AIM:To investigate the genetic basis of Weill-Marchesani syndrome(WMS)in a Chinese family and clarify the pathogenic mechanism of novel ADAMTS17 mutations.METHODS:Comprehensive clinical assessments and genetic analyse...AIM:To investigate the genetic basis of Weill-Marchesani syndrome(WMS)in a Chinese family and clarify the pathogenic mechanism of novel ADAMTS17 mutations.METHODS:Comprehensive clinical assessments and genetic analyses were performed on a Chinese family with two affected siblings.Whole-exome sequencing(WES)was conducted for the proband and other family members.Bioinformatics tools were used to evaluate the conservation,predicted pathogenicity,and structural effects of the identified ADAMTS17 variants.In addition,protein structure modeling was applied to assess the functional impacts of the mutations.RESULTS:The proband(a 32-year-old male)and his elder sister(42y)presented typical clinical features of WMS,including short stature,brachydactyly,high myopia,ectopia lentis,and secondary glaucoma.WES identified a novel compound heterozygous mutation in ADAMTS17:a splicing mutation(c.451-2A>G)inherited from the father and a missense mutation(c.1043G>A;p.C348Y)inherited from the mother.The splicing mutation disrupted normal mRNA splicing and processing,leading to premature translation termination.The missense mutation,which is located in the metalloprotease catalytic domain,was predicted to abolish a critical disulfide bond,thereby impairing protein stability.Both mutations exhibited high evolutionary conservation and were predicted to be pathogenic by multiple bioinformatics algorithms.CONCLUSION:A novel compound heterozygous mutation in ADAMTS17 is identified in this WMS-affected Chinese family,and its pathogenicity is verified via bioinformatics analysis and protein structural modeling.These findings are expected to facilitate the genetic diagnosis of WMS and deepen the understanding of its molecular pathogenesis.展开更多
骨关节炎(OA)是一种普遍的退行性关节疾病,其特征是软骨退化和关节炎症。血小板结合蛋白基序的解聚蛋白样金属蛋白酶(a disintegrin and metalloproteinase with thrombospondin motifs,AD⁃AMTS)家族成员在OA的发病机制中受到了广泛关注...骨关节炎(OA)是一种普遍的退行性关节疾病,其特征是软骨退化和关节炎症。血小板结合蛋白基序的解聚蛋白样金属蛋白酶(a disintegrin and metalloproteinase with thrombospondin motifs,AD⁃AMTS)家族成员在OA的发病机制中受到了广泛关注,尤其是ADAMTS⁃4和ADAMTS⁃5,它们降解软骨蛋白聚糖活性远高于其他成员。蛋白聚糖是ECM的重要组成部分,蛋白聚糖的降解导致软骨的结构和功能破坏,是OA发展的关键因素。本文综述了ADAMTS⁃4和ADAMTS⁃5的结构和功能,重点解析二者底物切割位点的序列选择性、三维构象偏好及翻译后修饰、变构效应,和微环境信号对其蛋白水解活性的多层次调控机制,同时回顾了国内外学者对其靶向药的研究及未来展望。展开更多
解整合素金属蛋白酶家族由膜锚定型和分泌型蛋白构成,分别是解整合素金属蛋白酶(a disintegrin and metalloproteinase, ADAMs)和具有血小板反应蛋基序的解整合素金属蛋白酶(a disintegrin-like and metalloproteinase with thrombospon...解整合素金属蛋白酶家族由膜锚定型和分泌型蛋白构成,分别是解整合素金属蛋白酶(a disintegrin and metalloproteinase, ADAMs)和具有血小板反应蛋基序的解整合素金属蛋白酶(a disintegrin-like and metalloproteinase with thrombospondin motifs, ADAMTS)。ADAMs和ADAMTS在多种肿瘤的发生、发展中发挥重要作用。在胃癌中,ADAMs和ADAMTS家族成员的异常表达与肿瘤的增殖、侵袭及转移密切相关,靶向ADAMs和ADAMTS的药物研发有望成为胃癌的有效的治疗手段。本文通过概述ADAMs和ADAMTS在胃癌中的研究进展,为其作为胃癌潜在治疗靶点提供理论依据。展开更多
