Katherine A. Rauen, MD, PhD

Affiliated

Dr. Rauen has two main research programs. One involves an exciting class of medical genetic syndromes which has recently emerged caused by germline mutations in genes associated with the Ras/mitogen-activated protein kinase (MAPK) pathway. The research program involves the clinical and basic science study of cancer syndromes with efforts to identify underlying genetic abnormalities affecting common developmental and cancer pathways. Two syndromes are focused upon: Costello syndrome (CS) and cardio-facio-cutaneous (CFC) syndrome. CS is a complex developmental disorder involving characteristic craniofacial features, failure to thrive, developmental delay, cardiac and skeletal anomalies and a predisposition to develop neoplasia, both benign and malignant. CS is caused by activating germline mutations in HRAS. Ras is a critical signaling hub in the cell and is activated by receptor tyrosine kinases, G-protein-coupled receptors, cytokine receptors and extracellular matrix receptors. The downstream effectors of Ras are many and control vital cellular functions including cell cycle progression, cell survival, motility, transcription, translation and membrane trafficking. CFC syndrome is a rare multiple congenital anomaly disorder, is caused by germline mutations in BRAF, MEK1 and MEK2 within the MAPK pathway, a downstream cascade effected by Ras. The type of BRAF mutations found in CFC recapitulates the different types of mutations found in cancer which cause an alteration of signaling down the MAPK pathway. However, in contrast to the mutation spectrum seen in cancer, the majority of BRAF mutations identified in CFC in Dr Rauen s lab are novel. Understanding the genetic role of HRAS in CS and BRAF, MEK1 and MEK2 in CFC syndrome is the first step in gaining insight to the role Ras and Raf plays in human development, cellular signaling and cancer pathogenesis. The second research program involves the application of array CGH in clinical genetics. Gene discovery efforts and genetic pathogenesis utilizing array CGH are ongoing projects in the laboratory.