Impaired intracellular transport can cause hereditary autoimmune conditions

Autoimmunity is defined as the immune response mounted by an organism against itself. Basal level autoimmune responses are an important part of the vertebrate immune system. They help to keep the immune cells primed and ready to respond quickly to an attack.  However, exaggerated autoimmune responses are unhealthy and lead to various pathological conditions.

About 3-5% of US population is affected by various autoimmune disorders. While exact molecular causes for many of them remain unidentified, they all appear to have a hereditary component. Defects in genes encoding immune proteins such as immunoglobulins, T-cell receptors and major histocompatibility complex (MHC) are the most common cause of autoimmune disorders. In recent years, a few animal studies have demonstrated that defects in certain non-immune genes can also lead to autoimmune disorders.

A ground-breaking study1 published in Nature Genetics from the laboratories of Drs. Jordan Orange and Anthony Shum in collaboration with Dr. James Lupski at the Baylor College of Medicine, Texas Children’s Hospital and University of California, San Francisco have identified a novel role for intracellular trafficking machinery in the development of a hereditary autoimmune disorder.

Most of the thirty patients from five unrelated families presented with similar symptoms of autoimmunity, namely, high-titer of autoantibodies, lung disease accompanied with acute bleeding, inflammatory arthritis with joint pain and renal disease. To identify the underlying genetic basis of this apparent Mendelian disorder, the authors performed whole exome sequencing of these patient’s DNA. 

Whole exome sequencing is the latest technology used to identify genetic mutations, especially rare variants. This involves sequencing a selected subset of protein coding genes. Using this technique, authors found that 21 out of 30 patients in this cohort carried mutations in the same gene, COPA, suggesting an autosomal dominant mode of inheritance. This means that inheritance of a single defective copy of this gene from either parent is sufficient for the disease presentation. Although they found four different variants of COPA among five families, interestingly, all of them disrupted the same functional domain of COPA protein. Taking all the data together, they conclude that malfunction of COPA could be the underlying cause of shared pathological symptoms.

COPA gene encodes coatomer subunit alpha protein, an integral component of the coat protein I (COPI) intracellular trafficking machinery. COPI is one of the carrier complexes that mediates retrograde transport of proteins from Golgi back to the endoplasmic reticulum (ER).

This study shows that all the four point mutations identified in patient families are located in COPA domain that is critical for the selection and sorting of specific cargoes into the retrograde trafficking pathway. Interestingly, they found signs of increased ER stress and Th17 cells, both of which had been previously observed in patients with clinical symptoms of autoimmunity.

Thus, this study has clearly demonstrated that impaired retrograde transport due to aberrant COPA function can lead to the observed autoimmune symptoms in the lungs and kidneys along with arthritis.

Exact mechanistic details of how COPA mutations cause these autoimmune symptoms remain to be elucidated. However, based on this study, it is evident these patients especially if they have a family history need to be examined for mutations in COPA gene.

Thus, this exciting study has identified a potential diagnostic tool and therapeutic target for a novel autoimmune disorder.


Watkin et al., COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis. Nat Genet. 2015 Apr 20. doi: 10.1038/ng.3279.