目的研究人脑胶质瘤中含血小板结合蛋白基序的解聚素金属4(ADAMTS4)蛋白酶和ADAMTS5蛋白酶的表达及其与胶质瘤病理分级之间的关系。方法采用免疫组化Envision二步法检测ADAMTS4及ADAMTS5蛋白酶在44例不同级别脑胶质瘤、11例瘤周脑组织...目的研究人脑胶质瘤中含血小板结合蛋白基序的解聚素金属4(ADAMTS4)蛋白酶和ADAMTS5蛋白酶的表达及其与胶质瘤病理分级之间的关系。方法采用免疫组化Envision二步法检测ADAMTS4及ADAMTS5蛋白酶在44例不同级别脑胶质瘤、11例瘤周脑组织中的表达,计算阳性细胞百分率,并通过Image Pro Plusversion 6.0(IPP)图像分析软件测量计算其平均光密度(MOD)值。结果 (1)ADAMTS4和ADAMTS5蛋白酶在瘤周脑组织中不表达或极低表达,而在胶质瘤组织中高表达,为棕黄色,主要表达定位于细胞外基质及细胞质中,两组差异有统计学意义(P<0.05)。进一步研究显示,其蛋白表达量随着肿瘤级别的升高而升高,WHO分级中低级别、高级别间差异有统计学意义(P<0.05)。(2)ADAMTS4与ADAMTS5蛋白酶在胶质瘤中表达呈正相关性(χ~2=5.614,r=0.357,P<0.05)。结论(1)ADAMTS4、ADAMTS5蛋白表达量随着胶质瘤级别的升高而升高,提示了ADAMTS4及ADAMTS5蛋白酶在胶质瘤的进展、侵袭中发挥着重要作用。(2)ADAMTS4与ADAMTS5蛋白表达呈正相关性,揭示了在胶质瘤的发生发展中这两种蛋白酶可能互相协同,两者的过表达共同促进了胶质瘤的侵袭。展开更多
含Ⅰ型血小板结合蛋白基序的解聚蛋白样金属蛋白酶ADAMTSs(a disintegrin and metallo-proteinase with thrombospondin motifs)是一类新的Zn2+依赖的金属蛋白酶家族,广泛存在于哺乳动物和无脊椎动物体内。从1997年发现第一个ADAMTSs家...含Ⅰ型血小板结合蛋白基序的解聚蛋白样金属蛋白酶ADAMTSs(a disintegrin and metallo-proteinase with thrombospondin motifs)是一类新的Zn2+依赖的金属蛋白酶家族,广泛存在于哺乳动物和无脊椎动物体内。从1997年发现第一个ADAMTSs家族成员以来,迄今共有19个成员被发现,在保持凝血系统的稳态、器官生成、炎症、生育等方面有重要作用。尽管其中大部分酶的功能尚不清楚,但已有研究显示该家族成员与多种疾病密切相关。ADAMTSs与基质金属蛋白酶MMPs、解聚蛋白样金属蛋白酶ADAMs同属金属蛋白酶家族,但在结构组成、组织细胞分布、底物作用的特异性、酶活性的调节等方面有明显差别。本文综述了其在结构功能及与疾病关系的研究进展。展开更多
文摘AIM:To investigate the genetic basis of Weill-Marchesani syndrome(WMS)in a Chinese family and clarify the pathogenic mechanism of novel ADAMTS17 mutations.METHODS:Comprehensive clinical assessments and genetic analyses were performed on a Chinese family with two affected siblings.Whole-exome sequencing(WES)was conducted for the proband and other family members.Bioinformatics tools were used to evaluate the conservation,predicted pathogenicity,and structural effects of the identified ADAMTS17 variants.In addition,protein structure modeling was applied to assess the functional impacts of the mutations.RESULTS:The proband(a 32-year-old male)and his elder sister(42y)presented typical clinical features of WMS,including short stature,brachydactyly,high myopia,ectopia lentis,and secondary glaucoma.WES identified a novel compound heterozygous mutation in ADAMTS17:a splicing mutation(c.451-2A>G)inherited from the father and a missense mutation(c.1043G>A;p.C348Y)inherited from the mother.The splicing mutation disrupted normal mRNA splicing and processing,leading to premature translation termination.The missense mutation,which is located in the metalloprotease catalytic domain,was predicted to abolish a critical disulfide bond,thereby impairing protein stability.Both mutations exhibited high evolutionary conservation and were predicted to be pathogenic by multiple bioinformatics algorithms.CONCLUSION:A novel compound heterozygous mutation in ADAMTS17 is identified in this WMS-affected Chinese family,and its pathogenicity is verified via bioinformatics analysis and protein structural modeling.These findings are expected to facilitate the genetic diagnosis of WMS and deepen the understanding of its molecular pathogenesis.
