Background We determined the diagnosis of hereditary hemorrhagic telangiectasis (HHT) in a suspected HHT family,identified ALK1 gene mutation and established a gene diagnosis method of HHT. The level of related plasma...Background We determined the diagnosis of hereditary hemorrhagic telangiectasis (HHT) in a suspected HHT family,identified ALK1 gene mutation and established a gene diagnosis method of HHT. The level of related plasma proteins (transforming growth factor β and thrombomodulin) were also analyzed.Methods Bleeding history and family history were collected; Dilatant nasal mucosal capillaries in proband were observed under nasal cavity endoscope; exons 3,7,8 of ALK1 gene in proband and her family members were amplified with polymerase chain reaction (PCR), and the PCR products were analyzed. Using enzyme-linked immunosorbent assay (ELISA),plasma TGF-β1 and TGF-β2 concentrations were measured. Plasma thrombomodulin (TM) level was detected by Western blotting.Results Of all family members,four had epstaxis,two had evident telangiectases on skin or mucosa. Gene screening results showed that C to T substitution at position 1231 in exon 8 of ALK1 gene (CGG→TGG) existed in proband,her affected brother and their father. The mutation did not exist in proband’s sister-in-law and nephew. Plasma TGF-β1 concentrations in the affected HHT was 20538,17194,13131 pg/ml,while that of normal control and unaffected family members was 15950,20297,12836 pg/ml,respectively. Plasma TGF-β2 in HHT patients was 14502,9550,10592 and that of normal controls 8579,20297,7680 pg/ml respectively. Level of plasma TM was in HHT subjects significantly lower than in normal subjects.Conclusions Chinese HHT individuals have mutant ALK1 gene,a C1231T variation on exon 8 of ALK1 is responsible for HHT clinical phenotypes in this family. ALK1 gene analysis,together with special clinical phenotypes and family history,provides a reliable method in diagnosing HHT. In affected HHT subjects,plasma TGFβ levels were not obviously different from those of normal subject; while plasma TM concentration was significantly lower than that in normal subjects. The significance and mechanism remain to be elucidated.展开更多
Objective To investigate the genetic basis of the pathogenesis of a Guangzhou (GZ 1) pedigree with primary open angle glaucoma (POAG) Methods DNA fragments of the trabecular meshwork inducible glucocorticoid res...Objective To investigate the genetic basis of the pathogenesis of a Guangzhou (GZ 1) pedigree with primary open angle glaucoma (POAG) Methods DNA fragments of the trabecular meshwork inducible glucocorticoid response protein (TIGR) gene from 4 typical POAG patients and 2 normal subjects were amplified by polymerase chain reaction (PCR) The amplified PCR fragment was cloned into a pT Adv vector, and direct sequencing was carried out on an ABI 373 automated DNA sequencer using dye terminator chemistry to detect the mutation Results The TIGR gene mutation was identified in the selected subjects of this pedigree This mutation is a “C to T” transition at position 370, different from that of western countries and equivalent to the position change found in Japanese patients with familial POAG No mutation was found in the TIGR gene fragment in 2 normal subjects of the pedigree Conclusions These preliminary results provide insights into the pathogenesis of POAG by the TIGR gene mutation, and into the underlying action of the different mutations in oriental and western peoples展开更多
目的分析两个伴皮层下梗死和白质脑病的常染色体显性遗传性脑动脉病（cerebral autosomal dominant arteriopathy with subeortieal infarct and leucoencephalopathy，CADASIL）家系NOTCH3基因的突变情况，为遗传咨询提供依据。方法收...目的分析两个伴皮层下梗死和白质脑病的常染色体显性遗传性脑动脉病（cerebral autosomal dominant arteriopathy with subeortieal infarct and leucoencephalopathy，CADASIL）家系NOTCH3基因的突变情况，为遗传咨询提供依据。方法收集2个临床疑诊为CADASIL家系的患者临床资料，分析其临床特征，并对先证者和家系成员以及100名健康对照者进行NOTCH3基因测序，对发现的突变用PolyPhen-2、SIFT等软件进行功能预测，以明确其致病性。结果两个家系的先证者均为中年起病，临床表现为反复脑缺血性发作、认知功能损害等，头颅磁共振成像显示多发腔隙性脑梗死和广泛的脑白质疏松。DNA测序显示先证者1存在NOTCH3基因第3外显子c．328C〉T（p．Arg110Cys）杂合突变，为已知致病突变，先证者2存在NOTCH3基因第6外显子c．1013G〉C（P．Cys338Ser）杂合突变，尚未见报道。在100名健康对照者中未检测到上述杂合突变。功能预测分析表明c．1013G〉C杂合突变可能对NOTCH3的编码蛋白产生重要的影响。结论两个家系的CADASIL病均由NOTCH3基因突变所致，其中NOTCH3基因第6外显子c．1013G〉C（P．Cys338Ser）杂合突变为cADASIL新的致病突变。展开更多
