一个早发型雄激素依赖性脱发（AGA）伴胰岛素抵抗家系的基因定位及克隆研究

Early-onset androgenetic alopecia(AGA) which has insulin resistance is known as a male-pattern baldness . It is dependent on androgen and determined by genetic and environment factors. There are many genes relevant with androgenetic alopecia, such as AR, 5-a reductase,HR et al, but there are no enough evidence which can prove these genes are pathopoiesia gene of AGA. We collected a five generations predigree of Early-onset Androgenetic alopecia(AGA). all patients are men, and it is possible that the family members have insulin resistance. With the analysis of this predigree it shows that the disease is autosomal dominant inheritance,and sex inheritance. It is possible that the pathopoiesia gene results in AGA through Androgen receptor(AR) and insulin resistance is an possible effect of the pathopoiesia gene. Or it is also possible that the gene which results in insulin resistance is linked tightly with the pathopoiesia gene. In order to map the pathopoiesia gene of AGA, we will use the gene wide-scan study to linkage analysis of the whole geneome. Simultaneously we will use expression chip with RNA from hair follicle to analysis the difference of gene expression. We also use OGTT to analyse the insulin resistance in this family. According to the strategy of function clone, we will select the candidate genes for AGA. With whole gene sequencing, PCR-sequencing and FISH, we can detect the difference of sequence between the Early-onset AGA patients and nomral controls in this predigree, and confirm this result with immunohistochemical technique.

早发型雄激素性脱发（AGA），是一种雄激素依赖性男性特征性秃头，男性患者及女性携带者伴有胰岛素抵抗，由遗传因素和环境因素决定。本课题收集了一五代早发型AGA家系，家系资料分析有雄激素依赖性脱发及胰岛素抵抗症状，脱发的遗传方式为常染色体伴性遗传病。我们拟对这个家系进行全基因组SNP连锁分析，进行定位候选克隆，然后对毛囊细胞RNA进行表达芯片研究，同时在全家系中开展OGTT胰岛素抵抗研究，进行功能候选克隆，选定候选基因后，将采用二代测序，PCR-测序和FISH检测患者和正常对照候选基因的差异，免疫组化验证，寻找早发型AGA的致病基因。本研究在国内第一次对一个五代家系进行全基因组芯片连锁分析，通过本研究第一次从基因水平了解早发型AGA与胰岛素抵抗的关系，本研究第一次在国内系统研究了AR受体的作用通路在AGA发病中的作用。

早发型雄激素性脱发（AGA），是一种雄激素依赖性男性特征性秃头，男性患者及女性携带者 伴有胰岛素抵抗，由遗传因素和环境因素决定。本课题收集了一五代早发型AGA家系，家系资 料分析有雄激素依赖性脱发及胰岛素抵抗症状，脱发的遗传方式为常染色体伴性遗传病，而胰岛素抵抗症状的遗传方式也为常染色体显性遗传。我们对这个家系进行全基因组SNP连锁分析和高通量二代测序分析，结果提示脱发致病基因候选区域可能在20q。经家系单体型分析，家系中脱发患者具有含TP53RK基因区域的相关单体型，但要找到脱发的致病基因，还需进一步的功能验证和体外实验验证。.家系表型分析结果提示家系中脱发与胰岛素抵抗症状可能不是同一基因或连锁基因导致；全基因分析结果提示膜蛋白基因TNDMX基因(实验室暂时命名)与胰岛素抵抗症状相关，家系中现有糖尿病患者均有M518突变。为进一步验证TNDMX基因与胰岛素抵抗的相关性，我们构建了TNDMX基因敲除（knockout）小鼠和M518敲入（knockin）小鼠。4个月大的纯合敲除小鼠在体重、糖耐量实验与胰岛素耐受实验与野生型小鼠相比差异明显。3个月大的杂合和纯合敲入小鼠在体重、糖耐量实验目前没有发现异常，但胰岛素耐受实验提示杂合和纯合敲入小鼠存在胰岛素敏感性下降，这与家系中糖尿病发病年龄较晚吻合。因此我们推测TNDMX基因与此家系胰岛素抵抗症状的具有相关性。本课题通过全基因测序及连锁分析，1、 选定了家系AGA基因候选区域为20q；2、TNDMX基因可能与家系中胰岛素抵抗症状相关。

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