Mutagenesis of Tbx3: a model of ulnar-mammary syndrome

Tbx3 突变：尺乳综合征模型

• 批准号: 6989787
• 负责人: Anne M MOON
• 金额: $ 32.85万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-15 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6989787
• 关键词: congenital disorders; congenital skeletal disorder; disease /disorder model; gene expression; gene mutation; laboratory mouse; model design /development; transcription factor

DESCRIPTION (provided by applicant): T-box genes encode a family of transcription factors that are expressed in multiple tissues and function in diverse genetic pathways during development. Mutations in humanTBX3 and TBX5 result in autosomal dominant, ulnar-mammary (UMS) and Holt-Oram syndromes, respectively, and TBX1 deficiency contributes to human deletion 22q11 syndromes. Patients with UMS have congenital limb, apocrine gland, tooth, and genital abnormalities. TBX3 loss-of-function mutations that disrupt DNA binding may cause some cases of UMS. Other mutations occur in regions required for protein-protein interactions or disrupt regulatory (activator or repressor) function. No genotype-phenotype correlations have been detected in affected humans. Murine Tbx3 null heterozygotes do not manifest the UMS phenotype and most homozygous null mutants die in midgestation. Thus, determining the specific effects of Tbx3 deficiency in different regions of the developing limb, or in other organs, requires conditional mutation of murine Tbx3. The goal of this project is to generate conditional mouse models of Tbx3 disruption and dysfunction and examine the molecular and cellular mechanisms by which mutations of Tbx3 cause birth defects, with an emphasis on the limb. We will disrupt Tbx3 function conditionally and use recombinase -mediated cassette exchange to mutate distinct Tbx3 protein functional domains. Alterations in gene expression, cellular differentiation, migration, proliferation and survival will be examined. We have already discovered a novel phenotype due to dominant negative effects of an Exon 7 mutation and propose to analyze its transcriptional function. Genotype -phenotype correlations may also be defined to direct new investigations in humans with UMS. The flexible model system we propose will be a valuable tool for developmental studies of many organs and lead to a deeper understanding of the genetic and molecular bases of congenital anomalies in humans.

描述（由申请人提供）：T-box 基因编码转录因子家族，这些转录因子在多种组织中表达，并在发育过程中在不同的遗传途径中发挥作用。人类 TBX3 和 TBX5 突变分别导致常染色体显性遗传、尺乳 (UMS) 和 Holt-Oram 综合征，而 TBX1 缺陷则导致人类 22q11 缺失综合征。 UMS 患者存在先天性肢体、顶浆腺、牙齿和生殖器异常。破坏 DNA 结合的 TBX3 功能丧失突变可能会导致某些 UMS 病例。其他突变发生在蛋白质-蛋白质相互作用所需的区域或破坏调节（激活子或阻遏子）功能。在受影响的人类中没有检测到基因型-表型相关性。小鼠 Tbx3 无效杂合子不表现出 UMS 表型，大多数纯合无效突变体在妊娠中期死亡。因此，确定 Tbx3 缺乏对发育中肢体的不同区域或其他器官的具体影响，需要对小鼠 Tbx3 进行条件突变。该项目的目标是生成 Tbx3 破坏和功能障碍的条件小鼠模型，并检查 Tbx3 突变导致出生缺陷（重点是肢体）的分子和细胞机制。我们将有条件地破坏 Tbx3 功能，并使用重组酶介导的盒交换来突变不同的 Tbx3 蛋白功能域。将检查基因表达、细胞分化、迁移、增殖和存活的变化。由于外显子 7 突变的显性负面影响，我们已经发现了一种新的表型，并建议分析其转录功能。基因型-表型相关性也可以被定义来指导对 UMS 人类的新研究。我们提出的灵活模型系统将成为许多器官发育研究的宝贵工具，并有助于更深入地了解人类先天异常的遗传和分子基础。