Pediatric Genomic Medicine Research
Simeon Boyd, M.D., Ph.D.
Birth defects are the leading cause of infant mortality in the United States, accounting for more than 20% of all infant deaths, yet the causes of about 70% of all birth defects are still unknown. My lab is involved in studies of non-Mendelian (multifactorial) birth defects, such as nonsyndromic craniosynostosis, bladder epispadias-exstrophy complex, and cleft lip and/or palate. Our ultimate goal is to identify genes and environmental factors contributing to the risk of these birth defects. Our initial approach involves recruitment and systematic evaluation of a large group of affected families. This allows for unbiased ascertainment of the clinical and epidemiologic characteristics of these defects and their phenotypic variability. Genome-wide linkage studies have been instrumental in elucidating the etiology of numerous single-gene diseases. For multifactorial traits such as most of the birth defects, these methods have proven less successful. Our strategy is to use case-parent trios with birth defects for SNP based association studies on groups of candidate genes or, more recently, using SNP chips for genome-wide coverage. It is important to emphasize that these approaches can be successfully used for genetic analysis of any complex trait, i.e. autism, diabetes, and hypertension. We are happy to collaborate and provide genetic expertise to clinicians and researchers interested in multifactorial human disorders.
My lab is also involved in identification and characterization of genetic syndromes due to defects of the intracellular secretory pathway. We have recently identified and characterized a new autosomal recessive genetic syndrome, Cranio-Lenticulo-Sutural dysplasia (CLSD; OMIM 607812). This syndrome manifests with early onset cataracts, facial dysmorphisms and late closing fontanels. After mapping CLSD to chromosome 14q13 we identified the causative mutation in SEC23A, an integral member of the COPII complex that transports proteins from the endoplasmic reticulum to the Golgi complex. After characterization of a morpholino zebrafish model we are now working on creating transgenic Sec23a deficient mice. This murine model will allow more detailed analysis of the secretory pathway and its role in health and disease. Using classical and reverse genetic approaches we plan to identify and characterize other human disorders caused by defects of the individual components of the secretory pathway.
For a list of the papers reporting our clinical and molecular research visit our study site: https://genetics.ucdmc.ucdavis.edu/Publications.cfm
Jinoh Kim, Ph.D.
Dr. Kim is an Associate Professor in the Department of Pediatrics, Division of Genomic Medicine at the UC Davis. He received a BS and MS from Seoul National University, obtained his PhD at University of Connecticut in Biochemistry and had a postdoctoral training in intracellular protein trafficking at UC Berkeley.
Protein secretion is essential for cell survival and proper human development. Most secretory proteins are synthesized in the endoplasmic reticulum (ER) and are transported to the Golgi complex before they are released from the cell. Dr. Kim’s laboratory studies how secretory proteins exit the ER.
Transport of proteins from the ER to the Golgi is catalyzed by cytosolic coat complex II (COPII: SAR1, SEC23/24 and SEC13/31). COPII proteins generate transport vesicles and package cargo molecules into the nascent vesicles at ER exit sites. These COPII vesicles fuse to ER-Golgi intermediate compartments (ERGIC) in mammalian cells. The ERGICs, then, are transported to the Golgi and mature into cis-Golgi.
Defects in COPII components cause various human diseases. In particular, mutations in SEC23A are linked to a craniofacial disease called cranio-lenticulo-sutural dysplasia (CLSD). By employing biochemical and cell biological tools, his laboratory has been characterizing molecular and cellular features of this disease. His laboratory has also generated mouse models to study the physiological consequences of COPII defects. His long-term goal is to understand how the assembly of COPII vesicles is integrated into vertebrate developmental processes.
Katherine Rauen, M.D., Ph.D.
Katherine (Kate) Rauen, M.D., Ph.D. is a Professor in the Department of Pediatrics, Division of Genomic Medicine at UC Davis where she currently serves as the Chief of Genomic Medicine. She received a M.S. in Physiology and a Ph.D. in Genetics from UC Davis doing research on gene dosage compensation and genetic evolution. She obtained her M.D. at UC Irvine where she also did research in cancer genetics. Dr. Rauen did her residency training in Pediatrics and fellowship in Medical Genetics at UC San Francisco.
Dr. Rauen is internationally known for her pioneering work in the application of array CGH in clinical genetics and as a leader and major contributor to the understanding of the “RASopathies”, the Ras/MAPK pathway genetics syndromes. Her research program involves the clinical and basic science study of cancer syndromes with effort to identify underlying genetic abnormalities affecting common developmental and cancer pathways. Dr. Rauen led the research team, including the CFC International Family Support Group that discovered the genetic cause of cardio-facio-cutaneous syndrome. She serves on the medical advisory board of CFC International and is a Co-Director for the Costello Syndrome Family Network.
Dr. Rauen is committed to academic medicine, medical education, and advancing best practices for patients with RASopathies. She has successfully obtained both intramural and extramural funding for her research activities. In her current research, the goal is to understand how myogenesis is affected by Ras/MAPK dysregulation, as well as the specific mechanism of action underlying this effect. She is examining novel germline mutations identified in the RASopathies to help understand how Ras dysregulation affects muscle development. The overarching goal is to utilize the results derived from these experiments to evaluate the effectiveness of rationally chosen inhibitors to correct the developmental effects of a dysregulated Ras pathway using in vitro and in vivo models of myogenesis.
Dr. Rauen has been awarded the Presidential Early Career Award for Scientists and Engineers (PECASE), the highest honor bestowed by the United States Government on science and engineering professionals in the early stages of their independent research careers.