HYPOHIDROTIC ECTODERMAL DYSPLASIA--GENETIC ANALYSIS

少汗性外胚层发育不良--遗传分析

• 批准号: 2458639
• 负责人: JONATHAN ZONANA
• 金额: $ 20.27万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-07-01 至 1998-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2458639
• 关键词: autosomal dominant trait; autosomal recessive trait; developmental genetics; disease /disorder classification; ectoderm; endonuclease; gene mutation; gene rearrangement; genetic disorder; genetic disorder diagnosis; genetic mapping; genetic markers; genetic polymorphism; histogenesis; human genetic material tag; human population genetics; human subject; hyperplasia; linkage mapping; molecular cloning; molecular genetics; molecular pathology; nucleic acid hybridization; nucleic acid probes; phenotype; prenatal diagnosis; pulsed field gel electrophoresis; radiotracer; restriction fragment length polymorphism; sex linked trait; skin hyperplasia; southern blotting

DESCRIPTION (Adapted from the applicant's abstract): The EDs are a heterogeneous collection of disorders of unknown pathogenesis. The need to develop new molecular approaches to their analysis has been noted, and the investigators believe that molecular genetic studies, specifically linkage analysis, will improve their classification, produce new diagnostic tools, and ultimately lead to identification of their molecular defects and to an understanding of the process of normal morphogenesis. The investigators propose to study two prototypic disorders, XLHED, the commonest of the EDs, and the Clouston syndrome, an hidrotic form of ED which is inherited as an autosomal dominant trait. For XLHED: The investigators will perform fine genetic mapping studies of the disorder, localized to Xp11.1-Xq21.1 region, to define the order of closely linked polymorphic marker loci in relation to the disease locus. The identification of close flanking markers is essential for both accurate diagnostic applications, and for the physical mapping and cloning of the XLHED locus. To this end, the investigators will screen for highly polymorphic (heterozygosity >70 percent) microsatellite DNA markers in the pericentromeric region of the X-chromosome. The investigators will utilize these markers to address the question of the existence and frequency of a proposed clinically indistinguishable autosomal recessive form of the disorder, which if unrecognized could cause serious diagnostic errors. In addition, a large number of unrelated males will be screened, initially with anonymous DNA probes, but ultimately with expressed and conserved sequences from the region, to identify sub-microscopic deletions involving the XLHED locus. For the Clouston syndrome: Its position on the human gene map, presently unknown, will be localized by the linkage analysis of two very large kindreds, utilizing a series of highly polymorphic loci (RFLPs and microsatellites) distributed over all autosomes (exclusion mapping). Potential candidate genes or chromosomal regions will be given priority. Once linkage is established, fine mapping will be performed, to lay the groundwork for subsequent physical mapping around the disease locus, and cloning of the gene.

描述（改编自申请人的摘要）： ED 是 未知发病机制的异质性疾病集合。 需要 已经注意到开发新的分子方法来进行分析，并且 研究人员认为，分子遗传学研究，特别是连锁 分析，将改进其分类，产生新的诊断工具， 并最终识别出它们的分子缺陷并得出 了解正常形态发生的过程。 调查人员 提议研究两种原型疾病，XLHED，最常见的 ED， 克劳斯顿综合征（Clouston Syndrome），一种多汗性 ED 形式，是遗传性的 常染色体显性性状。 对于 XLHED：研究人员将进行精细的遗传图谱研究 无序，定位于 Xp11.1-Xq21.1 区域，定义顺序 与疾病位点密切相关的多态性标记位点。 识别近距离侧翼标记对于准确定位至关重要 诊断应用，以及物理映射和克隆 XLHED 基因座。 为此，调查人员将筛选高度 多态性（杂合度 >70%）微卫星 DNA 标记 X 染色体的着丝粒周围区域。 调查人员将利用 这些标记来解决一个问题的存在和频率 提出临床上无法区分的常染色体隐性遗传形式 疾病，如果无法识别可能会导致严重的诊断错误。 在 此外，一开始将筛选大量无血缘关系的男性 使用匿名 DNA 探针，但最终使用表达和保守的 来自该区域的序列，以识别涉及的亚显微缺失 XLHED 基因座。 对于克劳斯顿综合症：目前它在人类基因图谱上的位置 未知，将通过两个非常大的连锁分析来定位 亲属，利用一系列高度多态性位点（RFLP 和 微卫星）分布在所有常染色体上（排除图谱）。 潜在的候选基因或染色体区域将被优先考虑。 一旦建立链接，将进行精细映射，以奠定基础 为后续疾病位点周围的物理绘图奠定基础，以及 基因的克隆。