GENETIC ANALYSIS OF HUMAN DEVELOPMENTAL ABNORMALITIES

人类结构异常的遗传学研究 有助于更好地理解正常和 胚胎发育异常。我们研究得最多的 人类常见的脑异常，无前脑畸形(HPE)， 发育中的前脑和中脑的结构缺陷。HPE是一种 与各种疾病相关的遗传异质性疾病 染色体异常。最近，人类Sonic基因的突变 Hedgehog(SHH)基因可引起家族性HPE。 此外，还发现了胆固醇生物合成的异常。 一种与HPE相关的遗传综合征。因此，其他还没有 不明原因的HPE引起的基因被认为是 Shh信号通路或参与胆固醇 生物合成。羊毛甾醇合成酶(LS)是其中的关键酶 在胆固醇合成的第一步。LS基因已经被 被定位到人类染色体21q22.3，一个已知的区域 在一些HPE患者中缺失。中国汉族人LS基因突变分析 对HPE患者进行了检查，以确定LS是否 另一个HPE候选基因。在此支持期间，我们 已经确定了人类LS基因的完整序列 已经设计了一种筛查策略来寻找基因突变 这可能是导致人类疾病的原因。在总共30个 对HPE患者进行筛查，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，并且 正在酵母中进行功能研究的单一突变 确定这种突变的影响。这些研究正在进行 为在不久的将来作为手稿提交而汇编。其他 我们正在仔细分析的候选基因包括：OEP， Dkk1、GLI1和GLI2。

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.