ISOLATION OF DISEASE GENES FROM CHROMOSOME 5

描述：该应用程序的目标是克隆和分析 发育不良 (DTD) 和特雷彻柯林斯综合征的基因 (TCOF1)。这两个基因都定位于狭窄的区域 人类染色体5.申请人选择了这些疾病基因 因为它们位于 5 号染色体的区域，这些区域具有 已经开发出重要的绘图工具（辐射混合面板和 YAC 和粘粒重叠群）。 DTD 是一种非常罕见的常染色体隐性遗传疾病，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， 这种情况在芬兰更为常见（0.8%），并且该基因具有 在芬兰家庭中被本地化到围绕 基因 CSF1R。 该区域被克隆到YAC中，申请人提出 为了开发跨区域的粘粒重叠群，确定编码 通过外显子捕获和 cDNA 捕获来识别区域，并筛选这些序列 针对 DTD 特有的突变。 DTD 中的有限材料 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疾病。 TCOF1基因也不太好 映射为 DTD，但现在已减少到 450 kb 间隔（从 900 上次申请时的 kb）。申请人提议 从该区域开发额外的遗传标记以缩小范围 TCOF1 的定位，并构建该减少的粘粒重叠群 地区。由于 TCOF1 是一种常染色体显性遗传疾病，申请人 将在体细胞中从受影响个体中分离出 5 号染色体 细胞杂交以促进候选基因的测序（通过避免 杂合子检测的需要）。否则，策略为 TCOF1 的隔离与 DTD 中描述的隔离非常相似。

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.