Developmental malformations of the cerebellum are common birth defects that often cause mental retardation or developmental delay, in addition to motor and visual handicaps. The most frequent cerebellar malformation is Dandy-Walker malformation (DWM), which is defined by hypoplasia of the cerebellar vermis, dilatation of the fourth ventricle, and often hydrocephalus. Although common, the specific causes of DWM remain undefined. While it is certain that environmental teratogens can cause DWM during embryogenesis, there is clear evidence that as yet undefined genetic factors are also responsible. The investigators have identified several DWM patients with chromosomal abnormalities. In particular, a subset of these patients has overlapping chromosomal deletions defining a small critical region that is hypothesized to identify a DWM locus. The experiments outlined in this application are focused on mutational and functional analysis of two excellent candidate genes, likely causative of DWM. To model DWM, the investigators will construct targeted mouse mutants for these two DWM candidate genes and assess the role of these genes during cerebellar development, based on the hypothesis that similar mechanisms underlie mouse and human CNS development. The identification of a DWM gene will represent a significant advance in the understanding of this common and often devastating brain malformation. It will also provide valuable diagnostic and prognostic information that can greatly influence treatment and genetic counseling. ? ?
