我国迪谢内肌营养不良分子遗传学研究概况

迪谢内肌营养不良（ＤＭＤ）是一种常见的致死性神经肌肉系统Ｘ连锁隐性遗传病,发病率为活产男婴的１／３５００。患者一般３～５岁发病,主要表现为全身骨骼肌进行性无力、萎缩和小腿腓肠肌假性肥大,随着病情加重,２０岁左右因呼吸衰竭死亡,迄今无有效的治疗方法。１...     

强直性肌营养不良症的分子遗传学研究进展

强直性肌营养不良症(myotonic dystrophy,DM)是一种常染色体显性遗传性神经肌肉疾病,发病率1/8000～1/20000,为最常见的累及成人的肌营养不良症。近年来的分子遗传学研究表明,19号染色体上的一蛋白激酶基因为本病的候选基因,且三联体(CTG)。拷贝数的增加与本病的发生有关。本文就最近几年有关DM的分子遗传学研究进展与本病的临床联系及有关DM的产前或症状前诊断等问题作一综述。     

眼咽型肌营养不良病理及分子遗传学研究

目的研究眼咽肌营养不良(ocu lopharyngeal muscu lar dystrophy,OPMD)的遗传学和病理形态学表现。方法应用透射电镜技术对6例患者提上睑肌进行超微结构观察和分析,并采用聚合酶链反应(PCR)产物直接测序法对来自3个家系的OPMD患者11例及其亲属共27名外周血进行检测。结果4例患者眼肌活检标本于电镜下可观察到特异性核内包涵体(intranuc lear inc lusions,INIs),在细胞核内出现率分别为18%、20%、34%及40%。而9例患者基因中存在(GCG)6重复序列拷贝数异常(GCG)8、(GCG)10,亲属中未发病者均未见重复序列的异常扩增。结论OPMD患者受累眼肌活组织检查于电镜下可见INIs,并且INIs出现比率与异常扩增数目成正比。OPMD患者存在(GCG)6重复序列的异常扩增,并且发病年龄与异常扩增数目成反比。     

肢带型肌营养不良的分子遗传学研究进展

肢带型肌营养不良是一种遗传模式和临床症状都高度不均一的常染色体遗传性肌营养不良症,主要表现为进行性的肩胛带和骨盆带肌无力和萎缩,仅有少数累及延髓肌及呼吸肌。以前由于对该类疾病认识甚少,临床诊断仅根据临床症状和遗传模式判断,无法明确分型。直至上世纪90年代以后,随着分子生物学的发展,对本组疾病的认识获得了较大突破。1995年,Bushby根据基因分析结果,并按照该病遗传方式的不同,以LGMD1和LGMD2分别表示常染色体显性遗传(1型)和常染色体隐性遗传(2型)[1]。随着新的肌营养不良的类型不断被发现,目前已确认的共有18个亚型,1型…     

Emery-Dreifuss肌营养不良遗传学研究进展

Emery-Dreifuss 肌营养不良(Emery-Dreifuss dystrophy,EDMD)是于1962年被首次报道,1979年被正式命名的罕见遗传性疾病,患病率约为0.39/10万[1,2].EDMD临床表现为特征性的三联征:即早期关节挛缩、进行性肌无力和萎缩以及心脏受累,心脏受累通常在20～30岁时开始出...     

面肩肱型肌营养不良的分子遗传学研究进展

面肩肱型肌营养不良(facioscapulohumeral muscular dystrophy, FSHD)最早于1884年报道,是成人中最常见的肌营养不良,国外报道发病率约为1/20 000,呈常染色体显性遗传,但近年来发现不少新(当代)突变的散发病例.多于10～20岁起病,主要表现为面肌、肩胛带肌和上臂肌群进行性无力及萎缩,不同患者在起病年龄及临床表型方面有很大差异.1990年Wijmenga等[1]将其定位于4q35,从而使FSHD研究进入分子水平.近年来研究发现,95%的病例与4q35区的一个高度多态性EcoRI片段呈紧密连锁关系.此片段可用p13E-11探针通过Southern杂交检测,正常人为35～300 kb,病人则为10～34 kb.     

