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Arch Iran Med. 2020;23(10): 688-696.
doi: 10.34172/aim.2020.87

Scopus ID: 85094808498
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Original Article

Functional Analysis of RELN S2486G Mutation and its Contribution to Pathogenesis of Ankylosing Spondylitis

Elika Esmaeilzadeh-Gharehdaghi 1 ORCID logo, Ehsan Razmara 2 ORCID logo, Amirreza Bitaraf 3, Ahmadreza Jamshidi 4, Mahdi Mahmoudi 4,5, Masoud Garshasbi 1* ORCID logo

1 Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
2 Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia
3 Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
4 Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
5 Inflammation Research Center, Tehran University of Medical Sciences, Tehran, Iran
*Corresponding Author: *Corresponding Author: Masoud Garshasbi, PhD; Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran. Tel: +98-21-82884569; Email:, Email: masoud.garshasbi@modares.ac.ir

Abstract

Background: Ankylosing spondylitis (AS; OMIM:106300) is a common complex inflammatory disease; in a previous study, we introduced a novel mutation in the RELN gene (OMIM: 600514) which was associated with AS. This study is designed to investigate the potential effect of RELN S2486G mutation on reelin secretion; additionally, we objected to evaluate the phospholipase A2 (PLA2G7) gene (OMIM: 601690) expression and platelet-activating factor-acetylhydrolase (PAF-AH) concentration as the downstream gene and the encoded protein.

Methods: The impact of the S2486G on reelin protein secretion was investigated in CHO-K1 and HEK-293T cells by constructing wild-type and mutant plasmids. Besides, the possible effect of the mutation on expression and concentration of PLA2G7 and PAF-AH in THP1 cells was assessed by quantitative real-time PCR (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. The study was performed at Tarbiat Modares University, Tehran, Iran, from 2016 to 2018.

Results: Our results showed that S2486G not only causes a significant reduction in reelin secretion in both HEK-293T and CHO-K1 cells, but also it leads to a significant reduction in PLA2G7 gene expression (P value < 0.001) and protein level of PAF-AH in THP-1 cells (P value < 0.003).

Conclusion: The S2486G mutation in RELN can alter inflammatory and, to some extent, osteogenesis pathways mediated by reduced secretion of reelin and also reduced expression of the PLA2G7 gene.

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Submitted: 15 Apr 2020
Revision: 14 Jun 2020
Accepted: 04 Jul 2020
ePublished: 01 Oct 2020
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