Career Summary
We use genetics, genomics and molecular biology to identify and characterize the genes predisposing to congenital malformations of the central nervous system (CNS) and the associated axial skeletal structures. Our laboratory is particularly interested in understanding the genetic and biological basis of two such malformations: neural tube defects (NTDs) and Chiari I malformation (CMI). These anomalies have a multifactorial etiology involving genetic and environmental factors that remain largely unknown.
Neural tube defects (NTDs), including spina bifida and anencephaly, represent a group of very common congenital malformations in humans, affecting 1-2 infants per 1000 births. They are caused by a partial or complete failure of the neural tube to close during embryogenesis. During my postdoctoral studies, I identified the gene mutated in Loop-tail, a well-established model for the study of NTDs in humans. This gene, designated as Vangl2, forms part of the non-canonical Frizzled (Fz)/Dishevelled (Dvl) membrane signaling pathway controlling the morphogenetic process of convergent extension (CE) that is central to gastrulation and neural tube closure. We recently identified mutations in a human homolog called VANGL1 that are associated with neural tube defects in humans, representing the first report of pathogenic mutations in a specific gene in human NTDs. For identification of novel genes involved in NTDs, we are pursuing three major approaches: (1) molecular genetic investigation of VANGL1, VANGL2 and other members of the non-canonical Fz/Dvl pathway in human NTDs, (2) molecular genetic studies of other novel chemically-induced mouse models and (3) whole-exome sequencing in familial cases of NTDs.
Chiari I malformation (CMI) is a common abnormality of the craniocerebral junction characterized by a caudal descent of the cerebellar tonsils into the spinal canal. CMI in humans is similar to a common condition in the Cavalier King Charles Spaniels (CKCS) and Brussels Griffon dog breeds. We will identify the gene(s) defective in CMI in the dog using linkage and association studies followed by a positional candidate gene approach. We will next investigate the human ortholog(s) of the dog CMI gene(s) to identify and characterize the gene(s) defective in CMI in humans.
Our studies of NTDs and CMI will help to better understand the underlying pathological mechanisms, which are crucial for studying and characterizing the gene-environment interactions in these diseases. Gene-environment studies will help design novel preventive strategies and better counseling for couples at risk. Furthermore, these studies will help elucidate some of the molecular and cellular mechanisms underlying the early development of the neural tube and its derivatives.