MOLECULAR ANALYSIS OF WILLIAMS SYNDROME

威廉姆斯综合症的分子分析

• 批准号: 7212247
• 负责人: Ananda L Roy
• 金额: $ 27.04万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7212247
• 关键词: MOLECULAR; ANALYSIS; WILLIAMS; SYNDROME

DESCRIPTION (provided by applicant): Williams-Beuren Syndrome (WBS) is a neuro-developmental disorder with multisystem manifestations, including supravalvar aortic stenosis (SVAS), hypercalcemia in infancy, mild to moderate mental retardation, cognitive defects and characteristic craniofacial features. The frequency of this genetic haploinsufficiency is estimated to be 1 in 20,000 live births. WBS is caused by a hemizygous microdeletion of approximately 1.5 MB, spanning 17 genes at chromosomal location 7q11.23. Despite these observations, we lack a complete understanding of molecular basis for this disorder. Although this multisystem dysfunction with unusual craniofacial, behavioral and cognitive features occurs most likely due to haplo-insufficiency of several genes, rare cases with much smaller deletions have provided clues to identifying specific genes that may be causal to distinctive physical and cognitive defects. Two of these genes, GTF21 and GTF3 encode the TFII-I family of transcription factors. TFII-I and its relative MusTRD1/BEN exhibit extensive and overlapping expression patterns in a variety of tissues during mouse pre- and post-implantation development, suggesting a functional role for these proteins in early development. These proteins are also abundantly expressed in the hippocampus, a portion of the brain that plays a role in learning and memory, further indicating that they may be causal to some WBS traits. While much has been learned about the TFII-I's mechanism of action, relatively little is known about how MusTRD1/BEN functions. To better understand the molecular basis for WBS, we propose to dissect the functional role of MusTRD1/BEN. We will proceed to analyze the physical and functional interactions of MusTRD1/BEN with Smad factors, which are critical for a variety of developmental processes. Finally, we will employ RNAi technologies to determine the biological role of this factor in osteoblast differentiation.

描述（由申请人提供）：Williams-Beuren综合征（WBS）是一种具有多系统表现的神经发育障碍，包括瓣上主动脉瓣狭窄（SVAS）、婴儿期高钙血症、轻度至中度智力迟钝、认知缺陷和特征性颅面特征。这种遗传性单倍不足的频率估计为1/20，000活产。WBS是由一个约1.5 MB的半合子微缺失引起的，跨越染色体位置7q11.23的17个基因。尽管有这些观察结果，我们缺乏对这种疾病的分子基础的完整理解。虽然这种具有不寻常的颅面、行为和认知特征的多系统功能障碍最有可能是由于几个基因的单倍不足而发生的，但具有小得多的缺失的罕见病例为识别可能导致独特的身体和认知缺陷的特定基因提供了线索。这些基因中的两个，GTF 21和GTF 3编码TFII-I家族的转录因子。TFII-I及其相关MusTRD 1/BEN在小鼠植入前和植入后发育过程中的各种组织中表现出广泛和重叠的表达模式，表明这些蛋白在早期发育中的功能作用。这些蛋白质也在海马体中大量表达，海马体是大脑的一部分，在学习和记忆中发挥作用，进一步表明它们可能是某些WBS特征的原因。虽然人们对TFII-I的作用机制了解很多，但对MusTRD 1/BEN的功能知之甚少。为了更好地理解WBS的分子基础，我们建议剖析MusTRD 1/BEN的功能作用。我们将继续分析MusTRD 1/BEN与Smad因子的物理和功能相互作用，这对各种发育过程至关重要。最后，我们将采用RNAi技术来确定该因子在成骨细胞分化中的生物学作用。