GENETIC ANALYSIS OF HUMAN DEVELOPMENTAL ABNORMALITIES

人类发育异常的遗传分析

• 批准号: 6109041
• 负责人: Maximilian Muenke
• 金额: --
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6109041
• 关键词: chromosome aberrations; congenital brain disorder; developmental genetics; embryogenesis; gene expression; gene mutation; genetic disorder; human subject; steroid biosynthesis; structural genes

Genetic studies of structural anomalies in humans help to better understand the underlying basis for normal and abnormal embryological development. We have studied the most common brain anomaly in humans, holoprosencephaly (HPE), a structural defect of the developing forebrain and midface. HPE is a genetically heterogeneous disorder associated with various chromosomal anomalies. Recently, mutations in the human Sonic Hedgehog (SHH) gene were shown to cause familial forms of HPE. Furthermore, anomalies in the cholesterol biosynthesis were found in a genetic syndrome associated with HPE. Thus, other yet unidentified HPE causing genes are postulated to be part of the SHH signaling pathway or are involved in the cholesterol biosynthesis. Lanosterol synthase (LS), is the key enzyme involved in the first step of the cholesterol synthesis. The LS gene has been mapped to human chromosome 21q22.3, a region known to be deleted in some HPE patients. Mutational analysis of the LS gene in HPE patients has been performed to determine whether LS is another HPE candidate gene. During this period of support, we have determined the entire sequence of the LS gene in humans and have devised a screening strategy to look for mutations in the gene that could be responsible for human disease. Out of a total of 30 HPE patients screened, we found over fifteen polymorphisms that did not segregate with the disease in the respective families and a single mutation that is being tested in functional studies in yeast to determine the effects of this mutation. These studies are being compiled for submission as a manuscript in the near future. Other candidate genes which we are carefull analyzing include: OEP, DKK1, and GLI1 and GLI2.

人类结构异常的遗传研究 帮助更好地了解正常和 异常的胚胎发展。我们研究了最多的 人类的常见大脑异常，全脑脑（HPE），A 发育前脑和中间的结构缺陷。 HPE是一个 遗传上异质性疾病与各种 染色体异常。最近，人类声音中的突变 刺猬（SHH）基因被证明引起家族形式的HPE。 此外，发现胆固醇生物合成中的异常 在与HPE相关的遗传综合征中。因此，其他 假定未识别的HPE引起基因是 SHH信号通路或参与胆固醇 生物合成。羊毛醇合酶（LS）是涉及的关键酶 在胆固醇合成的第一步。 LS基因已经 映射到人类染色体21q22.3，一个已知的区域 在一些HPE患者中删除。 LS基因的突变分析 已经进行了HPE患者以确定LS是否为 另一个HPE候选基因。在这段支持期间，我们 已经确定了人类LS基因的整个序列 已经设计了一种筛选策略来寻找基因中的突变 那可能是人类疾病的原因。总共30 HPE患者筛查了，我们发现超过15种多态性 在各个家庭中没有与该疾病隔离和 在酵母中的功能研究中测试的单个突变 确定该突变的效果。这些研究正在 在不久的将来汇编作为手稿提交。其他 我们仔细分析的候选基因包括：OEP， DKK1，GLI1和GLI2。