Analysis of a novel duplication locus causing human cerebellar malformation

描述（由申请人提供）：本提案的目标是表征人类染色体17p13上的一个新的复制位点，并将其作为定义导致人类Dandy-Walker畸形的遗传和发育机制的新途径。Dandy-Walker畸形是人类中后脑畸形中最常见的一种，每2500个新生儿中至少有1个患有此病，通常与共济失调、智力迟钝、发育迟缓和其他残疾有关。Dandy-Walker畸形的特征是小脑蚓部小且向上旋转，第四脑室囊性增大，后窝增大和变异性脑积水。尽管具有临床意义，但大多数Dandy- Walker病例的遗传和发育基础仍不清楚。我们最近发现了一组患有Dandy-Walker畸形和染色体17p13共同位点重复的患者。BAC转基因小鼠含有人类染色体17p13的DNA片段，再现了人类Dandy-Walker小脑表型的几个特征。用于产生转基因小鼠的17p13 DNA片段仅包含3个基因，其中没有一个先前涉及任何人类中后脑畸形疾病或正常小脑或后窝发育。我们假设我们的17p13重复区域包含一个新的Dandy-Walker致病基因(s)，这是小脑和后窝发育的一个新的调节因子。在Aim1中，我们建议在小鼠中进行基因表达分析，并对具有17p13重复的人类患者进行额外分析，以更精确地确定潜在的17p13 DWM候选基因。在目标2中，我们将创建人类17p13重复的BAC转基因小鼠模型，并使用它来确定导致DWM的发育机制。在Aim 3中，我们将使用BAC转基因小鼠鉴定17p13 Dandy-Walker畸形致病基因。我们期望我们的研究能够鉴定出新的Dandy-Walker致病基因，提供一种新的Dandy-Walker畸形小鼠模型，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针对Dandy-Walker畸形患者子集的特定治疗方法。

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. PUBLIC HEALTH RELEVANCE: Developmental mid-hindbrain malformations affect 1 per 2500 live births and are associated with ataxia, mental retardation, developmental delay and other abnormalities. The genetic and developmental basis of vast majority of these malformations is unknown. We propose to identify genetic abnormalities and developmental mechanisms underlying a subset of mid-hindbrain malformation cases, which will contribute to more accurate diagnosis and counseling in the short term, and to specific treatments for some of these disorders in the long term.