GENETICS OF INHERITED DISORDERS OF KERATINIZATION

表皮，不断自我更新的皮肤外层， 由几层单元格组成。最里面的基底细胞是 能够细胞分裂并产生超基底层的。 在终末分化过程中，皮肤细胞需要 角质层透明质颗粒，逐渐变小变平 最后去核并死亡，形成保护层 角质层是角蛋白，是一类存在于中间体中的蛋白质 所有上皮细胞的细丝。许多角化性疾病 有明确的遗传背景。其中包括鱼鳞病， 表皮松解性角化过度，牛皮癣等多种毛发疾病。 某些已知具有原发病的遗传性疾病 一种特定的酶或蛋白质缺陷可以在子宫内诊断。 分子生物学的最新进展已经非常快了 成功地将这些疾病的一些基因定位在 并为产前诊断提供了方法。在……里面 拟议的实验探索了检测限制 与人角蛋白相关的片段长度多态性 基因应该得到开发。为人类编码的DNA克隆 角蛋白将被分离和鉴定。一小部分样品 应对单个人类DNA进行筛查，以确定是否存在 利用角蛋白克隆进行限制性片段长度多态分析。 最后，角蛋白基因可能与 基因多态与先天疾病相关 应对角质化进行调查，以便在 遗传性角化性疾病的子宫诊断工具。 上述研究将由以计算机为基础的 中间丝基因与人类基因组序列的同源性分析 蛋白质序列。进化树将通过以下方式生成 “简约的系统发育分析”程序。脱氧核糖核酸 人类和猿类基因组之间的杂交也将是 分析过了。最后，我们将介绍基因工程DNA 含有人65Kd角蛋白基因的重组载体 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.