Hydrocephalus is a common human birth defect with an incidence of approximately 1/2,000 livebirths and results from the accumulation of cerebrospinal fluid (CSF) within the cerebral cavities and the space above the brain. The defect results from an imbalance between production and resorption of CSF, and arises from obstruction in normal CSF flow. The disorder is etiologically heterogeneous and can arise from both genetic (such as mutations in L1CAM) and non-genetic (such as intrauterine infection) factors. Several genetic forms of hydrocephalus are known and can occur as an isolated anomaly or as part of a recognized syndrome. The biological, genetic and molecular basis of hydrocephalus is very poorly understood. Several studies have suggested the existence of autosomal genes, and that the disorder is multifactorial requiring the interaction of multiple genes. Genetic mapping and positional cloning of the human genes would be ideal for elucidating the genetic basis of idiopathic hydrocephalus. However, ascertaining the large number of human families with multiple affected offspring that are necessary for linkage mapping is an arduous task. Fortunately, a number of excellent mouse mutations that lead to hydrocephalus are known. The identification of these mouse genes, the concomitant isolation of the corresponding human homologs, and a search for mutations in these genes in human patients, provide a promising avenue for understanding hydrocephalus. Additionally, biochemical and molecular studies of these mouse mutations can elucidate the normal development of the brain and the specific developmental abnormalities which lead to hydrocephalus. We propose to fine-structure map the mouse mutations ch (congenital hydrocephalus), hy-3 (hydrocephalus-3) and hyh (hydrocephalus with hop gait) and positionally clone ch. Additionally, we shall create a targeted mutation of the cloned ch gene and conduct functional expression studies of the natural and targeted ch mutations. Finally, we shall clone the human ch gene and analyze this gene for mutations in human patients. These studies, taken together, will shed light on new pathways that affect early brain development, pathways which when compromised lead to hydrocephalus.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD034857-02
Application #
2674043
Study Section
Special Emphasis Panel (ZRG2-BIOL-1 (03))
Project Start
1997-08-01
Project End
2001-07-31
Budget Start
1998-08-01
Budget End
1999-07-31
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Genetics
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106