MOLECULAR GENETICS OF AMELOGENESIS IMPERFECTA

成釉不全症是一种遗传性疾病 影响牙釉质的形成。 这一异质群体 疾病不仅存在不同类型的遗传（例如X连锁 显性或隐性和常染色体显性或隐性），而且 不同的临床表现（例如发育不全、钙化不全和 低成熟度）。AI的病因，发生在一般的 美国的人口比例约为1：14，000， 未知，除了两个X_linked AI家族， 映射到Xp 22染色体; 釉原蛋白结构基因 釉原蛋白基因缺失， 在这些家族中的一个家族中证实了这一点（Lagerstrom等人，1991）， 另一项研究证实了釉原蛋白基因的无义突变 X连锁AI个体（Aldred et al，1992）。 显然，由于 这种疾病呈现出异质性，似乎不同类型 釉原蛋白基因的突变可能是导致X连锁的 例 此外，常染色体遗传类型的AI，这占 大约85%的AI病例，不能归因于 釉原蛋白基因 本研究 提出了表征AI的分子基因型， 特别是常染色体遗传的AI类型。 我们将测试 假设常染色体类型的AI是缺陷的结果， 非釉原蛋白的结构或调控基因，如 酸性釉质蛋白（tuftelin）或参与牙釉质形成的釉质蛋白酶， 结构蛋白的加工。 我们建议检验这一假设 通过表征酸性釉质蛋白的人类基因， 釉质蛋白酶，然后筛选DNA突变， 常染色体遗传性AI患者。 此外，我们还将筛选 X染色体连锁的牙釉质蛋白基因（可能还有其他基因）突变 继承的AI 此外，Y连锁遗传的可能性， 虽然非常罕见，但仍将被探索。 以下具体目标将 为了表征主要的小鼠tuftelin cDNA;确定 人类tuftelins的染色体定位;确定人类 tuftelin基因的基因组结构和组织;确定 tuftelin与常染色体遗传型AI的连锁;确定 人类基因组结构和釉蛋白酶基因的组织; 检查和定义常染色体AI的分子基础;检查和 定义X连锁AI的分子基础，并检查和定义 Y连锁AI的分子基础。 所获得的结果将使特定的基因产物与 不同类型的人工智能，并将定义基因改变， 导致基因功能异常。 的生物学意义 我们的分子遗传学发现将由一个相关性决定 这些蛋白质的结构特征和 在本计划项目的其他部分获得的功能信息。 我们的三个子项目之间的集成将定义 釉质蛋白在生物矿化中的作用，并为了解 正常和异常釉质中的组织介导矿化 阵

Amelogenesis Imperfecta (AI) is a collection of several genetic disorders affecting the formation of tooth enamel. This heterogeneous group of diseases not only present different types of inheritance (e.g. X-linked dominant or recessive and autosomal dominant or recessive) but also different clinical manifestations (e.g. hypoplasia, hypocalcification and hypomaturation). The etiology of AI, which occurs in the general population in a ratio of about 1:14,000 in the USA, remains largely unknown except for two families with x_linked AI where the defect was mapped to the Xp22 chromosome; the chromosomal position for the amelogenin structural gene. A deletion in the amelogenin gene was demonstrated in one of these families (Lagerstrom et al, 1991), and a non-sense mutation in the amelogenin gene was demonstrated in another X-linked AI individual (Aldred et al, 1992). Clearly, due to the heterogeneity presented by this disease, it appears that different types of mutations in the amelogenin gene could be responsible for the X-linked cases. Furthermore, autosomal inherited types of AI, which account for approximately 85% of all AI cases, can not be attributed to the amelogenin gene. This study proposes to characterize the molecular genotype of AI, in particular the autosomal inherited types of AI. We will test the hypothesis that autosomal types of AI are the result of defects in the structural or regulatory genes for non-amelogenin proteins like the acidic enamel proteins (tuftelin) or the enamel proteases involved in the processing of structural proteins. We propose to test this hypothesis by characterizing the human genes for the acidic enamel proteins and enamel proteases and then screen for mutations in DNA obtained from patients with autosomal inherited AI. In addition, we will screen for mutations in the amelogenin gene (and perhaps other genes) in X-linked inherited AI. Furthermore, the possibility of Y-linked inheritance, although very rare, will be explored. The following Specific Aims will be pursued: To characterize the major(s) mouse tuftelin cDNAs; determine the chromosomal localization of human tuftelins; determine the human genomic structure and organization of the tuftelin gene; determine the linkage of tuftelin to autosomal inherited types of AI; determine the human genomic structure and organization of the enamel-proteases genes; to examine and define the molecular basis of autosomal AI; examine and define the molecular basis of X-linked AI and examine and define the molecular basis for Y-linked AI. The results obtained will correlate specific gene products to the different types of AI, and will define the genetic alterations responsible for abnormal gene function(s). The biological significance of our molecular genetic findings will be determined by a correlation between the structural characterization of these proteins and the functional information obtained in other parts of this Program Project. The integration between our three subprojects will define the role of enamel proteins in biomineralization, and provide a basis to understand tissue-mediated mineralization during normal and abnormal enamel formation.