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带间质缺失。 的 SMS患者的一致临床特征包括畸形特征， 身材矮小和发育迟缓 不同的临床特征包括 唇腭裂、先天性心脏病、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，侵略性和 自我毁灭的行为 我们已经确认了40多个无关的病人 通过高分辨率细胞遗传学证明del（17）（p11.2）， 在这些患者身上建立了淋巴母细胞系。 DNA和细胞 其中大多数父母的一方或双方也可以使用这些线路。 患者 这项研究的长期目标是了解分子基础 的SMS。 本申请提出确定 通过双光束激光流式细胞术检测关键患者中的缺失。 亲本 缺失的起源和分子程度将通过Southern杂交确定。 用定位到缺失区间的标记进行分析。 一组体细胞 细胞杂交，其中包括受影响的染色体17从关键短信删除 或易位患者将被构建。 重叠酵母 包含缺失区间的人工染色体克隆和克隆 将被分离并建立重叠群。 必要时添加其他标记物 将通过保留17p11.2的辐射杂交体的Alu-和LINE-PCR产生 序列，并通过显微切割克隆17p11.2。 一个长距离的身体检查 人类基因组中包含缺失区间的区域图 将被建造。 SMS患者中的删除断点将是 鉴定、克隆并确定序列。 一张基因图谱 小鼠基因组中的共振区域将使用保守的 从这些克隆中鉴定的序列。 将寻找表达序列 并筛选合适的cDNA文库以鉴定候选基因 负责行为和快速眼动睡眠异常，眼睛，心脏和 颅面异常和神经病变。 相关的物理和 17p11.2的表型图和候选基因的鉴定将有助于进一步研究17p11.2的表型。 长期提供有价值的信息的基础上，这些后者 并提供有价值的试剂用于诊断、治疗和 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.