GENETIC ANALYSIS OF HUMAN BRAIN DEVELOPMENT

人脑发育的遗传分析

• 批准号: 2502634
• 负责人: Maximilian Muenke
• 金额: $ 39.77万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-12-01 至 2001-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2502634
• 关键词: artificial chromosomes; brain; chromosome deletion; chromosome translocation; clinical research; congenital brain disorder; cytogenetics; developmental genetics; developmental neurobiology; early embryonic stage; fluorescent in situ hybridization; gene expression; gene mutation; gene rearrangement; human genetic material tag; human subject; in situ hybridization; molecular cloning; molecular pathology; neurogenetics; nucleic acid sequence; polymerase chain reaction; pulsed field gel electrophoresis; single strand conformation polymorphism; site directed mutagenesis

DESCRIPTION: (Adapted from Investigator's Abstract) This is a proposal to identify and characterize genes whose products are necessary for the development of the central nervous system. The strategy is to identify genes in which mutations cause holoprosencephaly (HPE) in humans. HPE is associated with abnormalities in midline development of the brain and face. Severe forms of HPE present with a single brain ventricle and cyclopia while milder cases have mental retardation and other developmental disabilities. Both familial and sporadic forms of HPE exist. Thus, the P.I. hypothesizes that HPE is caused by alterations in genes whose products are critical for proper early brain development. To address this hypothesis the P.I. has concerted molecular genetic analyses to those forms of HPA associated with cytogenetic deletions and translocations in 21q22.3 (HPE1), 2p21 (HPE2), 7q36 (HPE3), and 18p11.3 (HPE4). Recently, HPE3 was shown to be due to mutations in the human Sonic Hedgehog gene. Future efforts will be directed at five specific aims: 1) Map mutations in the human SHH gene in familial and sporadic HPE, 2) examine the biological consequences of the these mutations in SHH, 3) Determine whether other genes in the SHH signaling pathway are candidates for other forms of HPE, 4) Screen the critical chromosomal regions for HPE1 and HPE4 for candidate genes, and 5) Use positional cloning to identify and characterize HPE genes.

描述：（改编自研究者的摘要）这是一项建议 识别和表征其产物是必要的基因 中枢神经系统的发育。 策略是确定 突变导致人类前脑无裂畸形（HPE）的基因。 慧与是 与大脑和面部中线发育异常有关。 严重的 HPE 表现为单脑室和独眼 较轻的病例有智力低下和其他发育障碍。 HPE 存在家族性和散发性两种形式。 因此，P.I.假设 HPE 是由基因改变引起的，而基因的产物对于 适当的早期大脑发育。 为了解决这个假设，P.I.有 对与以下疾病相关的 HPA 形式进行协调一致的分子遗传学分析 21q22.3 (HPE1)、2p21 (HPE2) 中的细胞遗传学缺失和易位， 7q36 (HPE3) 和 18p11.3 (HPE4)。 最近，HPE3 被证明是由于 人类 Sonic Hedgehog 基因发生突变。 今后的努力方向将是 五个具体目标： 1) 绘制家族性人类 SHH 基因突变图谱 和零星的 HPE，2）检查这些的生物学后果 SHH 中的突变，3) 确定 SHH 信号传导中是否有其他基因 途径是其他形式 HPE 的候选者，4) 筛选关键的 HPE1 和 HPE4 的染色体区域作为候选基因，以及 5) 使用 定位克隆以鉴定和表征 HPE 基因。