基金ThisstudywassupportedbytheNationalNaturalScienceFoundationofChina (No 3 983 0 180 )
文摘Background We determined the diagnosis of hereditary hemorrhagic telangiectasis (HHT) in a suspected HHT family,identified ALK1 gene mutation and established a gene diagnosis method of HHT. The level of related plasma proteins (transforming growth factor β and thrombomodulin) were also analyzed.Methods Bleeding history and family history were collected; Dilatant nasal mucosal capillaries in proband were observed under nasal cavity endoscope; exons 3,7,8 of ALK1 gene in proband and her family members were amplified with polymerase chain reaction (PCR), and the PCR products were analyzed. Using enzyme-linked immunosorbent assay (ELISA),plasma TGF-β1 and TGF-β2 concentrations were measured. Plasma thrombomodulin (TM) level was detected by Western blotting.Results Of all family members,four had epstaxis,two had evident telangiectases on skin or mucosa. Gene screening results showed that C to T substitution at position 1231 in exon 8 of ALK1 gene (CGG→TGG) existed in proband,her affected brother and their father. The mutation did not exist in proband’s sister-in-law and nephew. Plasma TGF-β1 concentrations in the affected HHT was 20538,17194,13131 pg/ml,while that of normal control and unaffected family members was 15950,20297,12836 pg/ml,respectively. Plasma TGF-β2 in HHT patients was 14502,9550,10592 and that of normal controls 8579,20297,7680 pg/ml respectively. Level of plasma TM was in HHT subjects significantly lower than in normal subjects.Conclusions Chinese HHT individuals have mutant ALK1 gene,a C1231T variation on exon 8 of ALK1 is responsible for HHT clinical phenotypes in this family. ALK1 gene analysis,together with special clinical phenotypes and family history,provides a reliable method in diagnosing HHT. In affected HHT subjects,plasma TGFβ levels were not obviously different from those of normal subject; while plasma TM concentration was significantly lower than that in normal subjects. The significance and mechanism remain to be elucidated.
文摘Objective To investigate the genetic basis of the pathogenesis of a Guangzhou (GZ 1) pedigree with primary open angle glaucoma (POAG) Methods DNA fragments of the trabecular meshwork inducible glucocorticoid response protein (TIGR) gene from 4 typical POAG patients and 2 normal subjects were amplified by polymerase chain reaction (PCR) The amplified PCR fragment was cloned into a pT Adv vector, and direct sequencing was carried out on an ABI 373 automated DNA sequencer using dye terminator chemistry to detect the mutation Results The TIGR gene mutation was identified in the selected subjects of this pedigree This mutation is a “C to T” transition at position 370, different from that of western countries and equivalent to the position change found in Japanese patients with familial POAG No mutation was found in the TIGR gene fragment in 2 normal subjects of the pedigree Conclusions These preliminary results provide insights into the pathogenesis of POAG by the TIGR gene mutation, and into the underlying action of the different mutations in oriental and western peoples
文摘目的分析两个伴皮层下梗死和白质脑病的常染色体显性遗传性脑动脉病（cerebral autosomal dominant arteriopathy with subeortieal infarct and leucoencephalopathy，CADASIL）家系NOTCH3基因的突变情况，为遗传咨询提供依据。方法收集2个临床疑诊为CADASIL家系的患者临床资料，分析其临床特征，并对先证者和家系成员以及100名健康对照者进行NOTCH3基因测序，对发现的突变用PolyPhen-2、SIFT等软件进行功能预测，以明确其致病性。结果两个家系的先证者均为中年起病，临床表现为反复脑缺血性发作、认知功能损害等，头颅磁共振成像显示多发腔隙性脑梗死和广泛的脑白质疏松。DNA测序显示先证者1存在NOTCH3基因第3外显子c．328C〉T（p．Arg110Cys）杂合突变，为已知致病突变，先证者2存在NOTCH3基因第6外显子c．1013G〉C（P．Cys338Ser）杂合突变，尚未见报道。在100名健康对照者中未检测到上述杂合突变。功能预测分析表明c．1013G〉C杂合突变可能对NOTCH3的编码蛋白产生重要的影响。结论两个家系的CADASIL病均由NOTCH3基因突变所致，其中NOTCH3基因第6外显子c．1013G〉C（P．Cys338Ser）杂合突变为cADASIL新的致病突变。
