目的分析并确立1个先天性肌营养不良1A型（congenital muscular dystrophy type 1A，MDC1A）家系的临床、分子病理及遗传学特征。方法收集该家系患儿及父母的临床资料，对患儿进行腓肠肌活检，采用特异抗体行免疫组织化学染色，包括mero...目的分析并确立1个先天性肌营养不良1A型（congenital muscular dystrophy type 1A，MDC1A）家系的临床、分子病理及遗传学特征。方法收集该家系患儿及父母的临床资料，对患儿进行腓肠肌活检，采用特异抗体行免疫组织化学染色，包括merosin抗体、抗“抗肌萎缩相关糖蛋白（α—dystroglycan，α—DG）糖链抗体ⅡH6、抗β抗肌萎缩相关糖蛋白（β—dystroglycan，β—DG）抗体及抗肌萎缩蛋白（dystrophin）C末端（Dys—C）抗体；提取患儿及其父母外周血基因组DNA，PCR扩增LAMA2基因的65个外显子，以琼脂糖凝胶电泳鉴定PCR产物，PCR产物纯化后DNA直接测序，确定基因突变的类型，分析基因型和表型的关系。结果患儿自幼运动发育落后，肌病面容，肌酶中度升高，头颅MRI提示脑白质异常信号，临床诊断为先天性肌营养不良1A型。通过活检肌肉组织免疫学染色提示merosin完全缺失，dystrophin和DG表达正常。基因检测显示先证者LAMA2基因第5外显子c．817A〉T纯合突变，其父母分别为此位点杂合突变。结论本次研究进一步明确了MDC1A患儿的临床特点，通过分子遗传学分析发现该患儿为LAMA2基因c.
817A〉A（p．R273X）纯合无义突变，其突变基因分别来自父母，符合先天性肌营养不良1A型常染色体隐性遗传的规律，可确诊为先天性肌营养不良1A型。展开更多
先天性全身性脂肪营养不良1型(congenital generalized lipodystrophy type 1,CGL1)是由AGPAT2基因异常导致的常染色体隐性遗传疾病,主要临床表现为全身皮下脂肪消失、肌肉发达、皮下静脉明显、假性肢端肥大症、多毛、黑棘皮症等,常合...先天性全身性脂肪营养不良1型(congenital generalized lipodystrophy type 1,CGL1)是由AGPAT2基因异常导致的常染色体隐性遗传疾病,主要临床表现为全身皮下脂肪消失、肌肉发达、皮下静脉明显、假性肢端肥大症、多毛、黑棘皮症等,常合并代谢性疾病,易被误诊为代谢综合征、2型糖尿病、多囊卵巢综合征、肢端肥大症及库欣综合征等。同时,与部分脂肪萎缩综合征的鉴别在临床上存在难度。本研究回顾分析1例CGL1患者的临床和遗传特征,并结合国内外文献进行分析总结,从而有助于加深对该罕见疾病的认识。展开更多
先天性胫骨假关节（congenital pseudarthrosis of the tibia，CPT）是由于发育异常导致的胫骨畸形，表现为胫骨成角畸形、髓腔狭窄或囊肿等，最终形成不愈合的假关节。其发生率占新生儿的1／140000～1／250000。先天性胫骨假关节是骨...先天性胫骨假关节（congenital pseudarthrosis of the tibia，CPT）是由于发育异常导致的胫骨畸形，表现为胫骨成角畸形、髓腔狭窄或囊肿等，最终形成不愈合的假关节。其发生率占新生儿的1／140000～1／250000。先天性胫骨假关节是骨科领域了解较少、治疗极其困难的疾病。从1709年Hatzoecher首先报告本病以来，已有300余年历史，病因至今不完全清楚。曾有多种学说，如宫内压迫、产伤、血运障碍、全身代谢性疾病等，但都缺乏充足的证据。该病与1型神经纤维瘤病（NF1）存在复杂关系。本文从该病的病理学特点、骨发育相关细胞因子的表达、遗传学与基因学研究、及与1型神经纤维瘤病的关系等方面综述其病因学研究进展。展开更多
Mutations of lamin A/C (LMNA) cause a wide range of human disorders, including progeria, lipodystrophy, neuropathies and autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD). EDMD is also caused by X-linked rec...Mutations of lamin A/C (LMNA) cause a wide range of human disorders, including progeria, lipodystrophy, neuropathies and autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD). EDMD is also caused by X-linked recessive loss-of-function mutations of emerin, another component of the inner nuclear lamina that directly interacts with LMNA. One model for disease pathogenesis of LMNA and emerin mutations is cellspecific perturbations of the mRNA transcriptome in terminally differentiated cells. To test this model, we studied 125 human muscle biopsies from 13 diagnostic groups (125 U133A, 125 U133B microarrays), including EDMD patients with LMNA and emerin mutations. A Visual and Statistical Data Analyzer (VISDA) algorithm was used to statistically model cluster hierarchy, resulting in a tree of phenotypic classifications. Validations of the diagnostic tree included permutations of U133A and U133B arrays, and use of two probe set algorithms (MAS5.0 and MBE1). This showed that the two nuclear envelope defects (EDMD LMNA, EDMD emerin) were highly related disorders and were also related to fascioscapulohumeral muscular dystrophy (FSHD). FSHD has recently been hypothesized to involve abnormal interactions of chromatin with the nuclear envelope. To identify disease-specific transcripts for EDMD, we applied a leave-one-out (LOO) cross-validation approach using LMNA patient muscle as a test data set, with reverse transcription-polymerase chain reaction (RT-PCR) validations in both LMNA and emerin patient muscle. A high proportion of top-ranked and validated transcripts were components of the same transcriptional regulatory pathway involving Rb1 