Autoimmune Interstitial Lung, Joint, And Kidney Disease

A number sign (#) is used with this entry because of evidence that autoimmune interstitial lung, joint, and kidney disease (AILJK) is caused by heterozygous mutation in the COPA gene (601924) on chromosome 1q23.

Description

Autoimmune interstitial lung, joint, and kidney disease is an autosomal dominant systemic autoimmune disorder characterized by interstitial lung disease, inflammatory arthritis, and immune complex-mediated renal disease. Laboratory studies show high-titer autoantibodies. Symptoms appear in the first 2 decades of life, but there is incomplete penetrance (summary by Watkin et al., 2015).

Clinical Features

Watkin et al. (2015) reported 5 unrelated families in which a total of 21 individuals had an autoimmune disorder affecting the lungs and joints, and, in some patients, the kidney. The features of 9 patients from 5 families were reported in detail. The patients presented between 6 months and 7 years, mainly with joint pain, shortness of breath, or cough. All had interstitial lung disease, manifest as pulmonary hemorrhage, obstruction, restriction, or a diffusion capacity defect. Joint disease included nonerosive arthritis; 1 patient had avascular necrosis of distal femur and a pathologic fracture. Four patients had renal biopsies that showed immune complex crescentic glomerulonephritis with mesangial expansion, hypercellularity, and antibody deposition, and 1 patient required a renal transplant. Laboratory studies showed evidence of systemic inflammation, with increased C-reactive protein (CRP; 123260) and erythrocyte sedimentation rate. All patients were on long-term immunosuppressive medical therapy.

Inheritance

The transmission pattern of AILJK in the families reported by Watkin et al. (2015) was consistent with autosomal dominant inheritance with incomplete penetrance.

Molecular Genetics

In 30 individuals from 5 unrelated families with AILJK, Watkin et al. (2015) identified 4 different heterozygous missense mutations in the COPA gene (601924.0001-601924.0004). All mutations affected the WD40 domain. Nine mutation carriers were clinically unaffected, consistent with incomplete penetrance. Mutations in 4 of the families were found by whole-exome sequencing. In vitro studies of 2 COPA mutations (E241K, 601924.0003 and K230N, 601924.0004) showed that the mutant variants had impaired binding to proteins targeted for retrograde transport from the Golgi to the endoplasmic reticulum (ER). Patient-derived cells showed evidence of increased ER stress, and cellular expression of mutant COPA in HEK cells caused increased ER stress in a dominant-negative manner. Patient cells and transfected cells also showed a defect in autophagic function, which may have been due to impaired early endosomal function. Transfected cells showed upregulation of cytokines priming for a T- helper type 17 (Th-17) response, and patient-derived CD4+ T cells showed skewing toward a Th-17 phenotype implicated in autoimmunity. The findings suggested a link between a vesicular transport protein and an autoimmune syndrome manifest mainly as lung and joint disease.