MOLECULAR BASIS OF DARIER'S DISEASE

Darier病(DD)是一种常染色体遗传性疾病 导致异常角化的表皮紊乱。这个 研究计划是通过强调以下方面来确定DD的基本缺陷 DD角质形成细胞移植的基因连锁分析及研究 裸鼠或在皮肤等效物中培养。的可用性 几个大的家系、候选基因和其他遗传探针 提高这种方法取得成功的可能性。这个 疾病特别耐人寻味，因为它有过度角化。 提示细胞内成熟和分裂异常 和细胞分离提示细胞表面或细胞膜相关 异常现象。机械等环境因素的作用 引发这种疾病的创伤和阳光表明 无序分子可能不是已知的结构成分 流行病学和一种基因排除的方法来定义初级 应追查缺陷。 具体目标包括：1)鉴定其基因(S) 突变(S)是引起DD的原因。使用来自成员的DNA 几个已经确定的大家族患有DD，我们将评估 DD基因与根据以下条件选择的候选基因的连锁 表皮的临床和组织学特征 异常现象。如果我们只找到排除这些基因的数据，我们 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基因座 连接，然后是必要的物理技术，以“接近” DD基因。2)确定独立DD突变的数量 以确定是否存在一个以上的DD基因座。确定 DD基因突变的范围，将使评估 结构-功能关系比正常的基因产物和 DD产品(S)。3)证明基本的病理生理 DD的缺陷存在于#年移植研究的流行病学中 裸鼠和皮肤替代品。确定了 角质形成细胞培养过程中的病理生理缺陷 从DD患者那里解决为什么表型异常是最近的 发病和受环境影响，如季节性 变化和对紫外线B的敏感性。在以下两个上定义DD 遗传和生理水平将产生新的理解 应导致新的治疗方式的缺陷 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.