DEVELOPMENT OF MURINE MODELS FOR SMITH-MAGENIS SYNDROME

Smith-Magenis综合征是一种多发性先天性智力异常 与人类基因杂合缺失相关的发育迟缓综合征 17号染色体带p11.2 [del（p11.2）]。这种微缺失综合征 估计每20- 25 000名活产婴儿中至少有1人患病， 最常见的人类染色体缺失。临床 特征包括智力迟钝，身材矮小， 异常，短手指，小角膜，心脏发育缺陷 和肾脏，以及神经行为异常，如自我破坏， 攻击性行为、癫痫发作和缺乏快速眼动（REM）睡眠。 复杂的表型特征表明缺失了几个相邻的 基因，而表型效应被假设是由 单倍不足尽管在人类中已经鉴定出了17个基因， SMS共同缺失区，它们对这种复杂表型的贡献 仍然是推测。染色体17p11.2与32-34 cM区域同线 小鼠11号染色体很少有基因被定位到老鼠和 人类同线性区，包括：编码醛脱氢酶的Aldh 3 3，Llgl基因编码果蝇同源物的致死92） 巨大幼虫基因，Serk 1编码SAPK的蛋白激酶激活剂 信号转导级联，和Pmp 22基因编码的22 KD 外周髓磷脂蛋白;这三个都在33 cM的地图。中的其它基因 17p11.2可能也有鼠同源物。这项建议旨在 将小鼠同系染色体的基因组区域表征为17p11.2p12，并分析 小鼠基因座的单倍不足的后果是通过构建 敲除相关基因。作为项目资助的一部分， 试图使用染色体工程来构建不同的缺失， 小鼠11号染色体，含有部分 人工短信删除间隔。广泛表征工程 然后将对小鼠进行实验，以确定基因 单倍不足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， 将对人类发展和生物学产生重大影响。

Smith-Magenis syndrome (SMS) is a multiple congenital anomaly mental retardation syndrome associated with a heterozygous deletion of human chromosome 17 band p11.2 [del(p11.2)]. This micro-deletion syndrome has an estimated prevalence of at least 1 in 20-25,000 live births, making it one of the most frequently observed chromosomal deletions in humans. Clinical features include mental retardation, short stature, minor craniofacial anomalies, short fingers, microcornea, developmental defects of the heart and kidneys, and neurobehavioral abnormalities such as self destructive, aggressive behavior, seizures and absent rapid eye movement (REM) sleep. The complex phenotypic features suggest deletion of several contiguous genes, and the phenotypic effects are hypothesized to result from haploinsufficiency. Although seventeen genes have been identified in the SMS common deletion region, their contribution to this complex phenotype remains speculative. Chromosome 17p11.2 is syntenic to the 32-34 cM region of mouse chromosome 11. Few genes have been mapped to both the mouse and human regions of synteny including: Aldh3 encoding aldehyde dehydrogenase 3, the Llgl gene encoding the Drosophila homologue for the lethal 92) giant larvae gene, Serk1 encoding a protein kinase activator of the SAPK signal transduction cascade, and the Pmp22 gene encoding the 22 KD peripheral myelin protein; all three of which map at 33 cM. Other genes in 17p11.2 likely have murine homologues as well. This proposal seeks to characterize the genomic region of murine syteny to 17p11.2p12 and analyze the consequence of haploinsufficiency of the mouse loci by construction of knockouts of the genes involved. As part of the program project grant we seek to use chromosome engineering to construct different deletions of mouse chromosome 11 containing the syntenic regions for portions of 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 contributes to the understanding of the molecular basis of the SMS chromosomal micro-deletion syndrome and will have potent implications for human development and biology.