MEFV GENE STUDY USING TRANSGENIC MOUSE MODELS

使用转基因小鼠模型进行 MEFV 基因研究

• 批准号: 6433652
• 负责人: PU PAUL LIU
• 金额: --
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6433652
• 关键词: autoantigens; autosomal recessive trait; gene expression; gene mutation; gene targeting; genetic disorder; genetically modified animals; in situ hybridization; laboratory mouse; phenotype; protein structure function; rheumatism

Familial Mediterranean fever (FMF) is an autosomal recessive disease frequently seen in non-Ashkenazi Jews, Arabs, Armenians, and Turks. The main clinical features include periodic attacks of fever and serositis, and amyloidosis in the kidney. The gene mutated in this disease, MEFV, has been cloned and many missense mutations have been identified in affected individuals, in several exons of the gene. MEFV encodes a 3.7 kb transcript that is almost exlusively expressed in granulocytes. The encoded protein, pyrin, is a member of a family of proteins homologous to the Ro52 autoantigen. The function of pyrin is still unclear. It is likely that pyrin plays an important role in the inflammatory and immune response functions of mature granulocytes. In collaboration with Dr. Daniel Kastner, NIAMS, NIH, we are generating mice with either deletions or missense mutations (mimicking those in FMF patients) in the mouse MEFV gene, using standard gene targeting techniques. We have identified the mouse MEFV gene, constructed a gene targeting vector which was introduced into mouse embryonic stem (ES) cells to disrupt the mouse MEFV gene in exon 3. These ES cells have been used to generate mice with this MEFV mutation. So far mice with homozygous MEFV mutations are alive and apparently healthy. More detailed analyses of these mice are underway. - genetics, kidney disease, immunology

家族性地中海热（FMF）是一种常染色体隐性遗传病，常见于非德系犹太人、阿拉伯人、亚美尼亚人和土耳其人。主要临床特征包括周期性发热、浆膜炎和肾脏淀粉样变性。在这种疾病中突变的基因MEFV已经被克隆，并且在受影响的个体中已经在该基因的几个外显子中鉴定出许多错义突变。MEFV编码一个3.7kb的转录物，该转录物几乎只在粒细胞中表达。所编码的蛋白质pyrin是与Ro52自身抗原同源的蛋白质家族的成员。pyrin的功能尚不清楚。这可能是pyrin在成熟粒细胞的炎症和免疫反应功能中起重要作用。我们与NIAMS、NIH的丹尼尔卡斯特纳博士合作，使用标准基因靶向技术，在小鼠MEFV基因中产生缺失或错义突变（模拟FMF患者中的突变）的小鼠。本研究鉴定了小鼠MEFV基因，构建了基因打靶载体，将其导入小鼠胚胎干细胞，对小鼠MEFV基因第3外显子进行了破坏。这些ES细胞已被用于产生具有这种MEFV突变的小鼠。到目前为止，具有纯合MEFV突变的小鼠是活着的，并且明显健康。对这些小鼠的更详细分析正在进行中。- 遗传学、肾病、免疫学