假肥大型肌营养不良症的分子遗传学研究进展

本文综述了假肥大型肌营养不良症近几年来在分子遗传学方面的研究进展。涉及到有关DMD基因的染色体定位、基因鉴定、基因的结构本质、基因产物及其作用、DMD与BMD临床表现的差异及其可能的解释等方面。分子遗传学及遗传工程技术的发展为阐明本病的发病机理及提供有效的诊治手段开辟了广阔的前景。     

肢带型肌营养不良症的分子遗传学研究进展

肢带型肌营养不良症(LGMD),这一常染色体连锁遗传性疾病的研究近来发展迅速。肌纤维膜上新发现的蛋白复合物的分子结构,复合物中各个蛋白与LGMD类型的关系以及LGMD各致病基因的研究,正成为对该病研究的热点。这些研究为最终阐明LGMD的发病机理,为临床诊断和分型以及未来的基因治疗从分子水平提供了依据。     

D uchenne 型肌营养不良家系的临床及分子遗传学研究

目的：探讨Duchenne型肌营养不良（DMD）家系的临床及分子遗传学特征。方法收集并分析我院收治的2个DMD家系临床资料和基因检测结果,并结合既往相关文献,回顾该病在临床表现、分子遗传学等方面的特点。结果DMD儿童期隐匿起病,进行性加重,以肌无力、肌萎缩为特点,可伴肌肉假性肥大,血清肌酶水平异常增高,肌电图呈肌源性损害,肌肉活检呈肌病特征。本文报道的2个家系经基因检测家系1先证者为DMD基因的第3～21号外显子缺失,家系2先证者则为第8、9外显子重复突变,2个家系中的先证者基因均为纯合突变,且其母亲均为致病基因的携带者,符合X染色体隐性遗传的规律。结论早期识别DMD的临床特征有助于提高该病的诊断水平,基因检测是一种确诊DMD快速、有效的方法。     

眼咽型肌营养不良一家系临床与分子遗传学研究

目的探讨一考虑诊断眼咽型肌营养不良(oculopharyngeal muscular dystrophy,0PMD)家系的临床及分子生物学特点。方法收集该家系成员的临床资料,并经包括先证者在内的16位家族成员同意,收集其血样进行聚合酶链反应(PCR)基因验证分析。结果该家系成员男性患者起病以眼睑下垂为首发症状,而后开始逐渐出现以发音及吞咽困难为表现的咽部肌群和肢体乏力为表现的四肢近端肌群受累,而女性患者则往往以吞咽困难为首发表现。参与基因检测的家族成员中共发现10位存在多聚腺苷酸结合蛋白核l(PABPN1)基因的(GCG)6重复异常拷贝为(GCG)10,从而导致了丙氨酸的扩增。结论基因诊断及产前诊断是确诊及预防眼咽型肌营养不良的关键,眼睑下垂可能为携带(GCG)10突变男性OPMD患者的首发症状。     

Facio-scapula-humeral muscular dystrophy: clinical picture and molecular genetics

Facioscapulohumeral muscular dystrophy (FSHD) is a disorder of muscle with a progressive, often asymmetric wasting and weakness of facial, shoulder girdle and lower limbs muscles. No FSHD gene has been identified so far. The FSHD locus is known to be 4q35. The paper presents the clinical picture of FSHD including atypical cases, as well as its inter- and intrafamilial clinical variability. Molecular pathology and diagnostics of the condition are discussed, with particular attention paid to DNA analysis in FSHD.     

Molecular genetics in muscular dystrophy research: revolutionary progress

The contribution of "reverse genetic" strategies to neuromuscular disease research is evident in the progression of breakthroughs that have recently culminated in the cloning of the Duchenne muscular dystrophy (DMD) cDNA. The resultant improvements in our understanding of the genetic basis of Becker muscular dystrophy (BMD) and DMD serve as models for similar investigation of other heritable disorders. These genetic advances have outpaced concurrent work on the molecular pathogenesis of the dystrophic process, with the curious result that inferences about the DMD protein's amino acid sequence have preceded any information about its function or intracellular localization. In recognition that this foundation sets the stage for the rapid elucidation of the disease's pathogenesis, we review the experimental basis of such advances, with reference to relevant progress in basic myology, pathology, and molecular biology. We conclude with a view towards the ultimate clinical implications of these experimental breakthroughs.     

