Genetics of Brain Development

对大脑发育的复杂遗传学进行了研究，重点是那些导致人类最常见的结构性前脑畸形（holoproencephaly， HPE）的基因。这种大脑畸形可能是由环境或遗传原因造成的。这些研究的目的是通过对患有这种疾病的患者的研究来确定负责正常和异常大脑发育的基因。我们已经证明，大约四分之一的家族性和偶然性HPE病例是由六个这样的基因突变引起的（Roessler等人，1996年，1997年；Brown等人，1998年；Wallis等人，1999年；Gripp等人，2000年；Ming等人，2002年；dela Cruz等人，2002年）。其他与hedgehog通路相关或位于特定遗传位点的基因也可能导致HPE，目前正在积极研究中。我们预计，在寻找HPE的遗传原因时，将发现许多对正常大脑发育重要的基因。此外，这些调查的目的是确定环境因素，有助于HPE。动物模型显示，母体胆固醇过低会导致某些后代出现脑部异常。这些发现现在正在流行病学研究中进行测试，在这些研究中，怀孕期间母亲血清胆固醇水平低与出生结果相关。

A study of the complex genetics of brain development has been undertaken with an emphasis on those genes that cause the most common structural forebrain anomaly in humans, holoprosencephaly (HPE). This malformation of the brain can result from either environmental or genetic causes. It is the aim of these investigations to determine the genes responsible for both normal and abnormal brain development through the study of patients with this disorder. Mutations in six such genes has been shown by us to be responsible for approximately one quarter of familial and spsoradic cases of HPE (Roessler et al. 1996,1997; Brown et al., 1998; Wallis et al., 1999; Gripp et al., 2000; Ming et al., 2002; dela Cruz et al., 2002). Other genes either related to the hedgehog pathway or located at defined genetic loci may also contribute to HPE and are the subject of active investigation. We anticipate that many genes important for normal brain development will be identified in the search for genetic causes of HPE. In addition, the aim of these investigations is to identify environmental factors that contribute to HPE. Animal models have shown that low maternal cholesterol causes brain anomalies in some offspring. The findings are now being tested in epidemiological studies where low maternal serum cholesterol during pregnancy is correlated with birth outcome.