MOLECULAR GENETICS OF AMELOGENESIS IMPERFECTA

成釉发育不全(AI)是多种遗传性疾病的集合 影响牙釉质的形成。这是一群异质的 疾病不仅表现为不同类型的遗传(例如X连锁 显性或隐性和常染色体显性或隐性)，但也 不同的临床表现(如发育不良、低钙化和 性欲减退)。人工智能的病因学，它发生在一般 美国人口比例约为1：14,000，在很大程度上 除了两个有x_连锁AI的家庭外未知，在那里缺陷是 定位到Xp22染色体上；染色体位置 釉原蛋白结构基因。釉原蛋白基因的缺失是 在其中一个家庭中演示(Lagerstrom等人，1991)，以及一个 在另一例中发现釉原蛋白基因的无义突变 X连锁人工智能个体(Aldred等人，1992)。显然，由于 本病所呈现的异质性，表现为不同类型 的突变可能是X连锁的原因 案子。此外，常染色体遗传的人工智能类型，这是 大约85%的人工智能病例不能归因于 釉原蛋白基因。 这项研究建议表征AI的分子基因型，在 特别是常染色体遗传类型的人工智能。我们将测试 假设常染色体类型的人工智能是缺陷的结果 非釉原蛋白的结构或调节基因，如 酸性釉质蛋白(Tuftelin)或参与 结构蛋白的加工。我们建议检验这一假设 通过表征人类酸性釉质蛋白和 釉质蛋白水解酶，然后筛查从 常染色体遗传性AI患者。此外，我们还将筛选 X连锁的成釉蛋白基因(可能还有其他基因)的突变 遗传的人工智能。此外，Y连锁遗传的可能性， 虽然非常罕见，但将被探索。以下具体目标将 继续研究：鉴定(S)小鼠主要的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与常染色体遗传的AI类型的连锁；确定 人类釉蛋白水解酶基因的基因组结构和组织； 检查和确定常染色体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连锁人工智能的分子基础。 所获得的结果将把特定的基因产物与 不同类型的人工智能，并将定义基因改变 对基因功能异常负责(S)。它的生物学意义 我们的分子遗传学发现将由相关性决定 在这些蛋白质的结构特征和 在本计划项目的其他部分中获得的功能信息。 我们三个子项目之间的集成将定义 为了解釉质蛋白在生物矿化中的作用提供基础 正常牙釉质和异常牙釉质中的组织介导矿化 队形。

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.