Molecular Analysis of the Genes Involved in Cardiac Defects

为了分离与心脏形态发生有关的新基因，我们对人类21号和22号染色体的DNA重叠群进行了外显子捕获和基因组测序。我们还对心脏cDNA文库进行了cDNA筛选。我们在21号染色体上分离到了几个新基因，包括SIM（single-minded）、MNB（minibrain）、KNP（keio novel protein）1、KNP 3、KNP 4等，并与Antonarakis教授合作，发现了两个SIM基因，即SIM 1和SIM 2，并对其基因组结构和组织表达模式进行了研究。SIM基因被认为在大脑发育过程中起着转录因子的作用。我们发现了一个只在胚胎心脏表达的cDNA克隆，但它的整个结构尚未揭示。在与McDermid教授的合作中，我们发现了一个新的基因，该基因是小鼠Bid 2基因的人类同源物，据信该基因在心脏的形态发生过程中调节某些细胞类型。因此，我们在过去两年取得了良好的进展。此外，我们还分离到了另一个与自身免疫性疾病APECED的发病机制有关的新基因AIRE，AIRE基因导致自身免疫性疾病APECED的发病机制，AIRE基因产生的转录因子似乎在调节免疫应答的成熟过程中起作用。这一发现是与Antonarakis教授和克罗恩教授合作完成的。我们举办了一个关于自身免疫病的小型研讨会，邀请这两位教授和他们的研究人员与70名听众一起交流思想。在访问期间，我们进行了富有成果的讨论，并确定了未来的合作方向。

To isolate novel genes involved in the morphogenesis of heart, we performed exon trapping and genomic sequencing of the DNA contigs of human chromosomes 21 and 22. We also employed cDNA screening of heart cDNA library. We have isolated several novel genes from chromosome 21 including SIM (single-minded), MNB (minibrain), KNP (keio novel protein)1, KNP3, KNP4 and so on. In collaboration with Professor Antonarakis, we found two SIM genes, SIM1 and SIM2, and determined their genomic structures and tissue expresseion patterns. The SIM genes are thought to be functioning as trascription factors during the brain development. We found a cDNA clone which is expressed only in the heart of embryos but its entire structure is not yet unveiled. In collaboration with Professor McDermid, we detected a new gene which is a human homolog of mouse Bid2 gene which is believed to regulate certain cell types during the morphogenesis of heart. Thus, we have made a good progress for the past two years. Moreover, we were able to isolate another new gene AIRE which is responsible for the pathogenesis of an autoimmune disease APECED.The AIRE gene produces a pathogenesis of an autoimmune disease APECED.The AIRE gene produces a transcription factor which seems to play a role in regulating the maturation process of immune response. this finding was made in collaboration with Professors Antonarakis and Krohn. We had a mini-symposium on the autoimune disease by inviting these two professors and their research fellows to exchange ideas together with 70 audiences. During their stay, we had fruitful discussion and determined future directions of our collaboration.