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Extended report
Private rare deletions in SEC16A and MAMDC4 may represent novel pathogenic variants in familial axial spondyloarthritis
  1. Darren D O'Rielly1,
  2. Mohammed Uddin2,
  3. Dianne Codner1,
  4. Michael Hayley3,
  5. Jiayi Zhou4,
  6. Lourdes Pena-Castillo4,
  7. Ahmed A Mostafa1,
  8. S M Mahmudul Hasan1,
  9. William Liu1,
  10. Nigil Haroon5,
  11. Robert Inman5,
  12. Proton Rahman1
  1. 1Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada
  2. 2Program in Genetics and Genome Biology, The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada
  3. 3Biochemistry Department, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada
  4. 4Department of Computer Science, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada
  5. 5Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada
  1. Correspondence to Dr Proton Rahman, Faculty of Medicine, Memorial University, 154 LeMarchant Rd, St. John's, Newfoundland, Canada A1C 5B8; prahman{at}mun.ca

Abstract

Objective Axial spondyloarthritis (AxSpA) represents a group of inflammatory axial diseases that share common clinical and histopathological manifestations. Ankylosing spondylitis (AS) is the best characterised subset of AxSpA, and its genetic basis has been extensively investigated. Given that genome-wide association studies account for only 25% of AS heritability, the objective of this study was to discover rare, highly penetrant genetic variants in AxSpA pathogenesis using a well-characterised, multigenerational family.

Methods HLA-B*27 genotyping and exome sequencing was performed on DNA collected from available family members. Variant frequency was assessed by mining publically available datasets and using fragment analysis of unrelated AxSpA cases and unaffected controls. Gene expression was performed by qPCR, and protein expression was assessed by western blot analysis and immunofluorescence microscopy using patient-derived B-cell lines. Circular dichroism spectroscopy was performed to assess the impact of discovered variants on secondary structure.

Results This is the first report identifying two rare private familial variants in a multigenerational AxSpA family, an in-frame SEC16A deletion and an out-of-frame MAMDC4 deletion. Evidence suggests the causative mechanism for SEC16A appears to be a conformational change induced by deletion of three highly conserved amino acids from the intrinsically disordered Sec16A N-terminus and RNA-mediated decay for MAMDC4.

Conclusions The results suggest that it is the presence of rare syntenic SEC16A and MAMDC4 deletions that increases susceptibility to AxSpA in family members who carry the HLA-B*27 allele.

  • Ankylosing Spondylitis
  • Autoimmune Diseases
  • Inflammation
  • Spondyloarthritis
  • Low Back Pain

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