COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis.

ABSTRACT: Unbiased genetic studies have uncovered surprising molecular mechanisms in human cellular immunity and autoimmunity. We performed whole-exome sequencing and targeted sequencing in five families with an apparent mendelian syndrome of autoimmunity characterized by high-titer autoantibodies, inflammatory arthritis and interstitial lung disease. We identified four unique deleterious variants in the COPA gene (encoding coatomer subunit α) affecting the same functional domain. Hypothesizing that mutant COPA leads to defective intracellular transport via coat protein complex I (COPI), we show that COPA variants impair binding to proteins targeted for retrograde Golgi-to-ER transport. Additionally, expression of mutant COPA results in ER stress and the upregulation of cytokines priming for a T hel

SUBMITTER: Watkin LB 

PROVIDER: S-EPMC4513663 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature