Genetic Etiologies of Agenesis of the Corpus Callosum

胼胝体发育不全的遗传病因学

• 批准号: 6956091
• 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/6956091
• 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（申请人提供）：胼胝体在胎儿发育第8周至第14周之间形成，是连接两个大脑半球的主要纤维束。胼胝体发育不全 (ACC) 的活产发生率估计为 1:4,000。 ACC 患者可能有严重的发育障碍和癫痫发作，并且可能有认知和行为障碍，如自闭症、强迫症或注意力缺陷多动障碍。在未接受药物治疗的精神分裂症患者中也一致发现了胼胝体异常，这表明了解 ACC 的原因可能对了解其他神经行为障碍具有广泛的影响。 ACC 的遗传原因在很大程度上尚不清楚，然而，某些细胞遗传学位点在 ACC 患者中重复缺失，表明 ACC 基因存在于这些位点中，并且缺失该基因的一个副本可导致 ACC。流行病学数据表明，2% 的受影响个体的一级亲属患有 ACC，这与许多 ACC 患者可能患有新发致病突变的可能性一致。 ACC 基因剂量的这种作用在动物模型中也很明显；与胼胝体形成相关的基因的缺失经常会导致 CMS 中的多个寻路缺陷，而杂合性缺失可能只会导致胼胝体异常。 我们采取了全面的方法来研究至少 200 名 ACC 患者及其家人的临床、放射学和遗传特征。我们已经开始使用基因组微阵列测试我们的队列的染色体拷贝数变化。在前 25 名患者中，我们发现了 3 个与 ACC 相关的亚显微从头缺失，表明高达 20% 的 ACC 患者可能发生从头缺失。我们假设剩下的 80% 中的一些将在这些区间之一内包含的 ACC 致病基因中出现失活点突变。根据这些发现和假设，对于这笔赠款，我们建议实现以下目标： 1. 继续开发一个包含最初 200 名胼胝体发育不全/发育不全患者的临床、病史和放射学信息的综合数据库。 2. 利用 UCSF 32,000 BAG 微阵列对 200 名 ACC 患者缩小先前确定的 ACC 染色体区间并确定新的 ACC 区间。 3. 鉴定候选 ACC 基因中的失活突变，这些基因包含在三个 ACC 相关染色体区间：2q37.1、6q27 和 3q13.1。