Abstract: FR-PO1043
Familial Goodpasture’s Disease Associated with a Deletion in COL4A3: A Potential Clue to Etiology
Session Information
- Glomerular Diseases: Immunology and Inflammation - II
October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1202 Glomerular Diseases: Immunology and Inflammation
Authors
- Seeger, Harald, University Hospital Zurich, Zurich, Switzerland
- Pedchenko, Vadim, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Budko, Sergey, Vanderbilt Univ Medical Center, Nashville, Tennessee, United States
- Gaspert, Ariana, Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland
- Bergmann, Carsten, Center for Human Genetics, Ingelheim, Germany
- Lorenzen, Johan, University Hospital Zurich, Zurich, Switzerland
- Wuthrich, Rudolf P., University Hospital Zurich, Zurich, Switzerland
- Hudson, Billy G., Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Kistler, Andreas D., Kantonsspital Frauenfeld, Frauenfeld, Switzerland
Introduction
Goodpasture’s (GP) or anti-glomerular basement membrane (GBM) disease is characterized by glomerulonephritis (GN) and/or alveolar hemorrhage. It is caused by antibodies that bind the non-collagenous domain (NC1) of the collagen IV α345 network in the GBM and alveolar basement membranes. Antibodies bind to α3 and α5 NC1 monomers but not native α345NC1 hexamers, indicating that a perturbation of the quaternary structure of the hexamer is required for eliciting an autoimmune response. We describe a case of familial GP disease associated with a structural alteration in the α345NC1 domain.
Case Description
The index patient was affected at the age of 45 years by alveolar hemorrhage and renal failure due to GN with linear IgG deposits in the GBM and circulating anti-GBM antibodies. Her son developed the same clinical phenotype at the age of 24 years. Genetic analysis revealed a heterozygous 18 base pair deletion in both subjects in the region of the COL4A3 gene coding for the NC1 domain. The deletion contains the stop codon and leads to an elongated collagen α3NC1 domain, which substitutes 8 additional amino acid (AA) residues for the very last C-terminal AA.
Discussion
COL4A3 mutations typically cause autosomal Alport’s or thin basement membrane disease, yet there was no evidence for this in our patients. Anti-GBM antibodies behaved like in classical GP cases. They reacted with dissociated, but not native α345NC1hexamers, and bound to the wild type α3NC1 monomer at both EA and EB epitopes. Analysis of the 3D model of the α345 hexamer revealed that the mutant extension of 8 polar and hydrophobic residues is located proximal to the EA and EB epitopes. Potentially, the extension can fold into the crevice between both epitopes and lead to conformational changes that impact epitope presentation. The epitope structure may be altered to include residues of the extension or rendered accessible by the antibody. In conclusion, this is the first report of a COL4A3 mutation associated with GP disease. The occurrence of this mutation in two family members, with autoantibodies against the α3NC1 autoantigen, indicates that it plays a key role in disease etiology. The association of this mutation with disease may be a clue to the etiology of both familial and sporadic cases of GP disease.