His own interest in genomic medicine dates back 20 years, when he worked on the development of high-resolution genetic mapping of MEFV, the gene mutated in familial Mediterranean fever (FMF) in families of North African and Middle Eastern descent, he said.3
“The idea that you could use tools from the beginning of the Human Genome Project to discover the genes underlying what were, at that time, unexplained conditions, sounded like a really cool thing to do,” said Dr. Kastner. With only a few hundred genetic markers then known, early genomic research required the collection of large amounts of human DNA from donated placentas, he said. “We had to find out what chromosome the gene was on, and we hoped we would eventually find a gene teaching us something about inflammation. That’s exactly what happened. We did find a novel gene, and this protein product nobody knew anything about. There was a long process to figure out what this gene does and how it affects human disease.”
He and his colleagues in the International FMF Consortium discovered that pyrin, a domain on the MEFV gene, allows molecules in the innate immune system to associate with each other, which led to the discovery of a new signaling pathway. Rho-GTPase, which lives inside the cell membranes of certain leukocytes, normally leads to the activation of PKN-1, a kinase that in turn phosphorylates pyrin and prevents the activation of IL-1, an inflammatory cytokine. Bacterial toxins can inactivate Rho-GTPase and inhibit PKN-1, which then inhibits the phosphorylation of pyrin and leads to the formation of this inflammasome and IL-1 production in these patients, he said.
“So this knowledge has helped us understand this disease better, and has helped us treat patients,” said Dr. Kastner. Some FMF patients don’t respond to colchicine, the usual therapy, because the drug affects Rho-GPTase activity. “For those patients, we now know we can use IL-1 inhibitors. It’s made a huge difference in the lives of those people.”
Starting with their discoveries related to MEFV mutations and FMF, Dr. Kastner and other NIH researchers looked at mutations in other genes involved in the same pathway, and they found that several inflammatory diseases, including Muckle-Wells syndrome, familial cold autoinflammatory syndrome and neonatal-onset multisystem inflammatory disease (NOMID), were also related. Although children with NOMID often died before they reached adulthood, genomic research allowed rheumatologists to develop IL-1 inhibitors to treat it, and “now these kids are graduating from high school,” said Dr. Kastner.