GENETIC ANALYSIS OF HUMAN DEVELOPMENTAL ABNORMALITIES

人类结构异常的基因研究

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.