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Analysis of a novel duplication locus causing human cerebellar malformation

导致人类小脑畸形的新重复位点分析

基本信息

批准号：
8740708
负责人：
Viktor Chizhikov
金额：
$ 18.48万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-10-02 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8740708
关键词：
Analysis novel duplication locus causing

项目摘要

DESCRIPTION (provided by applicant): The goal of this proposal is to characterize a new locus of duplications on human chromosome 17p13 and to use it as a novel avenue to define genetic and developmental mechanisms leading to human Dandy-Walker malformation. Dandy-Walker malformation is the most frequent type of human mid-hindbrain malformations, which affects at least 1 in 2500 life births and is often associated with ataxia, mental retardation, developmental delay and other disabilities. Dandy-Walker malformation is characterized by a small and upwardly rotated cerebellar vermis, cystic enlargement of the 4th ventricle, enlarged posterior fossa and variable hydrocephalus. Despite clinical significance, the genetic and developmental basis of most Dandy- Walker cases remains unknown. We recently identified a group of patients with Dandy-Walker malformation and duplication of a common locus on chromosome 17p13. BAC transgenic mice, which contain a DNA fragment of human chromosome 17p13, recapitulated several features of the human Dandy-Walker cerebellar phenotype. The 17p13 DNA fragment used for generation of our transgenic mice contains only 3 genes, none of which has been previously implicated in any human mid-hindbrain malformation disorder or normal cerebellar or posterior fossa development. We hypothesize that our 17p13 duplication region contains a new Dandy-Walker causative gene(s), which is a novel regulator of cerebellar and posterior fossa development. In Aim1 we propose to perform gene expression analysis in the mouse and additional analysis of human patients with 17p13 duplications to more precisely define potential 17p13 DWM candidate genes. In Aim 2 we will create a BAC transgenic mouse model of our human 17p13 duplication and use it to identify the developmental mechanisms leading to DWM. In Aim 3 we will identify 17p13 Dandy-Walker malformation causative gene(s) using BAC transgenic mice. We expect that our study will identify novel Dandy-Walker causative gene(s), provide a new mouse model of Dandy-Walker malformation and uncover novel developmental mechanisms leading to this birth defect. Results of this project will contribute immediately to more accurate diagnosis and counseling of human mid-hindbrain disorders, and may eventually lead to development of specific treatments for a subset of patients with Dandy-Walker malformation.

描述（由申请人提供）：本提案的目标是表征人类染色体17 p13上的新重复位点，并将其用作定义导致人类Dandy-Walker畸形的遗传和发育机制的新途径。Dandy-Walker畸形是最常见的人类中后脑畸形类型，其影响至少1/2500的活产，并且通常与共济失调、智力迟钝、发育迟缓和其他残疾相关。Dandy-Walker畸形的特征是小脑蚓部小而向上旋转，第四脑室囊性扩大，后颅窝扩大和可变的脑积水。尽管有临床意义，但大多数丹迪-步行者病例的遗传和发育基础仍然未知。我们最近发现了一组患者Dandy-Walker畸形和染色体17 p13上的一个共同位点的重复。BAC转基因小鼠，其中含有人类染色体17 p13的DNA片段，概括了人类Dandy-Walker小脑表型的几个特征。用于产生我们的转基因小鼠的17 p13 DNA片段仅含有3个基因，其中没有一个先前与任何人类中后脑畸形疾病或正常小脑或后颅窝发育有关。我们假设我们的17 p13重复区域包含一个新的Dandy-Walker致病基因，这是一个新的小脑和后颅窝发育的调节因子。在Aim 1中，我们建议在小鼠中进行基因表达分析，并对具有17 p13重复的人类患者进行额外分析，以更精确地确定潜在的17 p13 DWM候选基因。在目标2中，我们将建立一个BAC转基因小鼠模型，我们的人17 p13重复，并使用它来确定导致DWM的发育机制。目的3：利用BAC转基因小鼠筛选17 p13 Dandy-Walker畸形致病基因。我们希望我们的研究将确定新的Dandy-Walker致病基因，提供一个新的Dandy-Walker畸形小鼠模型，并揭示导致这种出生缺陷的新的发育机制。该项目的结果将立即有助于更准确地诊断和咨询人类中后脑疾病，并可能最终导致开发特定的治疗与Dandy-Walker畸形患者的子集。