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基因编码一系列转录因子，这些转录因子在多种组织中表达，并在发育过程中通过多种遗传途径发挥作用。人类tbx3和TBX5的突变分别导致常染色体显性、尺乳（UMS）和Holt-Oram综合征，TBX1缺乏导致人类缺失22q11综合征。UMS患者有先天性肢体、大汗腺、牙齿和生殖器异常。破坏DNA结合的TBX3功能丧失突变可能导致一些UMS病例。其他突变发生在蛋白质相互作用或破坏调节（激活因子或抑制因子）功能所需的区域。在受影响的人群中未检测到基因型-表型相关性。小鼠Tbx3零杂合子不表现出UMS表型，大多数纯合零突变体在妊娠中期死亡。因此，要确定Tbx3缺乏对发育肢体不同区域或其他器官的具体影响，需要小鼠Tbx3的条件突变。该项目的目标是建立Tbx3破坏和功能障碍的条件小鼠模型，并研究Tbx3突变导致出生缺陷的分子和细胞机制，重点是肢体。我们将有条件地破坏Tbx3的功能，并使用重组酶介导的盒式交换来突变不同的Tbx3蛋白功能域。基因表达，细胞分化，迁移，增殖和生存的改变将被检查。我们已经发现了一种新的表型，由于显性负作用的外显子7突变，并提出分析其转录功能。基因型-表型相关性也可以定义为指导新的研究与人类的UMS。我们提出的灵活模型系统将为许多器官的发育研究提供有价值的工具，并导致对人类先天性异常的遗传和分子基础的深入了解。