文摘骨关节炎(OA)是一种普遍的退行性关节疾病,其特征是软骨退化和关节炎症。血小板结合蛋白基序的解聚蛋白样金属蛋白酶(a disintegrin and metalloproteinase with thrombospondin motifs,AD⁃AMTS)家族成员在OA的发病机制中受到了广泛关注,尤其是ADAMTS⁃4和ADAMTS⁃5,它们降解软骨蛋白聚糖活性远高于其他成员。蛋白聚糖是ECM的重要组成部分,蛋白聚糖的降解导致软骨的结构和功能破坏,是OA发展的关键因素。本文综述了ADAMTS⁃4和ADAMTS⁃5的结构和功能,重点解析二者底物切割位点的序列选择性、三维构象偏好及翻译后修饰、变构效应,和微环境信号对其蛋白水解活性的多层次调控机制,同时回顾了国内外学者对其靶向药的研究及未来展望。
文摘解整合素金属蛋白酶家族由膜锚定型和分泌型蛋白构成,分别是解整合素金属蛋白酶(a disintegrin and metalloproteinase, ADAMs)和具有血小板反应蛋基序的解整合素金属蛋白酶(a disintegrin-like and metalloproteinase with thrombospondin motifs, ADAMTS)。ADAMs和ADAMTS在多种肿瘤的发生、发展中发挥重要作用。在胃癌中,ADAMs和ADAMTS家族成员的异常表达与肿瘤的增殖、侵袭及转移密切相关,靶向ADAMs和ADAMTS的药物研发有望成为胃癌的有效的治疗手段。本文通过概述ADAMs和ADAMTS在胃癌中的研究进展,为其作为胃癌潜在治疗靶点提供理论依据。
文摘目的研究人脑胶质瘤中含血小板结合蛋白基序的解聚素金属4(ADAMTS4)蛋白酶和ADAMTS5蛋白酶的表达及其与胶质瘤病理分级之间的关系。方法采用免疫组化Envision二步法检测ADAMTS4及ADAMTS5蛋白酶在44例不同级别脑胶质瘤、11例瘤周脑组织中的表达,计算阳性细胞百分率,并通过Image Pro Plusversion 6.0(IPP)图像分析软件测量计算其平均光密度(MOD)值。结果 (1)ADAMTS4和ADAMTS5蛋白酶在瘤周脑组织中不表达或极低表达,而在胶质瘤组织中高表达,为棕黄色,主要表达定位于细胞外基质及细胞质中,两组差异有统计学意义(P<0.05)。进一步研究显示,其蛋白表达量随着肿瘤级别的升高而升高,WHO分级中低级别、高级别间差异有统计学意义(P<0.05)。(2)ADAMTS4与ADAMTS5蛋白酶在胶质瘤中表达呈正相关性(χ~2=5.614,r=0.357,P<0.05)。结论(1)ADAMTS4、ADAMTS5蛋白表达量随着胶质瘤级别的升高而升高,提示了ADAMTS4及ADAMTS5蛋白酶在胶质瘤的进展、侵袭中发挥着重要作用。(2)ADAMTS4与ADAMTS5蛋白表达呈正相关性,揭示了在胶质瘤的发生发展中这两种蛋白酶可能互相协同,两者的过表达共同促进了胶质瘤的侵袭。
文摘含Ⅰ型血小板结合蛋白基序的解聚蛋白样金属蛋白酶ADAMTSs(a disintegrin and metallo-proteinase with thrombospondin motifs)是一类新的Zn2+依赖的金属蛋白酶家族,广泛存在于哺乳动物和无脊椎动物体内。从1997年发现第一个ADAMTSs家族成员以来,迄今共有19个成员被发现,在保持凝血系统的稳态、器官生成、炎症、生育等方面有重要作用。尽管其中大部分酶的功能尚不清楚,但已有研究显示该家族成员与多种疾病密切相关。ADAMTSs与基质金属蛋白酶MMPs、解聚蛋白样金属蛋白酶ADAMs同属金属蛋白酶家族,但在结构组成、组织细胞分布、底物作用的特异性、酶活性的调节等方面有明显差别。本文综述了其在结构功能及与疾病关系的研究进展。