and MyoD during muscle regeneration (CRI-1, CREBBP, NapIL1, ECREBBP/p300), where each was specifically upregulated in EDMD. Using a muscle regeneration time series (27 time points) we develop a transcriptional model for downstream consequences of LMNA and emerin mutations. We propose that key interactions between the nuclear envelope and Rb and MyoD fail in EDMD at the point of myoblast exit from the cell cycle, leading to poorly coordinated phosphorylation and acetylation steps. Our data is consistent with mutations of nuclear lamina components leading to destabilization of the transcriptome in differentiated cells.展开更多
文摘先天性全身性脂肪营养不良1型(congenital generalized lipodystrophy type 1,CGL1)是由AGPAT2基因异常导致的常染色体隐性遗传疾病,主要临床表现为全身皮下脂肪消失、肌肉发达、皮下静脉明显、假性肢端肥大症、多毛、黑棘皮症等,常合并代谢性疾病,易被误诊为代谢综合征、2型糖尿病、多囊卵巢综合征、肢端肥大症及库欣综合征等。同时,与部分脂肪萎缩综合征的鉴别在临床上存在难度。本研究回顾分析1例CGL1患者的临床和遗传特征,并结合国内外文献进行分析总结,从而有助于加深对该罕见疾病的认识。
文摘先天性胫骨假关节（congenital pseudarthrosis of the tibia，CPT）是由于发育异常导致的胫骨畸形，表现为胫骨成角畸形、髓腔狭窄或囊肿等，最终形成不愈合的假关节。其发生率占新生儿的1／140000～1／250000。先天性胫骨假关节是骨科领域了解较少、治疗极其困难的疾病。从1709年Hatzoecher首先报告本病以来，已有300余年历史，病因至今不完全清楚。曾有多种学说，如宫内压迫、产伤、血运障碍、全身代谢性疾病等，但都缺乏充足的证据。该病与1型神经纤维瘤病（NF1）存在复杂关系。本文从该病的病理学特点、骨发育相关细胞因子的表达、遗传学与基因学研究、及与1型神经纤维瘤病的关系等方面综述其病因学研究进展。
文摘Mutations of lamin A/C (LMNA) cause a wide range of human disorders, including progeria, lipodystrophy, neuropathies and autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD). EDMD is also caused by X-linked recessive loss-of-function mutations of emerin, another component of the inner nuclear lamina that directly interacts with LMNA. One model for disease pathogenesis of LMNA and emerin mutations is cellspecific perturbations of the mRNA transcriptome in terminally differentiated cells. To test this model, we studied 125 human muscle biopsies from 13 diagnostic groups (125 U133A, 125 U133B microarrays), including EDMD patients with LMNA and emerin mutations. A Visual and Statistical Data Analyzer (VISDA) algorithm was used to statistically model cluster hierarchy, resulting in a tree of phenotypic classifications. Validations of the diagnostic tree included permutations of U133A and U133B arrays, and use of two probe set algorithms (MAS5.0 and MBE1). This showed that the two nuclear envelope defects (EDMD LMNA, EDMD emerin) were highly related disorders and were also related to fascioscapulohumeral muscular dystrophy (FSHD). FSHD has recently been hypothesized to involve abnormal interactions of chromatin with the nuclear envelope. To identify disease-specific transcripts for EDMD, we applied a leave-one-out (LOO) cross-validation approach using LMNA patient muscle as a test data set, with reverse transcription-polymerase chain reaction (RT-PCR) validations in both LMNA and emerin patient muscle. A high proportion of top-ranked and validated transcripts were components of the same transcriptional regulatory pathway involving Rb1 and MyoD during muscle regeneration (CRI-1, CREBBP, NapIL1, ECREBBP/p300), where each was specifically upregulated in EDMD. Using a muscle regeneration time series (27 time points) we develop a transcriptional model for downstream consequences of LMNA and emerin mutations. We propose that key interactions between the nuclear envelope and Rb and MyoD fail in EDMD at the point of myoblast exit from the cell cycle, leading to poorly coordinated phosphorylation and acetylation steps. Our data is consistent with mutations of nuclear lamina components leading to destabilization of the transcriptome in differentiated cells.