面-肩-肱型肌营养不良症分子学机制研究进展

面-肩-肱型肌营养不良症(FSHD)呈常染色体显性遗传,以面肌、肩胛带肌和上臂肌群肌无力和肌萎缩发病,逐渐累及躯干肌群和下肢肌群,临床异质性较高,预后相对较好。临床分型包括FSHD1型和FSHD2型,前者与4q35区域D4Z4串联重复序列缺失有关,其上游简单序列长度多态性和下游特殊等位序列4qA/4qB具有选择致病性。4q35区域DNA低甲基化启动表观遗传效应,使D4Z4串联重复序列内DUX4基因去抑制致异常表达,导致多种肌细胞损害效应。后者由DNA甲基化调控基因——SMCHD1基因突变所致。支持面-肩-肱型肌营养不良症是毒性功能获得性疾病学说,为其治疗研究提供重要靶点。     

Molecular genetics of facioscapulohumeral muscular dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant neuromuscular disorder. The disease affects specific muscles of the face, shoulder-girdle and upper arm. The biochemical defect underlying FSHD is unknown and there are no specific tests that are diagnostic of FSHD. Genetic linkage studies have mapped the FSHD gene to chromosome 4q35. A DNA marker (p13E-11; D4F104S1, formerly D4S810) has been isolated which recognizes two highly polymorphic loci detectable by EcoRI or HindIII; one locus maps to chromosome 4q35 and shows fragments between about 50 and 320 kb. In FSHD patients deletions occur within this EcoRI/HindIII fragment, yielding fragments that are usually smaller than 28 kb. Characterization of the polymorphic fragments demonstrates that they consist of a 3.2 kb tandem repeat; their number can range between approximately 12 and 96 within the 4q35-specific fragments. In FSHD patients, an integral number of these tandem repeats are deleted, leaving at maximum eight copies.     

Limb-girdle muscular dystrophies--from genetics to molecular pathology

The limb-girdle muscular dystrophies are a diverse group of muscle-wasting disorders characteristically affecting the large muscles of the pelvic and shoulder girdles. Molecular genetic analyses have demonstrated causative mutations in the genes encoding a disparate collection of proteins involved in all aspects of muscle cell biology. Muscular dystrophy includes a spectrum of disorders caused by loss of the linkage between the extracellular matrix and the actin cytoskeleton. Within this are the forms of limb-girdle muscular dystrophy caused by deficiencies of the sarcoglycan complex and by aberrant glycosylation of alpha-dystroglycan caused by mutations in the fukutin-related protein gene. However, other forms of this disease have distinct pathophysiological mechanisms. For example, deficiency of dysferlin disrupts sarcolemmal membrane repair, whilst loss of calpain-3 may exert its pathological influence either by perturbation of the IkappaBalpha/NF-kappaB pathway, or through calpain-dependent cytoskeletal remodelling. Caveolin-3 is implicated in numerous cell-signalling pathways and involved in the biogenesis of the T-tubule system. Alterations in the nuclear lamina caused by mutations in laminA/C, sarcomeric changes in titin, telethonin or myotilin at the Z-disc, and subtle changes in the extracellular matrix proteins laminin-alpha2 or collagen VI can all lead to a limb-girdle muscular dystrophy phenotype, although the specific pathological mechanisms remain obscure. Differential diagnosis of these disorders requires the careful application of a broad range of disciplines: clinical assessment, immunohistochemistry and immunoblotting using a panel of antibodies and extensive molecular genetic analyses.     

Recent advances in congenital muscular dystrophy research

Congenital muscular dystrophy (CMD) is a group of heterogeneous disorders characterized clinically by delayed milestones due to generalized muscle weakness and dystrophic muscle pathology. The discovery of fukutin, responsible gene for Fukuyama CMD (FCMD) and defective glycosylation in its muscle biopsy has lead significant advances in CMD researches, especially disorders with glycosylation defects to a dystroglycan (alphaDG). The highly glycosylated a DG is one of the major dystrophin-associated proteins anchored a basement membrane protein, laminin 2 to the dystrophin molecule. The disorders with the defective glycosylation are now categorized as a dystroglycanopathies which include FCMD, muscle-eye-brain (MEB) disease, Walker-Warburg syndrome (WWS) and diseases with mutations in fukutin-related protein (FKRP) and LARGE genes. Among them, MEB and WWS were proven to have mutations in the glycosyltransferase genes, POMGnT1 (protein O-mannose beta 1,2-N-acetylglucosaminyl/transferase 1) and POMT1 (protein O-mannosyltransferase 1), respectively, though others are still unknown how the glycosylation defect is induced. Although the disease with FKRP mutation has variable phenotypes from CMD to limb-girdle muscular dystrophy, others with defective to decreased a DG show CMD, central nervous system involvement with migration disorder (polymicrogyria) and ocular abnormalities.