Analysis of polymorphisms in the colchicine binding site of tubulin in colchicine-resistant familial Mediterranean fever

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ORIGINAL ARTICLE

Analysis of polymorphisms in the colchicine binding site of tubulin in colchicine‑resistant familial Mediterranean fever patients Tayfun Hilmi Akbaba1 · Gizem Ustabas1 · Muserref Kasap‑Cuceloglu2 · Seza Ozen2 · Banu Balci‑Peynircioglu1  Received: 8 June 2020 / Accepted: 29 October 2020 © Springer Nature B.V. 2020

Abstract Familial Mediterranean fever is a hereditary autoinflammatory syndrome. The typical treatment for the disease is colchicine. However, a subset of patients are not responsive to colchicine. In this study, polymorphisms in the colchicine-binding site of the TUBB1 gene, which encodes a tubulin isoform specific to leukocytes, were investigated in patients with colchicineresistant disease. FMF patients who were followed in the Department of Pediatric Rheumatology at Hacettepe University were included in this study. Colchicine resistance was defined as ongoing disease activity (≥ 1 attack/month over 3 months or persistently elevated CRP) while taking the maximum tolerated dose of colchicine. A total of 62 Turkish FMF patients (42 colchicine-responsive and 20 colchicine-resistant) and a control group of healthy children were included in the study. DNA was extracted for analysis of TUBB1, and the colchicine binding site was sequenced. We did not observe A248T (rs148237574) or M257V (rs759579888), two variations that were previously associated with colchicine resistance in an in silico analysis. We did detect T274M (rs35565630), R306H (rs772479017), and R307H (rs6070697) variants in the FMF patients, but there was no statistically significant difference between the colchicine-responsive and colchicine-resistant groups. This is the first study to evaluate TUBB1 gene polymorphisms in the colchicine binding site in patients with FMF. Our data do not support the hypothesis that these polymorphisms are a possible cause of colchicine resistance in FMF patients. Keywords  Colchicine resistance · Familial Mediterranean fever · Polymorphism · TUBB1 · Tubulin

Introduction Familial Mediterranean fever (FMF) is a monogenic hereditary autoinflammatory disease caused by mutations in MEFV, which encodes pyrin, a protein involved in the regulation of neutrophil activity, that is characterized by recurrent inflammatory attacks of fever and serositis. FMF is a rare disease worldwide; however, it is not a rare disease among groups living in eastern Mediterranean regions, such as Turks, Jews, Arabs, and Armenians. Among these groups, Electronic supplementary material  The online version of this article (https​://doi.org/10.1007/s1103​3-020-05957​-8) contains supplementary material, which is available to authorized users. * Banu Balci‑Peynircioglu [email protected] 1



Department of Medical Biology, Hacettepe University Faculty of Medicine, Ankara, Turkey



Division of Rheumatology, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey

2

the prevalence varies between 1/5 and 1/2000 [1]. In FMF, 366 variants in MEFV have been identified, and the M694V/ M694V variant is a