一结节性硬化症家系临床特点及致病基因突变分析

发布时间：2018-08-02 09:30

【摘要】：目的结节性硬化症(Tuberous Sclerosis Complex,TSC)是一种常染色体显性遗传的神经皮肤综合征,以全身各系统的错构瘤样增生为主要特征,以面部血管纤维瘤、癫痫发作、智能减退为主要临床表现。其致病基因分别为TSC1和TSC2基因,两者均为肿瘤抑制基因,分别编码错构瘤蛋白(hamartin)和马铃薯球蛋白(tuberin)。本研究旨在对一结节性硬化症家系进行基因突变分析,明确其基因突变位点、类型,区分其为家族性还是散发性,为TSC的诊断提供确切依据。方法收集1例临床确诊结节性硬化症患者、其父母及妹妹的临床资料,提取患者及其3名家系成员(父母、妹妹)的外周血DNA,应用聚合酶链反应(PCR)扩增TSC1和TSC2基因所有的外显子编码区,并以Hisq3000高通量测序仪对PCR反应产物测序进行序列分析。结果患者女性,有腰背部斑驳样皮肤改变,腰骶部鲨革斑,伴有色素脱失斑,脑电图提示左枕、左后颞部棘慢、尖慢波发放,颅脑CT发现左枕部钙化,无明显智力障碍,无抽搐发作史。该家系共3名女性受累,均达到TSC临床确诊标准,对患者父母及其妹妹的DNA样本进行基因测序验证。基因测序结果发现2个突变位点,在TSC1基因上发现一个无义突变c.2071CT(p.Arg691Ter);在TSC2基因上发现一个错义突变c.1973AC(p.Lys658Thr)。其妹妹及母亲亦携带此两者突变。结论同一家系中,相同基因型患者之间可有不同的临床表型,且随着病程、年龄的增长,其临床表型更趋于严重。基因检测发现该家系中存在两个TSC基因突变位点:c.2071CT与c.1973AC。c.2071CT为致病性突变,c.1973AC临床意义尚不明确,需进一步动物实验及蛋白功能测定证实。本研究中首次发现TSC1基因第17外显子rs118203631位点上的突变病例中存在家族性遗传。
[Abstract]:Objective (Tuberous Sclerosis complex sclerosis is an autosomal dominant neurocutaneous syndrome characterized by hamartoma-like hyperplasia, facial hemangiofibroma, epileptic seizure and hypointelligence. The pathogenicity genes are TSC1 and TSC2 genes, both of which are tumor suppressor genes and encode hamartoma protein (hamartin) and Potato globulin (tuberin). Respectively. The purpose of this study was to analyze the gene mutation of a family with nodular sclerosis, to identify the mutation site and type, and to distinguish the gene mutation between familial and sporadic, so as to provide an accurate basis for the diagnosis of TSC. Methods the clinical data of one patient with clinically diagnosed nodular sclerosis and their parents and sisters were collected, and the patients and their three family members (parents) were extracted. All exon coding regions of TSC1 and TSC2 gene were amplified by polymerase chain reaction (PCR) and sequenced by Hisq3000 high-throughput sequencer. Results in the female patients, there were mottled skin changes in the back of the waist and sacrum with pigmentation loss, electroencephalogram (EEG) indicating that the left occipital, left posterior temporal spine was slow, the apical slow wave was released, the left occipital calcification was found by brain CT, and there was no obvious mental disorder. No history of convulsions. Three women from this family were involved and all met the criteria of clinical diagnosis of TSC. The DNA samples of parents and sisters of the patients were confirmed by gene sequencing. Two mutation sites were found in the gene sequencing, one nonsense mutation c.2071CT (p.Arg691Ter) was found in TSC1 gene and one missense mutation c.1973AC (p.Lys658Thr) was found in TSC2 gene. His sister and mother also carried both mutations. Conclusion there are different clinical phenotypes among patients with the same genotype in the same family, and the clinical phenotypes tend to be more serious with the increase of disease course and age. It was found that there were two mutations of TSC gene in this family: c.2071CT and c.1973AC.c.2071CT as pathogenicity mutations. The clinical significance of this mutation is not clear, which needs to be confirmed by animal experiments and protein function tests. In this study, familial inheritance was first found in the mutation at the rs118203631 locus of exon 17 of TSC1 gene.
【学位授予单位】：广西医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R596;R747.9

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