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COPA syndrome is a rare monogenic disorder caused by heterozygous mutations in the COPA gene (HGNC:2230), leading to an autosomal dominant presentation of autoimmune interstitial lung disease and arthritis (MONDO_0014629). Multiple independent case reports and multi‐patient studies have described patients presenting with lung abnormalities, joint and kidney involvement, and inflammatory symptoms. Clinical features encompass abnormal lung morphology, abnormal joint morphology, fatigue, exertional dyspnea, clubbing, and arthritis, with some patients also experiencing sepsis and respiratory failure. These findings have been robustly replicated across diverse cohorts and geographical populations (PMID:29137621, PMID:31455335).
Genetic evidence supporting the association is substantial. In several studies, a recurrent missense mutation, c.721G>A (p.Glu241Lys), was identified and shown to segregate with disease across affected families (PMID:29137621, PMID:28956095). Additional case series have reported similar pathogenic variants such as c.718T>C (p.Trp240Arg) and others, demonstrating that multiple pathogenic alleles in COPA underlie a common disease phenotype. Segregation analyses reveal that numerous affected relatives across different families support the gene-disease causal relationship, with approximately 19 additional segregating individuals observed in combined reports.
At a molecular level, the pathogenic missense mutations disrupt a highly conserved WD40 domain in the COPA protein. Functional studies have demonstrated that these mutations impair ER-to-Golgi transport, leading to ER stress, abnormal activation of the stimulator of interferon genes (STING) pathway, and an augmented type I interferon response (PMID:25894502, PMID:33982886). Such experimental findings provide mechanistic insights that harmonize with clinical observations involving multi-organ inflammatory disease.
The reported genetic alterations, particularly the recurrent c.721G>A (p.Glu241Lys) variant, are absent from large control cohorts, further underscoring their pathogenicity. The convergence of robust genetic evidence, including segregation in multiple families and replication across independent cohorts, alongside functional assays that recapitulate key aspects of the disease phenotype, firmly supports a strong gene-disease association.
In summary, the comprehensive integration of case reports, multi-patient studies, and functional assessments establishes that COPA mutations are a definitive cause of autoimmune interstitial lung disease-arthritis syndrome. This association is crucial for diagnostic decision-making, informs potential therapeutic strategies, and lays the groundwork for future clinical application.
Key Take‑home: The robust genetic and functional evidence confirming COPA mutations in autoimmune interstitial lung disease-arthritis syndrome supports their clinical utility in diagnosis and targeted management.
Gene–Disease AssociationStrongMultiple independent studies report the recurrent c.721G>A (p.Glu241Lys) mutation in COPA in over 23 probands with consistent segregation and absence in controls (PMID:29137621, PMID:31455335). Genetic EvidenceStrongRecurrent, pathogenic missense variants identified in COPA across several families with clear segregation support, including detailed reports of c.721G>A and related alleles. Functional EvidenceStrongMultiple functional studies demonstrate that COPA mutations impair ER-Golgi transport and hyperactivate the STING pathway, leading to an augmented type I interferon response that recapitulates the clinical phenotype. |