The introduction of next-generation DNA sequencing platforms led to unprecedented opportunities for gene discovery in structural brain disorders (SBDs), resulting in the identification of several novel genes fundamental in human cerebral and cerebellar development. Despite their success, these studies also revealed significant challenges associated with disease gene discovery in these disorders confirming, once again, their locus and phenotypic heterogeneity. Based on our experience that has been successful in identifying several SBD genes over the past several years, we now propose to ascertain additional cases and biological samples, followed by mutational screening for genes previously associated with SBDs. We will perform exome sequencing of the SBD 'mutation negative'cohort to discover novel genes followed by comprehensive studies to investigate these newly identified genes, using bioinformatics analyses to determine their temporal and spatial expression patterns during embryonic brain development, experimentally validating with in situ hybridization and immunostaining and studying the effects of the variants at the protein level, both by using available patient derived material, such as skin fibroblast cultures, as well as over-expression and inhibition experiments. For a limited number of genes, we aim to establish induced pluripotent stem cell lines and use Drosophila melanogaster RNAi lines and in utero electroporation in mouse to further examine the biological consequences of the mutations during neural development. These studies will continue to unravel the molecular pathways that underlie the complex events that result in formation of the human brain, setting the stage for more detailed future biological studies.

Public Health Relevance

Structural brain malformations represent a diverse group of genetic disorders that result in abnormal formation of the brain. We propose to use the latest genetic technologies to discover new genes that are associated with these diseases. The proposed research is relevant to public health because understanding the genetic basis of these rare brain abnormalities could lead to fundamental new insights into how the human brain develops and might serve as the basis of future biology based treatments in a group of common neurodevelopmental disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH103616-01
Application #
8674761
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Addington, Anjene M
Project Start
2014-04-05
Project End
2016-03-31
Budget Start
2014-04-05
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
$804,125
Indirect Cost
$321,167
Name
Yale University
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520