A MURINE MODEL OF SMITH-MAGENIS SYNDROME

Smith-Magenis综合征（SMS）是一种与人类染色体l7p11.2杂合缺失相关的多发性先天性异常精神发育迟滞综合征。 这种微缺失综合征的出生率估计为1/20- 25，000，使其成为人类最常见的染色体缺失之一。 临床特征包括精神发育迟缓、周围神经病变、身材矮小、轻微颅面异常、短手指、小角膜、心脏和肾脏发育缺陷以及神经行为异常。 复杂的表型表明几个相邻基因的缺失，并假设是由于单倍不足。 虽然几个基因已被确定在SMS常见的缺失区间，他们的贡献，这个复杂的表型仍然是推测。染色体17p11.2与小鼠染色体11的32-34 cM区域同线。 一些基因已经被定位到小鼠和人类的同线性区域。 l7p11.2中的其他基因也可能具有鼠同源物。 该提议试图通过使用染色体工程构建小鼠11号染色体上与人SMS缺失区间同线的那些区域的缺失来表征哪个基因或基因组负责SMS。 然后将对工程小鼠进行广泛表征以确定基因单倍不足的后果。 这些分析将有助于了解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要影响。该提案的职业发展目标旨在为候选人提供人类疾病基因鉴定和分析所需的工具，以及开发人类疾病小鼠模型的能力。 贝勒医学院提供了一个环境，是无与伦比的发展鼠模型，非常适合准备高度积极的个人在学术医学的职业生涯。 指导科学家发展奖将进一步促进这一进程。

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.