A MURINE MODEL OF SMITH-MAGENIS SYNDROME

史密斯-马吉尼斯综合征小鼠模型

• 批准号: 6380146
• 负责人: CORNELIUS F BOERKOEL
• 金额: $ 11.61万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6380146
• 关键词: artificial chromosomes; chromosome deletion; disease /disorder model; gene deletion mutation; genetic manipulation; genetic models; laboratory mouse; linkage mapping; mental retardation; model design /development; syndrome

Smith-Magenis syndrome (SMS) is a multiple congenital anomaly mental retardation syndrome associated with a heterozygous deletion of human chromosome l7p11.2. This microdeletion syndrome has an estimated birth incidence of 1 in 20-25,000, making it one of the most frequently observed chromosomal deletions in humans. Clinical features include mental retardation, peripheral neuropathy, short stature, minor craniofacial anomalies, short fingers, microcornea, developmental defects of the heart and kidneys, and neurobehavioral abnormalities. The complex phenotype suggests deletion of several contiguous genes and is hypothesized to result from haploinsufficiency. Although several genes have been identified in the SMS common deletion interval, their contribution to this complex phenotype remains speculative. Chromosome 17p11.2 is syntenic to the 32-34 cM region of murine chromosome 11. Several genes have been mapped to both the mouse and human regions of synteny. Other genes in l7p11.2 also likely have murine homologues. This proposal seeks to characterize which gene or group of genes is responsible for SMS by using chromosome engineering to construct deletions of those regions of mouse chromosome 11 that are syntenic for the human SMS deletion interval. Extensive characterization of the engineered mice will then be performed to determine the consequences of gene haploinsufficiency. These analyses will contribute to the understanding of the molecular basis of the SMS chromosomal microdeletion syndrome and will have potent implications for human development and biology. The career development aims of this proposal have been designed to provide the candidate with the tools necessary for human disease gene identification and analysis as well as with the capability of developing murine models of human disease. Baylor College of Medicine provides an environment that is unparalleled for developing murine models and that is ideally suited to prepare highly motivated individuals for careers in academic medicine. The Mentored Scientist Development Award would further facilitate this process.

Smith-Magenis综合征是一种与人类染色体17p11.2杂合性缺失相关的多发性先天性异常智力低下综合征。据估计，这种微缺失综合征的出生发病率为每20-25,000人中就有1例，使其成为人类最常见的染色体缺失之一。临床特征包括智力低下、周围神经病变、身材矮小、轻微的头面部异常、手指短小、小角膜、心脏和肾脏发育缺陷以及神经行为异常。这种复杂的表型意味着几个连续基因的缺失，并被假设为单倍体不足所致。尽管已在SMS共同缺失区间中发现了几个基因，但它们对这一复杂表型的贡献仍是推测的。染色体17p11.2与小鼠11号染色体32-34 cM区域共线。有几个基因已被定位到小鼠和人类的共线区域。17p11.2中的其他基因也可能与老鼠有同源基因。这项建议试图通过使用染色体工程来构建与人类短信缺失区间同线的小鼠11号染色体区域的缺失，从而确定哪个基因或哪组基因对短信负有责任。然后，将对转基因小鼠进行广泛的表征，以确定基因单倍体不足的后果。这些分析将有助于理解SMS染色体微缺失综合征的分子基础，并将对人类发育和生物学产生重大影响。这项提议的职业发展目标旨在为候选人提供鉴定和分析人类疾病基因所需的工具，以及开发人类疾病小鼠模型的能力。贝勒医学院为发展小鼠模型提供了无与伦比的环境，非常适合为学术医学事业做准备。导师科学家发展奖将进一步促进这一进程。