The Genetic Basis of Mid-Hindbrain Malformations

中后脑畸形的遗传基础

• 批准号: 7122079
• 负责人: William B. Dobyns
• 金额: $ 40.4万
• 依托单位: UNIVERSITY OF CHICAGO
• 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 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7122079
• 关键词: cerebellar disorders; clinical research; comparative genomic hybridization; congenital disorders; developmental neurobiology; diagnosis; genetic mapping; genotype; human subject; in situ hybridization; laboratory mouse; linkage mapping; mesencephalon; molecular cloning; molecular genetics; neurogenetics; patient oriented research; phenotype; rhombencephalon; syndrome

DESCRIPTION (provided by applicant): Malformations of the brainstem and cerebellum are collectively a relatively common (at least 0.24 per 1000 births) cause of developmental disabilities in humans that have been understudied compared to other types of brain malformations. The best known and most common of these is Dandy-Walker malformation (DWM), but this is often confused with isolated cerebellar vermis hypoplasia (CVH) and the molar tooth malformation (MTM) seen in Joubert syndrome and related disorders. Here we propose a comprehensive approach to syndrome delineation and gene identification for these 3 overlapping malformations. We approach them together as most clinicians have difficulty distinguishing between them, and our experience to date suggests that mild variants of DWM and MTM may be very difficult or impossible to distinguish from isolated CVH. Our preliminary studies have resulted in significant progress in our understanding of these disorders, and include useful clinical delineation combined with identification of at least 4 potentially important causative genes and physical mapping of several more. Specifically, we have found the first causative genes for CVH (OPHN1), DWM (ZIC1 and ZIC4) and MTM (AHI1 and NPHP1), and mapped additional causative genes for DWM to chromosome 6p25 and for MTM to chromosomes 7 and 13. We have already ascertained sufficient subjects for to allow identification of the 6p25 DWM gene, and to map additional hindbrain malformation genes. Our experience with genotype-phenotype analysis will allow progress to be quickly translated to clinical usefulness. Overall, we believe that intensive studies of these malformations and their causative genes are very timely, and will advance knowledge regarding brain development in general, and contribute to the diagnosis and medical care of the individuals and families affected by these disorders.

描述（由申请人提供）：脑干和小脑畸形是人类发育障碍的一种相对常见的原因（至少每1000名新生儿中有0.24例），与其他类型的脑畸形相比，尚未得到充分研究。其中最著名和最常见的是Dandy-Walker畸形（DWM），但它经常与Joubert综合征和相关疾病中的孤立性小脑蚓部发育不全（CVH）和臼齿畸形（MTM）相混淆。在这里，我们提出了一个全面的方法来综合征划定和基因识别这3个重叠畸形。由于大多数临床医生很难区分它们，我们将它们放在一起，迄今为止的经验表明，DWM和MTM的轻度变异可能很难或不可能与孤立的CVH区分开来。我们的初步研究在我们对这些疾病的理解方面取得了重大进展，包括有用的临床描述，以及至少4个潜在重要致病基因的鉴定和多个物理作图。具体而言，我们已经发现了CVH（OPHN 1），DWM（ZIC 1和ZIC 4）和MTM（AHI 1和NPHP 1）的第一个致病基因，并将DWM的其他致病基因定位到染色体6p 25，将MTM定位到染色体7和13。我们已经确定了足够的主题，让6p 25 DWM基因的鉴定，并绘制额外的后脑畸形基因。我们在基因型-表型分析方面的经验将使进展迅速转化为临床实用性。总的来说，我们认为，对这些畸形及其致病基因的深入研究是非常及时的，将促进对大脑发育的一般知识，并有助于受这些疾病影响的个人和家庭的诊断和医疗护理。