CANDIDATE GENES FOR DG1 AND ADAI

人类遗传性牙釉质和牙本质形成疾病的分子病因学研究相对较少：无釉发育不全（AI）、牙本质发育不全（DGI）和牙本质发育不良（DD）。常染色体显性（AD）型AI（约占所有病例的85%）的连锁研究仅将一种类型（局部发育不全AI (AIH2)）定位到人类染色体4q21上，该区域包含成釉细胞素和漆膜素基因，长度为4 Mb。研究表明，4q21的相同一般区域包含三种牙本质疾病的重叠关键基因位点，分别是DGI II型（DGI-II）、DGI III型（DGI-III）和DD II型（DD-II）。这个重叠区域包含一个牙本质/骨“基因簇”，包括骨桥蛋白、骨唾液蛋白、牙本质基质蛋白I和牙本质唾液磷酸蛋白。突变分析研究尚未确定导致这些疾病的基因。R01延续更新的目标是描述导致DGI-II、DGI-III、DD- II和AD形式AI的主要遗传缺陷。我们将扩大我们的努力，通过新确定的信息家庭，包括II型DD和其他AD形式的人工智能。本研究基于单一牙本质和牙釉质基质蛋白/蛋白酶的特异性突变在DGI、DD和AD形式AI的发病机制中起致病作用的假设。为了验证这一假设，我们将确定这些牙齿遗传疾病的信息家族，建立或排除与4q21上的DGI/DD或AIH2关键疾病位点的联系，并对潜在的候选基因进行突变分析。将通过对其他家族进行更广泛的标记基因分型，对这些疾病位点进行精细的连锁研究。排除4q2i的ADAI家族，将检测与染色体1、11和19上其他候选牙釉质基因位点的连锁关系，并绘制关键疾病位点。如果排除ADAI家族与所有潜在基因位点的连锁，则将实施全基因组搜索。最后，利用构建的DGI/DD和AIH2序列，通过定位克隆方法鉴定4q21上潜在的新的候选牙齿基因。这些信息将有助于我们了解这些疾病的分子基础，提供更好的诊断工具，增加我们对牙齿蛋白质功能的了解，并协助设计治疗方法。

Relatively little in known about the molecular etiology of the human genetic diseases of enamel and dentin formation: amelogenesis imperfecta (AI), dentinogenesis imperfecta (DGI), and dentin dysplasia (DD). Linkage studies for autosomal dominant (AD) forms of AI, approximately 85% of all cases, have mapped only one type, local hypoplastic AI (AIH2), to human chromosome 4q21 within a 4 Mb region containing the genes for ameloblastin and enamelin. This same general region of 4q21 has been shown to contain the overlapping critical gene loci for three dentin diseases, DGI type II (DGI-II), DGI type III (DGI-III), and DD type II (DD-II). This overlapping region contains a dentin/bone "gene cluster", including osteopontin, bone sialoprotein, dentin matrix protein I, and dentin sialophosphoprotein. Mutational analysis studies have yet to establish the genes causing these diseases. The goal of this R01 continuation renewal is the delineation of the primary genetic defects that are responsible for the diseases DGI-II, DGI-III, DD- II, and the AD forms of AI. We will expand our efforts to include DD type II and other AD forms of AI through newly ascertained informative families. This study is based on the hypothesis that specific mutations within single dentin and enamel matrix proteins/proteinases have a causative role in the pathogenesis of DGI, DD and the AD forms of AI. To test this hypothesis we will ascertain informative families with these dental genetic diseases, establish or exclude linkage to the DGI/DD or AIH2 Critical disease loci on 4q21, and perform mutational analysis of potential candidate genes. Refined linkage studies will be performed on these disease loci through more extensive marker genotyping of additional families. ADAI families excluded from 4q2i, will be tested for linkage to other candidate enamel gene loci on chromosomes 1, 11, and 19, and the critical disease loci mapped. If ADAI families are excluded from linkage to all potential gene loci, a genome-wide search will be implemented. Finally, through positional cloning approaches identify potential new candidate tooth genes on 4q21 using constructed DGI/DD and AIH2 contigs. This information will contribute to our understanding of the molecular bases of these diseases, provide better diagnosis tools, increase our knowledge related to the function(s) of tooth proteins, and assisting in the design of treatment therapies.