ISOLATION OF DISEASE GENES FROM CHROMOSOME 5

描述：此应用程序的目标是克隆和分析 遗传性发育不良(DTD)和Treacher-Collins综合征的基因 (TCOF1)。这两个基因都被定位在狭窄的 人类5号染色体。申请者已经选择了这些疾病基因 因为它们位于5号染色体上 已经开发了重要的测绘工具(辐射混合电池板和 YAC和粘粒重叠群)。 DTD是一种非常罕见的常染色体隐性遗传病，其特征是 软骨发育不良(包括身材矮小和关节发育不良)。然而， 这种情况在芬兰更常见(0.8%)，而且这种基因有 在芬兰家庭中被本地化到60kb的间隔 CSF1R基因。这一区域在YAC中被克隆，申请者提出 要在该地区开发粘粒重叠群，请确定编码 外显子捕获和cDNA捕获的区域，并筛选这些序列 DTD特有的突变。来自DTD的有限数量的材料 有爱沙尼亚背景的家庭可供分析。 TCOF1是一种常染色体显性遗传病。TCOF1基因就不是这样了 映射为DTD，但现在已减少到450 kb间隔(从900 上一次申请时的大小)。申请者建议 开发更多来自该地区的遗传标记以缩小 TCOF1的定位，并构建该简化的粘粒重叠群 区域。由于TCOF1是一种常染色体显性遗传病，申请者 将从患病个体的体细胞中分离出5‘S染色体 细胞杂交以促进候选基因的测序(通过避免 杂合子检测的必要性)。否则， TCOF1的隔离与DTD的隔离非常相似。

DESCRIPTION: The goals of this application are to clone and analyze the genes for diastrophic dysplasia (DTD) and Treacher Collins syndrome (TCOF1). Both of these genes have been localized to narrow regions of human chromosome 5. The applicants have selected these disease genes because they are located in regions of chromosome 5 for which they have already developed significant mapping tools (radiation hybrid panels and YAC and cosmid contigs). DTD is a very rare autosomal recessive disorder characterized by chondrodysplasia (including short stature and joint dysplasia). However, this condition is more common in Finland (0.8 percent), and the gene has been localized in Finnish families to a 60 kb interval surrounding the gene CSF1R. This region is cloned in YACs, and the applicants propose to develop a cosmid contig across the region, identify the coding regions by exon trapping and cDNA capture, and screen these sequences for mutations specific to DTD. A limited amount of material from a DTD family of Estonian background is available for analysis. TCOF1 is an autosomal dominant disorder. The TCOF1 gene is not as well mapped as DTD, but has now been reduced to a 450 kb interval (from 900 kb at the time of the previous application). The applicants propose to develop additional genetic markers from this region to narrow the localization of TCOF1, and to construct a cosmid contig of this reduced region. Since TCOF1 is an autosomal dominant disorder, the applicants will isolate the chromosome 5's from affected individuals in somatic cell hybrids to facilitate sequencing of candidate genes (by avoiding the need for heterozygote detection). Otherwise, the strategy for the isolation of TCOF1 is very similar to that described for DTD.