0521定位克隆-路李(课外)解读.ppt

IHH基因的研究 使用老鼠IHH基因mRNA 设计引物 扩增出编码基因、启动子基因、连结区域 三个家系分别发现 外显子1的283位点存在G--A的转变，意味着Glu95?Lys的转变 外显子2的391位点存在G ?A的转变，意味着Glu131 ?Lys的转变 外显子1的300位点存在C ?A的转变，意味着Asp100 ?Glu的转变 限制性内切酶消化发现突变的特异性 IHH基因分析 对该基因机制进行了研究 通过小鼠的SHH基因分析 表达蛋白与人的IIH高度相似 三种突变可能导致 干扰了它与天然受体的结合 使其与其他受体结合 小鼠的IHH基因的外显子1上的缺失导致上肢短小、末端的不分化 在第三个家系中意外发现短指和身高的相关性 定位克隆的案例 －－家族性短指（趾）基因的定位克隆 关于短指畸形 看看这手有什么不同？ 贺林研究室 1903年的发现－－百年之谜 找到三个大的隔离的家系 对各种表形作了归类 精确定位在第二号染色体的长臂2q35－q36区域 找到了致病基因IHH 家谱分析 对联各家系的辐射照片进行了鉴定 两个家系一个来自湖南省，另一个来自贵州省。 病例分型 1951年科学家根据指（趾）的畸形情况将可遗传的短指畸形分成了5类－A、B、C、D、E. 指（趾）的中间关节变短是短指（趾）畸形（BDA）的主要特征。 BDA又有几个亚型。研究对象是BDA-1。 Figure 3 Finger and toe features of family 1. The pictures provide the numbers of the individuals. Anomalies were mainly confined to the middle phalanges. In some affected individuals, all the middle phalanges were missing or fused to the distal ones (e.g., individuals 6 and 20). In some affected family members, one to three fingers had middle phalanges missing or fused (e.g., individual 30 had the middle phalanges of digit 5 missing; individual 23 had the middle phalanges of digits 2 and 5 missing; and individuals 8 and 16 had the middle phalanges of digits 2, 4, and 5 missing).The proximal phalanges of the thumbs were markedly shortened and broadened in most of the affected members (e.g., individuals 16, 20, 23, 30, and 31). All affected adults in this family had the feature of thin shafts and broad epiphyses of metacarpals and proximal phalanges, but affected children did not have such a feature (e.g., individual 31, 11 years old; and individual 36, 5 years old).The clinodactyly of the second, fourth, or third fingers was present in most of the affected family members (e.g., individuals 8, 16, 23, 30, 31, and 36). All the manifestations described above are common to other reports reviewed by Fitch (1979). The distal phalanges and metacarpals were also shortened in two of the affected family members: individual 6 and individual 16. Individual 6 had very short distal phalanges in digit