In the next five years, exome sequencing will become available for whoever needs it.
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SAN FRANCISCO—Early in his career, Daniel Kastner, MD, PhD, scientific director at the National Human Genome Research Institute, saw a 24-year-old patient with a lifelong history of recurrent fever and severe episodes of arthritis. A colleague told him it was most likely familial Mediterranean fever (FMF).
There was little then known about its mechanisms, and a curiosity about the inner workings of the disease led him to a decades-long pursuit. The quest for knowledge about the single gene responsible for the disease, recounted by Dr. Kastner in his Paul Klemperer, MD, Memorial Lecture given at the 2015 ACR/ARHP Annual Meeting, has, many years later, resulted in a detailed model and is a lesson in scientific doggedness.
At the time he saw the 24-year-old patient, FMF was known to be caused by a single gene, but “nothing was known about the gene itself,” including its chromosomal location or its protein product, Dr. Kastner said. The Human Genome Project was just taking off, and Dr. Kastner considered it a well-timed “scientific opportunity.”
Gene Identification
Meeting in 1989 in Israel, he and colleagues drew blood from FMF patients and their families. He then used those samples to study the DNA, eventually mapping the gene to the distal part of chromosome 16. His lab then further narrowed down the region, and, in 1997, discovered a novel gene that encodes a protein they called pyrin, after pyrexia for fever.
Dr. Kastner
Then, Dr. Kastner said, they had to figure out what the gene did.
They found that the terminal end of the protein encoded a 90-amino-acid section—called the pyrin domain—that can form a cognate interaction, meaning it can interact with other pyrin domains in other proteins. They found that the pyrin domain of the pyrin protein interacts with the pyrin domain of the ASC protein. That protein has a domain called CARD, which interacts with the CARD domain of Caspase-1, the enzyme that activates pro-IL-1-beta into IL-1, a major mediator of fever and inflammation.
This finding gave clinicians a tool for distinguishing patients with FMF, and offered the opportunity to use IL-1 inhibitors in patients who didn’t respond to standard treatments—a therapeutic option that has been vital for many patients, Dr. Kastner said.
About Pyrin
Many “inflammasome” molecules like pyrin are sensors for microbial infections—but researchers, at that point, still didn’t know the function of pyrin. A team of researchers in Beijing then reported that the pyrin inflammasome is activated by the toxins of certain bacteria—including Clostridium botulinum and Clostridium difficile—that interact with and inactivate Rho-GTP-ase (RhoA), binding proteins that regulate a wide variety of cell functions.
