GENETICS OF INHERITED DISORDERS OF KERATINIZATION

表皮，不断自我更新的皮肤外层， 由几层细胞组成。 最里面的基底细胞是 能够进行细胞分裂并产生基底上层。 在皮肤细胞终末分化过程中， 透明角质颗粒逐渐变小变平 最后去核并形成保护层 角质层是角蛋白，一个在中间层中发现的蛋白质家族， 所有上皮细胞的细丝。 许多角质化疾病 有明确的遗传背景。 包括鱼鳞病， 表皮角化过度、银屑病和许多毛发疾病。 某些遗传性疾病，已知有一个主要的 特定酶或蛋白质的缺陷可以在子宫内诊断出来。 分子生物学的最新进展已经非常 成功地将这些患病的基因定位在 hyman基因组，并提供产前诊断的方法。 在 所提出的实验探测了 人角蛋白片段长度多态性 基因将被开发。 人类基因组DNA克隆 角蛋白将被分离和表征。 一个小样本的 应筛选个体人类DNA中是否存在 使用角蛋白克隆的限制性片段长度多态性。 最后，角蛋白基因与 多态性与先天性疾病有关， 角化应进行调查，以制定可靠的， 遗传性角化疾病的子宫诊断工具。 上述研究将由一个以计算机为基础的 中间丝蛋白基因与 蛋白质序列 进化树将由 “系统发育分析使用简约”程序。 DNA 人类和猿类基因组之间的杂交也将是 分析了 最后，我们将介绍基因工程DNA 将含有人65Kd角蛋白基因的构建体转化成 哺乳动物细胞

Epidermis, the constantly self-renewing outer layer of skin, consists of several layers of cells. The innermost basal cells are capable of cell division and give rise to the suprabasal layers. During the course of terminal differentiation skin cells anquire keratohyalin granules, become progressively smaller and flatter and finally anucleate and die forming a protective stratum corneum are keratins, a family of proteins found in intermediate filaments of all epithelial cells. Many keratinization disorders have a clear genetic background. These include ichthyoses, epidermolytic hyperkeratosis, psoriasis and many disease of hair. Certain inherited diseases which are known to have a primary defect in a specific enzyme or protein can be diagnoses in utero. Recent progress in molecular biology has been already very successful in both mapping some of these diseased loci on the hyman genome and providing methods for prenatal diagnosis. In the proposed experiments probes for detecting restriction fragment length polymorphisms associated with human keratin genes shall be developed. DNA clones coding for the human keratins will be isolated and characterized. A small sample of individual human DNAs shall be screened for presence of restriction fragment length polymorphisms using keratin clones. finally, the possibility that keratin genes associated polymorphisms are in linkage with inborn disorders of keratinization shall be investigated in order to develop reliable in utero diagnostic tools for inherited disorders of keratinization. The above studies will be complemented by a computer-based analysis of homologies among intermediate filament gene and protein sequences. Evolutionary trees will be generated by "Phylogeny Analysis Using Parsimony" programs. DNA hybridization between human and simian genomes will also be analyzed. Finally, we shall introduce genetically engineered DNA constructs containing the human 65Kd keratin gene into mammalian cells.