MOLECULAR BASIS OF DARIER'S DISEASE

Darier病（DD）是一种常染色体显性遗传病 导致紊乱的异常角质化表皮。 的 研究计划是通过强调 DD角质形成细胞移植的基因连锁分析及研究 裸鼠或在皮肤等同物中培养。 的可用性 几个大的谱系，候选基因和其他遗传探针 提高这种方法成功的可能性。 的 这种疾病特别有趣，因为它有角化过度， 提示细胞内成熟和分裂异常 和细胞分离表明细胞表面或细胞膜相关 异常 机械等环境因素的作用 创伤和阳光在沉淀疾病表明， 无序的分子可能不是该化合物的已知结构组分。 流行病学和基因排除方法来定义主要的 缺陷应该追究。 详细目的包括：1）鉴定其 突变导致DD。 使用来自 几个大的已经确定与DD的kinases，我们将评估 DD基因与基于以下选择的候选基因的连锁： 表皮的临床和组织学特征 异常 如果我们只找到排除这些基因的数据， 将开始使用探针在全基因组范围内搜索DD基因 识别基因组中的多态位点， 联系，然后是必要的物理技术，以“关闭”的 DD基因。2)确定独立DD突变的数量 以确定是否存在多于一个DD基因座。 确定 DD基因突变的范围，将使评估 结构-功能关系改善了正常的基因产物， DD产品。3)证明了基本的病理生理学 DD缺陷存在于移植研究的流行病学中， 裸鼠和皮肤等同物。 测定 培养的角质形成细胞行为的病理生理缺陷 从DD患者，以解决为什么表型异常是晚 发病和受环境影响，如季节性 变化和紫外线B敏感性。 定义DD， 基因和生理水平将产生新的理解， 这些缺陷应该导致新的治疗方式， DD.

Darier's disease (DD) is an autosomal doniinant genetic disorder resulting in a disordered abnormally keratinizing epidermis. The research plan is to identify the basic defect in DD by emphasizing gene linkage analysis and studies of DD keratinocytes transplanted to nude mice or cultured in skin equivalents. The avaflability of several large pedigrees, candidate genes and other genetic probes enhance the likelihood of the success of such an approach. The disease is particularly intriguing since it has hyperkeratosis suggesting abnormalities of intracellular maturation and clefting and cell separation suggesting cell surface or cell membrane related abnormalities. The role of environmental factors such as mechanical trauma and sunlight in precipitating the disorder suggest thit the disordered molecular may not be a known structural component of the epidemiis and that a gene exclusion approach to define the primary defect should be pursued. Detailed Aims include: 1) Identification of the gene(s) whose mutation(s) are responsible for DD. Using DNA from members of several large already-identified kindreds with DD and we will assess linkage of the DD gene to candidate genes selected on the basis of the clinical and histologic characteristics of the epidermal abnormalities. Should we find only data excluding these genes, we will embark on a genome-wide search for the DD gene using probes recognizing polymorphic loci throughout the genome for genetic linkage and then physical techniques necessary to "close in" on the DD gene. 2) Determination of the number of independent DD mutations to ascertain whether there are more than one DD locus. Determining the range of DD gene mutations, will enable assessment of structure-function relationships better the normal gene product and the DD product(s). 3) Proving that the basic pathophysiological defect in DD resides in the epidemiis by transplantation studies in nude mice and skin equivalents. Determination of the pathophysiological defects in the behavior of keratinocytes cultured from DD patients to address why phenotypic abnormalities are of late onset and subject to environmental influence such as seasonal changes and ultraviolet B sensitivity. Defining DD on both the genetic and physiological levels will yield new understanding of the defects which should lead to new therapeutic modalities for treating DD.