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学研究 有助于更好地了解正常和 胚胎发育异常我们研究了 人类常见的大脑异常，前脑无裂畸形（HPE）， 发育中的前脑和面中部的结构缺陷。HPE是一个 遗传异质性疾病与各种 染色体异常最近，人类声波基因的突变 Hedgehog（SHH）基因被证明是引起家族性HPE的原因。 此外，发现胆固醇生物合成异常 与HPE相关的遗传综合征。另一方面， 未经鉴定的HPE致病基因被假定为是HPE的一部分。 SHH信号通路或参与胆固醇 生物合成羊毛甾醇合成酶（LS）是参与这一过程的关键酶 胆固醇合成的第一步。LS基因已经被 定位于人类染色体21q22.3，这是一个已知的 在一些HPE患者中删除。大肠杆菌LS基因突变分析 已对HPE患者进行了检查，以确定LS是否 HPE候选基因在此期间，我们 已经确定了人类LS基因的整个序列， 设计了一种筛选策略来寻找基因突变 可能导致人类疾病总共30个 HPE患者筛选，我们发现超过15个多态性， 在各自的家庭中没有与疾病隔离， 在酵母的功能研究中正在测试的单一突变， 确定这种突变的影响。这些研究正在 在不久的将来作为手稿提交。其他 我们正在仔细分析的候选基因包括：OEP， DKK 1、GLI1和GLI2。