Abstract

Background and Study Aim: To date, especially alterations of genes on exon 10 have been considered in Mediterranean fever (MEFV), but it is not clear whether all these alterations are disease-causing mutations.

We studied ERAP-1 gene mutations in people with FMF gene mutations without FMF phenotype. We compared our results with our previous study which we studied ERAP-1 gene mutations in patients with FMF and with ulcerative colitis (which has been shown to have a relation with ERAP-1 gene mutations before).

Patients and Methods: This is a retrospective study. We studied ERAP-1 gene mutation in blood samples (had been kept in -70°C before for different studies) from 51 people with FMF gene mutations without FMF disease. Some of these people also were followed for about 5 years whether FMF comes out.

Results: There were 10 cases without ERAP-1 mutations at Exon-3 and 6 cases without ERAP-1 mutations at Exon-10. Any ERAP-1 mutations were not obtained in three cases both for Exon-3 and 10.

There were 41 ERAP-1 gene mutations at Exon-3 and 48 at Exon-10. Exon-3 mutations were usually Codon 127 mutation for 35 patients whether it was single mutation or with multiple mutations. It was totally different our ERAP-1 mutation in patients with FMF for Exon-3. Because in our previous study, if there were ERAP-1 gene mutations at exon-3, [c.380G>C p.(Arg127Pro)] mutation always existed in patients with FMF Conclusion: As a conclusion, ERAP-1 may be the second needed genetic mutation to produce the disease, 2) Certain ERAP-1 genetic mutation may produce FMF together with certain pyrin gene mutation.

Keywords: Familial Mediterranean Fever; ERAP-1; Inflammation; M694

References

1. Aksentijevich I and Kastner DL. “Genetics of monogenic autoinflammatory diseases: past successes, future challenges”. Nature Reviews Rheumatology 7 (2011): 469-478.
2. Gulbuz Sezgin., et al. “The association of endoplasmic reticulum aminopeptidase-1 (ERAP-1) with Familial Mediterranean Fever (FMF)”. United European Gastroenterology Journal1 (2016): 92-96.
3. Daniels M., et al. “Familial mediterranean fever: high gene frequency among the non-askenazi jewish populations in Israel”. American Journal of Medical Genetics 55 (1995): 311-314.
4. Odabas AR., et al. “Familial mediterranean fever”. South Medical Journal12 (2002): 1400-1403.
5. Gershoni-Baruch R., et al. “Male sex coupled with articular manifestations cause a 4-fold increase in susceptibility to amyloidosis in patients with familial mediterranean fever homozygous for the M694V- MEFV mutation”. Journal of Rheumatology2 (2003): 308-312.
6. Zaks N., et al. “Analysis of the three most common MEFV mutations in 412 patients with familial mediterranean fever”. Israel Medical Association Journal (IMAJ) 8 (2003): 585-588.
7. Brik R., et al. “Familial mediterranean fever: clinical and genetic characterization in a mixed pediatric population of jewish and arap patiens”. Pediatrics 5 (1999): e70.
8. Konstantopoulos K., et al. “Familial mediterranean fever associated pyrin mutations in Greece”. Annals of the Rheumatic Diseases 5 (2003): 479-481.
9. Medlej HM., et al. “Genetic screening of fourteen mutations in jordanian familial mediterranean fever patients”. Human Mutation4 (2000): 384.
10. Tunca M., et al. “On behalf of the Turkish FMF Study Group. The results of a nationwide, multicenter analysis of the clinical and genetic characteristics of the Turkish FMF patients (abstract)”. Clinical and Experimental Rheumatology 20 (2002): S92.
11. Livneh A., et al. “Criteria for the diagnosis of familial mediterranean fever”. Arthritis Rheum10 (1997): 1879-1885.
12. Dig Giaglis S., et al. “Increased frequency of mutations in the gene responsible for familial Mediterranean fever (MEFV) in a cohort of patients with ulcerative colitis: evidence for a potential disease-modifying effect?” Digestive Diseases4 (2006): 687-692.
13. Fierabracci A., et al. “The putative role of endoplasmic reticulum aminopeptidases in autoimmunity: Insights from genomic-wide association studies”. Autoimmune Review (2012).
14. Saric T., et al. “An IFN-gamma-induced aminopeptidase in the ER, ERAP1, trims precursors to MHC class I-presented peptides”. Nature Immunology 3 (2002): 1169-1176.
15. Serwold T., et al. “ERAAP customizes peptides for MHC class I molecules in the endoplasmic reticulum”. Nature 419 (2002): 480-483.
16. Tanioka T., et al. “Human leukocyte-derived arginine aminopeptidase. The third member of the oxytocinase subfamily of aminopeptidases”. Journal of Biological Chemistry 278 (2003): 32275-32283.
17. York IA., et al. “The ER aminopeptidase ERAP1 enhances or limits antigen presentation by trimming epitopes to 8-9 residues”. Nature Immunology 3 (2002): 1177-1184.
18. Saveanu L., et al. “Concerted peptide trimming by human ERAP1and ERAP2 aminopeptidase complexes in the endoplasmic reticulum”. Nature Immunology 6 (2005): 689-697.

Citation

Citation: Selim Nalbant., et al. “Endoplasmic Reticulum Aminopeptidase-1 (ERAP-1) Mutations in People with Familial Mediterranean Fever (FMF) Gene Mutations Without Disease”. Acta Scientific Gastrointestinal Disorders 3.12 (2020): 04-10.

Copyright

Copyright: © 2020 Selim Nalbant., et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.