Jonathan Pevsner, PhD
Jonathan Pevsner is an Associate Professor in the Department of Neurology (Kennedy Krieger Institute) and the Department of Psychiatry (Johns Hopkins Medicine). He received his bachelor's degree from Haverford College, his Ph.D. from Johns Hopkins, and did his postdoctoral training at Stanford University. His laboratory studies the genetics of childhood brain disorders, and he began research on Sturge-Weber syndrome in 1999. He is the recipient of multiple teaching awards and wrote a textbook, Bioinformatics and Functional Genomics (2009).
Abstract
A major goal of Sturge-Weber syndrome research has been to identify the underlying genetic mutation. Recent developments in technology allow us to determine the sequence of essentially all 3 billion base pairs in the human genome. We hypothesized that by sequencing the genome twice--from an affected part of the body (such as a port-wine stain) and from an unaffected part (such as blood)--we could compare the sequence within an individual to identify an altered gene. We obtained pairs of whole genome sequences from three individuals with Sturge-Weber syndrome and identified a single base pair change in the gene GNAQ on chromosome 9. This mutation occurred selectively in affected samples. We then confirmed this mutation by exhaustive sequencing of 90 samples from 50 individuals. This showed that nearly all affected skin samples, and many affected brain samples, harbor a mutation in GNAQ. This mutation is somatic (that is, it occurs early in development but is not inherited from the parents), and mosaic (it occurs in some but not all parts of the body; and within an affected region the amount of mutated sequence ranges from 1% to 18%). The full name of GNAQ is guanine nucleotide binding protein (G protein), q polypeptide. This gene encodes a protein, Gaq, that has been extensively studied for over 20 years. Gaq acts as a switch on the inside wall of many cells. When a variety of receptors on the cell surface receive a signal from outside the cell, Gaq has a key role in activating downstream pathways. The specific mutation that occurs in Sturge-Weber syndrome and port-wine stains persistently activates Gaq, inappropriately activating downstream pathways. Possible therapeutic approaches to Sturge-Weber syndrome include applying drugs to down-regulated Gaq activity.