Developmental disorders have a large impact on the individual, family and society. While some disorders—such as certain forms of mental retardation—can have a clear genetic basis, others—such as autism and attention deficit disorder—arise from gene-environment interactions.
Developmental disorders represents a major cause of morbidity and mortality at all stages of the life cycle, and results in a significant economic cost to Canadians. Fewer than 50% of human conceptions survive the first few weeks of embryonic life, and the vast majority of these are lost due to genetic abnormalities. At birth, about 3% of infants have a recognizable birth defect which is typically of genetic origin. Congenital malformations and chromosomal abnormalities make up 21.3% of infant deaths in British Columbia. In adulthood, up to 5% of Canadians will exhibit a gene-related impairment or disability and at least 50% of the population will develop a disease that has a strong genetic component, such as heart disease, cancer, diabetes, arthritis, multiple sclerosis and Alzheimer's Disease. As yet, most of these diseases are not curable. An essential feature for creation of novel, effective therapies for genetic diseases is development of appropriate animal models for human disease and the tools to study these models.
We study both single gene and more complex developmental disorders using the integrated power of genomics, informatics, and mice in an experimental model system to drive discovery about normal and abnormal development and to inform new therapeutic interventions. We are one of the few centres around the world who focus on developmental disorders of the brain, an area that we feel is largely underserved. In doing this, we combine laboratory experiments and observations with super high-resolution imaging techniques and cutting-edge informatics to study the development of the fetal brain and track the onset, mechanism, and progression of neurodevelopmental disorders.
We are currently employing a unique genetic and developmental mouse model of brain pathology, called the Lurcher mutant mouse, in our study of Autism Spectrum Disorders (ASDs). The Lurcher mutant mouse loses all of its Purkinje cells over 2 to 3 weeks of life, akin to the last trimester (perinatal period) of the human. Purkinje cells are inhibitory projection neurons which constitute the sole output of all motor coordination in the cerebellar cortex. We use this mouse to explore how Purkinje cell losses affect the function of the central nervous system (CNS) at behavioural, physiological, neurochemical and anatomical levels, as seen in ASDs and other neurodevelopmental disorders.
Mittleman G, Goldowitz D, Heck DH, Blaha CD. Cerebellar modulation of frontal cortex dopamine efflux in mice: relevance to autism and schizophrenia. Synapse 62(7):544-50. (2008) PMID 18435424
Cook MN, Dunning JP, Wiley RG, Chesler EJ, Johnson DK, Miller DR, Goldowitz D. Neurobehavioral mutants identified in an ENU-mutagenesis project. Mamm. Genome 18(8):559-72. (2007) PMID 17629744
Du X, Jensen P, Goldowitz D, Hamre KM. Wild-type cells rescue genotypically Math1-null hair cells in the inner ears of chimeric mice. Dev. Biol. 305(2):430-8. (2007) PMID 17397818