Genetic Etiologies of Agenesis of the Corpus Callosum

胼胝体发育不全的遗传病因学

• 批准号: 7121094
• 负责人: Elliott Sherr
• 金额: $ 16.14万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7121094
• 关键词: blood chemistry; brain morphology; chromosome aberrations; clinical research; congenital brain disorder; corpus callosums; developmental disease /disorder; developmental genetics; developmental neurobiology; disease /disorder etiology; embryogenesis; family genetics; gene expression; gene mutation; genetic screening; high throughput technology; human genetic material tag; human subject; microarray technology; molecular biology information system; polymerase chain reaction

DESCRIPTION (provided by applicant): The corpus callosum, formed between the 8th and 14th weeks of fetal development, is the principal fiber tract that connects the two cerebral hemispheres. Agenesis of the corpus callosum (ACC) has an estimated incidence of 1:4,000 live births. Patients with ACC can have significant developmental disability and seizures and may have cognitive and behavioral impairment such as autism, obsessive compulsive disorder or attention deficit hyperactivity disorder. Callosal anomalies have also been found consistently in drug-naive schizophrenic patients, suggesting that understanding the causes of ACC may have broad implications for understanding other neurobehavioral disorders. The genetic causes for ACC are largely unknown, however, certain cytogenetic loci are repeatedly deleted in ACC patients, suggesting that ACC genes reside in these loci and that missing one copy of the gene can cause ACC. Epidemiological data suggest that 2% of affected individuals have first-degree relatives with ACC, consistent with the possibility that many ACC patients may have de novo causative mutations. This role for gene dosage in ACC is also evident in animal models; deletion of genes involved in callosal formation frequently results in multiple pathfinding defects in the CMS, whereas heterozygous deletion may only result in callosal anomalies. We have undertaken a comprehensive approach to study the clinical, radiographic and genetic features of at least 200 ACC patients and their families. We have begun to test our cohort for chromosomal copy number changes using genomic microarrays. In the first 25 patients, we identified three submicroscopic de novo deletions that correlate with ACC, suggesting that de novo deletions may occur in up to 20% of ACC patients. We hypothesize that some of the remaining 80% will have inactivating point mutations in ACC causative genes contained within one of these intervals. In light of these findings and hypotheses, for this grant we propose to tackle the following Aims: 1. To continue to develop a comprehensive database of clinical, historical and radiologic information on an initial 200 patients with callosal agenesis/dysgenesis. 2. To narrow down previously identified ACC chromosomal intervals and to identify novel ACC intervals utilizing the UCSF 32,000 BAG microarray on 200 ACC patients. 3. To identify inactivating mutations in candidate ACC genes, which are contained in three ACC-associated chromosomal intervals: 2q37.1, 6q27 and 3q13.1.

描述（由申请人提供）：在胎儿发育的第8周和14周之间形成的call体是连接两个脑半球的主要纤维道。 call体的发育不全（ACC）的发病率为1：4,000。 ACC患者可以患有明显的发育障碍和癫痫发作，并且可能患有认知和行为障碍，例如自闭症，强迫症或注意力缺陷多动障碍。在药物精神分裂症患者中也始终发现了callosal异常，这表明了解ACC的原因可能对理解其他神经行为疾病具有广泛的影响。 ACC的遗传原因在很大程度上尚不清楚，但是，某些细胞遗传学基因座在ACC患者中反复删除，这表明ACC基因位于这些基因座中，并且缺少基因的一个副本会导致ACC。流行病学数据表明，有2％的受影响个体具有ACC的一级亲戚，这与许多ACC患者可能具有从头病变的突变的可能性一致。在动物模型中，基因剂量在ACC中的作用也很明显。 callosal形成涉及的基因的删除经常导致CMS中多种探路缺陷，而杂合缺失只会导致callosal异常。 我们采取了一种全面的方法来研究至少200名ACC患者及其家人的临床，放射线和遗传特征。我们已经开始使用基因组微阵列测试我们的同类染色体拷贝数变化。在前25位患者中，我们确定了与ACC相关的三个从头删除率，这表明从最多20％的ACC患者中可能发生从头删除。我们假设其余的80％中的某些将在其中一个间隔中包含的ACC致病基因中灭活点突变。鉴于这些发现和假设，对于这项赠款，我们建议解决以下目标： 1。继续开发有关最初200例Callosal Adenesis/失调患者的临床，历史和放射学信息的全面数据库。 2。要缩小先前确定的ACC染色体间隔，并使用UCSF 32,000 Bag Microarray识别新的ACC间隔，以识别200名ACC患者。 3。确定候选ACC基因中的灭活突变，这些突变包含三个与ACC相关的染色体间隔：2Q37.1、6Q27和3Q113.1。