneal nerve from the two probands demonstrated demyelination and myelin sheath hyperplasia, as well as an ＇onion-like＇ structure in the Charcot-Marie-Tooth disease type 1A patient. We observed an irregular thickened myelin sheath and ＇mouse-nibbled＇-Iike changes in the patient with hereditary neuropathy with liability to pressure palsies. In the Charcot-Marie-Tooth disease type 1A patient, nerve electrophysiological examination revealed moderate-to-severe reductions in the motor and sensory conduction velocities of the bilateral median nerve, ulnar nerve, tibial nerve, and sural nerve. Moreover, the compound muscle action potential amplitude was decreased. In the patient with hereditary neuropathy with liability to pressure palsies, the nerve conduction velocity of the bilateral tibial nerve and sural nerve was moderately reduced, and the nerve conduction velocity of the median nerve and ulnar nerve of both upper extremities was slightly reduced.

关键词： Charcot-Marie-Tooth disease hereditary neuropathy with liability to pressure palsies peripheral myelin protein 22 gene mutation PCR-double digestion method myelin sheath action potentia neuropathology neural regeneration

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腓骨肌萎缩症相关测评量表的临床应用

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中华神经科杂志 2019年第6期52卷 510-515页

作者：张捷君张如旭中南大学湘雅三医院神经内科长沙410013

腓骨肌萎缩症(Charcot-Marie-Tooth disease,CMT)是一组最常见的具有高度临床和遗传异质性的周围神经单基因遗传病。随着CMT不同基因亚型孤儿药物的研发,选用规范化的量表对于评估药物的治疗效果和临床自然病程至关重要。目前针对CMT患... 详细信息

腓骨肌萎缩症(Charcot-Marie-Tooth disease,CMT)是一组最常见的具有高度临床和遗传异质性的周围神经单基因遗传病。随着CMT不同基因亚型孤儿药物的研发,选用规范化的量表对于评估药物的治疗效果和临床自然病程至关重要。目前针对CMT患者的功能障碍严重程度、治疗效果、生活质量及预后等方面有不同类型的测评工具,文中我们对临床上常用的CMT相关测评量表进行了综述。

关键词：腓骨肌萎缩症周围神经系统疾病评分量表

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腓骨肌萎缩症1A亚型的发病机制及靶向药物研究进展

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中华医学遗传学杂志 2020年第5期37卷 578-583页

作者：曹婉芊张如旭中南大学湘雅三医院神经内科长沙410013

腓骨肌萎缩症(Charcot-Marie-Tooth disease,CMT)是一组常见的累及周围神经的单基因遗传病,其发病率约为1/2500。CMT1A是CMT最常见的亚型,约占确诊病例的50%。目前认为CMT1A的病因为外周髓鞘蛋白22基因重复突变,导致基因表达调控机制紊... 详细信息

腓骨肌萎缩症(Charcot-Marie-Tooth disease,CMT)是一组常见的累及周围神经的单基因遗传病,其发病率约为1/2500。CMT1A是CMT最常见的亚型,约占确诊病例的50%。目前认为CMT1A的病因为外周髓鞘蛋白22基因重复突变,导致基因表达调控机制紊乱,与NRG1/ErbB通路失调、脂质代谢障碍等多种因素共同影响施旺细胞髓鞘形成。目前CMT1A患者的治疗以对症支持为主,针对上述可能的发病机制,CMT1A的靶向治疗药物正在研发中。本文就CMT1A的发病机制和靶向治疗药物的研究进展做一综述。

关键词：腓骨肌萎缩症药物疗法发病机制

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Recommendations for the diagnosis and treatment of paroxysmal kinesigemc dyskinesia: an expert consensus in China

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Translational Neurodegeneration 2021年第1期10卷 67-76页

作者： Li Cao Xiaojun Huang Ning Wang Zhiying Wu Cheng zhang Weihong Gu Shuyan Cong Jianhua Ma Ling Wei Yanchun Deng Qi Fang Qi Niu Jin Wang Zhaoxia Wang You Yin Jinyong Tian Shufen Tian Hongyan Bi Hong Jiang Xiaorong Liu Yang Lu Meizhen Sun Jianjun Wu Erhe Xu Tao Chen Tao Chen Xu Chen Wei Li Shujian Li Qinghua Li Xiaonan Song Ying Tang Ping Yang Yun Yang Min zhang Xiong zhang Yuhu zhang ruxu zhang Yi Ouyang Jintai Yu Quanzhong Hu Qing Ke Yuanrong Yao Zhe Zhao Xiuhe Zhao Guohua Zhao Furu Liang Nan Cheng Jianhong Han Rong Peng Shengdi Chen Beisha Tang Department of Neurology Ruijin Hospital Shanghai Jiao Tong University School of MedicineShanghaiChina Department of Neurology The Sixth People's Hospital Shanghai Jiaotong UniversityShanghaiChina Department of Neurology and Institute of Neurology The First Affiliated HospitalFujian Medical University/Fujian Key Laboratory of Molecular NeurologyFujian Medical UniversityFuzhouChina Department of Neurology and Research Center of Neurology The Second Affiliated Hospital/Key Laboratory of Medical Neurobiology of Zhejiang ProvinceZhejiang University School of MedicineHangzhouChina Department of Neurology The First Affiliated HospitalSun Yat-sen UniversityGuangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases/National Key Clinical Department and Key Discipline of NeurologyGuangzhouChina Department of Neurology China-Japan Friendship HospitalMovement Disorder and Neurogenetics Research CenterBeijingChina Department of Neurology Shengjing Hospital of China Medical UniversityShenyangChina Department of Neurology The First Affiliated Hospital of Xinjiang Medical UniversityUrumqiChina Department of Neurology The First Affiliated Hospital of Anhui Medical UniversityCollaborative Innovation Center for Neuropsychiatric Disorders and Mental HealthAnhui Medical University/Anhui Province Key Laboratory of Cognition and Neuropsychiatry DisordersHefeiChina Department of Neurology Xijing HospitalFourth Military Medical UniversityXi'anChina Department of Neurology The First Affiliated Hospital of Soochow UniversitySuzhouChina Department of Neurology The First Affiliated Hospital of Nanjing Medical UniversityNanjingChina Department of Neurology The First Affiliated Hospital of Guangxi Medical UniversityNanningChina Department of Neurology Peking University First HospitalBeijingChina Department of Neurology Changzheng Hospitalthe PLA Naval Medical UniversityShanghaiChina Department of Neurology and Department of Emergency Guizhou Provincial People's Hospital

Paroxysmal dyskinesias are a group of neurological diseases characterized by intermittent episodes of involuntary movements with different *** kinesigenic dyskinesia(PKD)is the most common type of paroxysmal dyskinesia and can be divided into primary and secondary types based on the ***,PKD is characterized by recurrent and transient attacks of involuntary movements precipitated by a sudden voluntary *** major cause of primary PKD is genetic abnormalities,and the inheritance pattern of PKD is mainly autosomal-dominant with incomplete *** proline-rich transmembrane protein 2(PRRT2)was the first identified causative gene of PKD,accounting for the majority of PKD cases *** increasing number of studies has revealed the clinical and genetic characteristics,as well as the underlying mechanisms of *** seeking the views of domestic experts,we propose an expert consensus regarding the diagnosis and treatment of PKD to help establish standardized clinical evaluation and therapies for *** this consensus,we review the clinical manifestations,etiology,clinical diagnostic criteria and therapeutic recommendations for PKD,and results of genetic analyses in PKD patients performed in domestic hospitals.

关键词： Paroxysmal kinesigenic dyskinesia Diagnosis and treatment Expert consensus China

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