PMID- 25956157 OWN - NLM STAT- MEDLINE DCOM- 20160721 LR - 20201113 IS - 1468-2060 (Electronic) IS - 0003-4967 (Print) IS - 0003-4967 (Linking) VI - 75 IP - 4 DP - 2016 Apr TI - Private rare deletions in SEC16A and MAMDC4 may represent novel pathogenic variants in familial axial spondyloarthritis. PG - 772-9 LID - 10.1136/annrheumdis-2014-206484 [doi] AB - 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. CI - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/ FAU - O'Rielly, Darren D AU - O'Rielly DD AD - Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada. FAU - Uddin, Mohammed AU - Uddin M AD - Program in Genetics and Genome Biology, The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada. FAU - Codner, Dianne AU - Codner D AD - Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada. FAU - Hayley, Michael AU - Hayley M AD - Biochemistry Department, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada. FAU - Zhou, Jiayi AU - Zhou J AD - Department of Computer Science, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada. FAU - Pena-Castillo, Lourdes AU - Pena-Castillo L AD - Department of Computer Science, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada. FAU - Mostafa, Ahmed A AU - Mostafa AA AD - Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada. FAU - Hasan, S M Mahmudul AU - Hasan SM AD - Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada. FAU - Liu, William AU - Liu W AD - Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada. FAU - Haroon, Nigil AU - Haroon N AD - Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada. FAU - Inman, Robert AU - Inman R AD - Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada. FAU - Rahman, Proton AU - Rahman P AD - Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada. LA - eng GR - FRN 127002/Canadian Institutes of Health Research/Canada PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150508 PL - England TA - Ann Rheum Dis JT - Annals of the rheumatic diseases JID - 0372355 RN - 0 (HLA-B27 Antigen) RN - 0 (Proteins) RN - 0 (SEC16A protein, human) RN - 0 (Vesicular Transport Proteins) RN - Chromosome 10, monosomy 10q SB - IM MH - Adolescent MH - Adult MH - B-Lymphocytes/*metabolism MH - Blotting, Western MH - Child MH - Chromosome Deletion MH - Chromosomes, Human, Pair 10 MH - Circular Dichroism MH - Female MH - Genetic Linkage MH - HLA-B27 Antigen/*genetics MH - Heterozygote MH - Humans MH - Male MH - Microscopy, Fluorescence MH - Mutation MH - Pedigree MH - Polymerase Chain Reaction MH - Proteins/*genetics/metabolism MH - Spondylarthropathies/*genetics MH - Vesicular Transport Proteins/*genetics/metabolism PMC - PMC4819618 OTO - NOTNLM OT - Ankylosing Spondylitis OT - Autoimmune Diseases OT - Inflammation OT - Low Back Pain OT - Spondyloarthritis EDAT- 2015/05/10 06:00 MHDA- 2016/07/22 06:00 PMCR- 2016/04/04 CRDT- 2015/05/10 06:00 PHST- 2014/08/15 00:00 [received] PHST- 2015/03/07 00:00 [accepted] PHST- 2015/05/10 06:00 [entrez] PHST- 2015/05/10 06:00 [pubmed] PHST- 2016/07/22 06:00 [medline] PHST- 2016/04/04 00:00 [pmc-release] AID - annrheumdis-2014-206484 [pii] AID - 10.1136/annrheumdis-2014-206484 [doi] PST - ppublish SO - Ann Rheum Dis. 2016 Apr;75(4):772-9. doi: 10.1136/annrheumdis-2014-206484. Epub 2015 May 8.