COPA Syndrome is an autoimmune disease which affects multiple organ systems, primarily the lungs and the joints. Most patients experience interstitial lung disease and arthritis, and some experience renal symptoms such as glomerulonephritis. These symptoms usually arise in early childhood.
Interstitial lung disease (ILD) is characterized by inflammation of the lungs, which often leads to scarring. Affected people primarily have difficulty breathing, but since many diseases fall under the category of ILD, individuals may experience a range of other symptoms. ILD can be treated with steroids to reduce inflammation, supplementary oxygen, and in severe cases, a lung transplant may be necessary.
Arthritis involves inflammation of the joints. Because COPA Syndrome generally appears in children, they are diagnosed with juvenile arthritis. Arthritis manifests as swelling and pain at the affected joints, and can affect a person’s mobility. Arthritis can be treated with anti-inflammatory pain medication, immunosuppressants, and/or steroids.
COPA Syndrome is caused by a mutation in the COPA gene. This disease has the properties of incomplete penetrance and variable expressivity: not everyone with a mutation will experience symptoms, and those affected will experience different symptoms to different degrees of severity.
Within a cell, proteins are synthesized in the endoplasmic reticulum (ER) and sent to the Golgi apparatus to be packaged and sorted before being sent to their destination. Retrograde transport of proteins sent from the Golgi back to the ER is guided by the COPI coatomer, which is a protein complex composed of seven protein subunits.
One of the protein subunits is COPα, which recognizes cargo proteins marked with a dilysine motif for retrograde transport. COPα binds the cargo at its dilysine motif and induces the budding-off of a vesicle in which the bound cargo and COPI travel towards the ER.
Intracellular transport processes are complex and present many opportunities for error. These processes are also crucial to many larger bodily functions; their defectiveness has been implicated in a number of diseases. Defects in COPα are similarly damaging.
Mechanisms of COPA Syndrome
COPA Syndrome is caused by a mutation in COPA, the gene that encodes COPα. There are seven individual documented mutations that can cause COPA Syndrome. These mutations arise spontaneously in germ cells (affecting only the resulting child) or are inherited in an autosomal dominant manner.
The proposed mechanism through which mutations in COPA cause disease is as follows:
A mutated COPA gene produces a mutated protein.
The mutated protein is unable to efficiently bind the dilysine motif of cargo proteins.
The ER is unable to process the mutant protein, inducing ER stress.
The cell reacts to ER stress with the unfolded protein response (UPR).
UPR pathways involve an inflammatory immune response.
Areas of the body such as the lungs and the joints become inflamed.