Whole exome sequencing of patients from five unrelated families with similar symptoms of autoimmunity involving inflammatory arthritis and interstitial lung disease (affecting the tissue and space around the air sacs) has identified the genetic mutation that causes this disorder, said researchers led by those at Baylor College of Medicine and Texas Children’s Hospital in a report that appears online today in the journal Nature Genetics.
The gene involved is called coatomer subunit alpha (COPA), and Dr. Jordan Orange, chief of immunology, allergy and rheumatology and director of the Texas Children's Hospital Center for Human Immunobiology and a professor of pediatrics at Baylor, dubbed the new disorder COPA syndrome. The study was a collaboration with the Baylor-Hopkins Center for Mendelian Genomics and the University of California, San Francisco.
COPA syndrome is an autosomal dominant genetic condition that can vary in severity. Autosomal dominant means that if a person inherits the mutated gene, he or she has the disease, which usually starts in childhood and typically involves both lung disease and arthritis.
Orange, Dr. James Lupski, professor of molecular and human genetics and pediatrics at Baylor and co-director of the Center for Mendelian Genomics at Baylor and Johns Hopkins, and Dr. Anthony Shum from UCSF led the study.
Comparing the whole exomes of the patients to those of siblings who were unaffected by the disease allowed the team to identify the mutated gene.
“The fact that we discovered five unrelated families and over 20 individuals in just over two and half years of investigating leads me to believe that this is by no means ultra rare,” said Orange. “We are excited to learn how variants of this disease might be more broadly applicable and might be instructive to our overall understanding and treatment of arthritis.”
Orange and his team at Texas Children’s and Baylor are now also trying to conceive better ways to minimize the negative effects to the body’s cells of having a defective COPA gene.
“We are making headway in controlling the bad behavior demonstrated by cells that contain a mutant COPA as it places extraordinary stress upon one specific compartment within the cells,” said Orange. “We are evaluating certain known clinical immunomodulatory drugs in the lab for their effects upon patient cells and hope that it quickly gives us insight into how better to treat the patients themselves.”
Orange suggests that anyone who has arthritis and interstitial lung disease together should be evaluated for the mutated COPA gene.
Patients with the newly discovered syndrome have a poor prognosis, and at present can only be treated with anti-inflammatory and immunosuppressant drugs. Many have lung disease so severe that they must receive lung transplants.
“But thanks to biological mechanisms revealed in the research, patients could soon have access to a wider range of therapies,” said Shum, an assistant professor of medicine at UCSF and co-senior author of the new study. “We believe that there are small molecules in development that can help correctly traffic the proteins that are misdirected in this syndrome, so that’s something we really want to go after.”
Others who took part in this study include Kwanghyuk Lee, Regie L P Santos-Cortez, Tomasz Gambin, Samantha Penney, Claudia Gonzaga-Jauregui, Shalini N Jhangiani, Suzanne M Leal, N Tony Eissa, Richard A Gibbs and Donna M Muzny from Baylor; Levi B Watkin, Timothy J Vece, Lisa R Forbes, Emily M Mace, Sarah K Nicholas, Karen Nahmod, George Makedonas, Debra L Canter, Asbjørg Stray-Pedersen, Dongfang Liu, from Baylor and Texas Children’s; John Hicks from Texas Children’s; Birthe Jessen, Max Jan, Maike Thamsen, Christopher S Law, Mickie H Cheng, Mark S Anderson, Feroz R Papa, Noah Zaitlen, Ling Fung Tang, Pui-Yan Kwok, Kirk D Jones, Michael D Rosenblum, Michael R Waterfield, from University of California, San Francisco; Sharon D Dell from Hospital for Sick Children in Ontario, Canada; and Eric Boerwinkle from University of Texas–Houston Health Science Center.
Funding for this work came from the U.S. National Institutes of Health (Grant R01AI067946, K08HL095659, K23NS078056, AI053831), the Jeffrey Modell Foundation, the Foundation of the American Thoracic Society, the Pulmonary Fibrosis Foundation, the Nina Ireland Lung Disease Program, the U.S. National Human Genome Research Institute Institute/National Heart, Lung, and Blood Institute (Grant U54HG006542 ).
The new, state-of-the-art Center for Human Immunobiology at Texas Children’s pairs world-class basic science immunologists with cutting-edge technologies and integrates them into a clinical setting through an expert team of clinical immunologists. Together they work to advance new mechanistic understanding of the human immune system.
“We took advantage of the resources available through the Baylor-Hopkins Center for Mendelian Genomics to discover the gene responsible for this devastating disease” said Dr. Wojciech Wiszniewski, an assistant professor of molecular and human genetics at Baylor and a clinical geneticist at the Texas Children’s Hospital Genetics Clinic, and a coauthor of the study.