COPA mutations disrupt intracellular transport and cause a novel autoimmune syndrome characterized by chronic pulmonary disease with pulmonary hemorrhages. W. Wiszniewski1, L. B. Watkin2, B. Jessen3, T. Vece2, L. Forbes2, C. Gonzaga-Jauregui1, S. N. Jhangiani4, D. M. Muzny4, E. Boerwinkle5, R. A. Gibbs4, A. Shum3, J. Orange2, J. R. Lupski1 1) Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; 2) Texas Childrens Hospital, Houston, TX; 3) UCSF School of Medicine, San Francisco, CA; 4) Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX; 5) Human Genetics Center and Institute of Molecular Medicine, University of Texas-Houston Health Science Center, Houston, TX,.
Autoimmune disorders are a group of clinically heterogeneous diseases that result from dysregulation of immunologic mechanisms. The genetic contribution to autoimmune disease ranges from simple Mendelian inheritance of causative alleles to the complex interactions of multiple weak loci influencing risk. Despite the rapid advances in genome-wide genetic analysis, substantial components of the heritable risk remain unexplained. Here, we report a novel hereditary autoimmune syndrome where affected individuals develop chronic pulmonary disease with pulmonary hemorrhages and other autoinflamatory manifestations including arthritis and nephropathy. We performed whole-exome sequencing in five affected subjects from three large pedigrees. We identified missense mutations in COPA (OMIM# 601924), a novel gene encoding a cargo protein involved in intracellular protein transport in the affected members of all three families. COPA is a component of the COPI coatomer complex that is important for retrograde Golgi to ER transport. All mutations were localized to a functionally important WD40 domain, predicted to be pathogenic by available bioinformatics tools and shown to segregate with the disease phenotype in multi generation families. These predictions were further supported by results of functional studies that demonstrated evidence of i) increase in ER stress, ii) abnormal size of endolysosomes, and iii) impaired autophagy. These latter cellular abnormalities have been described in other autoimmune diseases. In conclusion we demonstrated that abnormal intracellular transport caused by specific COPA mutations may trigger increased ER stress and impaired autophagy that leads to dysregulation of immunologic mechanisms and secondary autoimmune disorder affecting the lung and joints.