MOLECULAR GENETICS OF DELL7PLL.2 MICRODELETION SYNDROME

Del(17)(p11.2)或Smith-Magenis综合征(SMS)是一种多发性先天性 异常/精神发育迟滞综合征与 17号染色体短臂p11.2带的间隙缺失 始终如一的短信患者的临床特征包括畸形特征， 身材矮小，发育迟缓。不同的临床特征包括 唇腭裂、先天性心脏缺陷、小角膜、睡眠障碍 包括缺乏快速眼动睡眠，周围神经病变的迹象，攻击性和 自我毁灭的行为。我们已经确认了40多名无关的患者 用高分辨细胞遗传学方法显示del(17)(p11.2) 在这些患者身上建立了淋巴母细胞系。DNA与细胞 大多数线路的一个或两个父级上也提供了线路 病人。 这项研究的长期目标是了解分子基础。 一条短信。此应用程序建议确定 应用双光束激光流式细胞术检测关键患者的缺失。父母 缺失的来源和分子范围将由Southern来确定 利用映射到删除间隔的标记进行分析。一组躯体 包括受影响的17号染色体的细胞杂交 或易位患者将被建造。重叠酵母 包含缺失区间的人工染色体克隆和粘粒 将被分离并建立重叠群。其他标记(如果必要) 将由保留17p11.2的辐射杂交种的Alu-和Line-PCR产生 序列和17p11.2基因的显微切割克隆。远程体能训练 人类基因组中包含缺失区间的区域图 将会被建造。短信患者中的删除断点将为 鉴定、克隆并测定序列。一张人类的遗传图谱 小鼠基因组中的共振区将使用保守的 从这些克隆中鉴定出的序列。将寻找表达序列 并筛选合适的cdna文库以确定候选基因。 负责行为和快速眼动睡眠异常，眼睛，心脏和 头面部异常和神经病。相关的物理和 17p11.2的表型图谱和候选基因的鉴定将在 在后者基础上长期提供了有价值的信息 为疾病的诊断、治疗和治疗提供有价值的试剂 可能会纠正这种综合症。

Del(17)(p11.2) or Smith-Magenis syndrome (SMS) is a multiple congenital anomaly/mental retardation syndrome which is associated with an interstitial deletion of band p11.2 of the short arm of chromosome 17. The consistent clinical features of SMS patients include dysmorphic features, short stature, and developmental delay. Variable clinical features include cleft lip/palate, congenital heart defects, microcornea, sleep disturbances including absent REM sleep, signs of peripheral neuropathy, aggressive and self-destructive behavior. We have identified over 40 unrelated patients demonstrating del(17)(p11.2) by high resolution cytogenetics and established lymphoblastoid cell lines on these patients. DNA and cell lines are also available on one or both parents of the majority of these patients. The long term objective of this study is to understand the molecular basis of SMS. This application proposes to determine the approximate size of the deletion in key patients by dual beam laser flow cytometry. The parental origin and molecular extent of the deletions will be determined by Southern analysis with markers mapping to the deletion interval. A panel of somatic cell hybrids which include the affected chromosome 17 from key SMS deletion or translocation patients will be constructed. Overlapping yeast artificial chromosome clones and cosmids encompassing the deletion interval will be isolated and contigs established. Additional markers if essential will be created by Alu- and LINE-PCR of radiation hybrids retaining 17p11.2 sequences and by microdissection cloning of 17p11.2. A long range physical map of the region encompassing the deletion interval in the human genome will be constructed. The deletion breakpoints in SMS patients will be identified, cloned and the sequence determined. A genetic map of the syntonic regions in the mouse genome will be obtained using conserved sequences identified from these clones. Expressed sequences will be sought and appropriate cDNA libraries will be screened to identify candidate genes responsible for behavioral and REM sleep abnormalities, ocular, cardiac and craniofacial abnormalities and for neuropathy. The correlated physical and phenotype map of 17p11.2 and the identification of candidate genes will in the long term provide valuable information on the basis of these latter disorders and provide valuable reagents for the diagnosis, treatment and possibly correction of this syndrome.