DEVELOPMENT OF MURINE MODELS FOR SMITH-MAGENIS SYNDROME

史密斯-马吉尼斯综合征小鼠模型的开发

• 批准号: 6453009
• 负责人: JAMES R. LUPSKI
• 金额: $ 14.57万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-11 至 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6453009
• 关键词: artificial chromosomes; bacteria; chromosome deletion; complementary DNA; disease /disorder model; embryonic stem cell; gene deletion mutation; gene targeting; genetic disorder; genetic library; genetic mapping; genetic recombination; genetic screening; genetically modified animals; haploidy; laboratory mouse; mental retardation; model design /development; nucleic acid repetitive sequence; phenotype; pulsed field gel electrophoresis

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.

Smith-Magenis综合征（SMS）是多个先天性异常精神 与人类的杂合缺失相关的延迟综合征 染色体17条带P11.2 [DEL（P11.2）]。这种微缺失综合征有一个 估计的患病率在20-25,000个活产中至少有1个 在人类中最常观察到的染色体缺失。临床 功能包括智力低下，身材矮小，小颅面 异常，手指短，微孔，心脏发育缺陷 和肾脏，神经行为异常，例如自我破坏性， 侵略性行为，癫痫发作和没有快速眼动（REM）睡眠。 复杂的表型特征表明删除了几个连续的 基因和表型作用被认为是由 单倍不足。尽管已经在 SMS公共缺失区域，它们对这种复杂表型的贡献 仍然投机。 17p11.2染色体与32-34 cm区域同步 小鼠染色体11。很少有基因映射到小鼠和 人类的同步区域，包括：编码醛脱氢酶的ALDH3 3，编码致命的果蝇同源物的LLGL基因92） 巨型幼虫基因，SERK1编码SAPK的蛋白激酶激活剂 信号转导级联和编码22 kD的PMP22基因 外周髓磷脂蛋白；所有三个地图为33厘米。其他基因 17p11.2也可能具有鼠的同源物。该提议试图 表征鼠辅导的基因组区域至17p11.2p12并分析 通过构建鼠标基因座的单倍弥补的结果 涉及基因的敲除。作为计划项目赠款的一部分我们 寻求使用染色体工程来构建不同的删除 小鼠染色体11包含部分的同步区域 人类SMS删除间隔。工程的广泛表征 然后将进行小鼠以确定基因的后果 单倍不足。这些分析将有助于理解 SMS染色体微脱落综合征的分子基础和 将对人类发展和生物学产生有效的影响。