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.
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.
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