Whole-exome sequencing reveals a rare interferon gamma receptor 1 mutation associated with myasthenia gravis
Our study is aimed to explore the underlying genetic basis of myasthenia gravis. We collected a Chinese pedigree with myasthenia gravis, and whole-exome sequencing was performed on the two affected siblings and their parents. The candidate pathogenic gene was identified by bioinformatics filtering, which was further verified by Sanger sequencing. The homozygous mutation c.G40A (p.V14M) in interferon gamma receptor 1was identified. Moreover, the mutation was also detected in 3 cases of 44 sporadic myasthenia gravis patients. The p.V14M substitution in interferon gamma receptor 1 may affect the signal peptide function and the translocation on cell membrane, which could disrupt the binding of the ligand of interferon gamma and antibody production, contributing to myasthenia gravis susceptibility. We discovered that a rare variant c.G40A in interferon gamma receptor 1 potentially contributes to the myasthenia gravis pathogenesis. Further functional studies are needed to confirm the effect of the interferon gamma receptor 1 on the myasthenia gravis phenotype.
KeywordsMyasthenia gravis Autoimmune disease Whole-exome sequencing Interferon gamma receptor 1 Pathologenesis
This work was supported by the Shijiazhuang Science and Technology Bureau Foundation (No. 131460613), Science and Technology Agency Foundation of Hebei Province (No. 14277758D), Natural Science Foundation of Hebei Province (No. H2015106020), and Key Project of Hebei Provincial Administration of Traditional Chinese Medicine (No. 2014221).
Compliance with ethical standards
Conflicts of interest
The authors declare that they have no conflict of interest.
Research involving human participants
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
- 5.Tola MR, Caniatti LM, Casetta I, Granieri E, Conighi C, Quatrale R, Monetti VC, Paolino E, Govoni V, Pascarella R et al (1994) Immunogenetic heterogeneity and associated autoimmune disorders in myasthenia gravis: a population-based survey in the province of Ferrara, northern Italy. Acta Neurol Scand 90(5):318–323CrossRefPubMedGoogle Scholar
- 6.Celesia GG (1965) Myasthenia gravis in two siblings. Arch Neurol 12(2):206–210. https://doi.org/10.1001/archneur.1965.00460260096011 CrossRefPubMedGoogle Scholar
- 7.Osserman KE, Teng P (1956) Studies in myasthenia gravis: neonatal and juvenile types. J Mount Sinai Hospital, New York 23(5):711–727Google Scholar
- 10.Thomas (1961) Current status of the epidemiology and genetics of myasthenia gravis. Proceedings of the Myasthenia gravis Proc 2nd Int Symp, SpringfieldGoogle Scholar
- 14.Brueton L, Huson S, Thompson E, Vincent A, Hawke S, Price J, et al (eds) (1994) Myasthenia-gravis-an important cause of the Pena-Shokeir phenotype. J Med Genet. British Med Journal Publ Group British Med Assoc House, Tavistock Square, LondonGoogle Scholar
- 17.Giraud M, Taubert R, Vandiedonck C, Ke X, Levi-Strauss M, Pagani F, Baralle FE, Eymard B, Tranchant C, Gajdos P, Vincent A, Willcox N, Beeson D, Kyewski B, Garchon HJ (2007) An IRF8-binding promoter variant and AIRE control CHRNA1 promiscuous expression in thymus. Nature 448(7156):934–937. https://doi.org/10.1038/nature06066 CrossRefPubMedGoogle Scholar
- 18.Maselli RA, Arredondo J, Nguyen J, Lara M, Ng F, Ngo M, Pham JM, Yi Q, Stajich JM, McDonald K, Hauser MA, Wollmann RL (2014) Exome sequencing detection of two untranslated GFPT1 mutations in a family with limb-girdle myasthenia. Clin Genet 85(2):166–171. https://doi.org/10.1111/cge.12118 CrossRefPubMedGoogle Scholar
- 21.McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, Garimella K, Altshuler D, Gabriel S, Daly M, DePristo MA (2010) The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 20(9):1297–1303. https://doi.org/10.1101/gr.107524.110 CrossRefPubMedPubMedCentralGoogle Scholar
- 22.Cibulskis K, Lawrence MS, Carter SL, Sivachenko A, Jaffe D, Sougnez C, Gabriel S, Meyerson M, Lander ES, Getz G (2013) Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat Biotechnol 31(3):213–219. https://doi.org/10.1038/nbt.2514 CrossRefPubMedPubMedCentralGoogle Scholar
- 28.Krawetz SA (2000) Bioinformatics methods and protocols. Humana Press, New YorkGoogle Scholar
- 30.Faber-Elmann A, Grabovsky V, Dayan M, Sela M, Alon R, Mozes E (2000) Cytokine profile and T cell adhesiveness to endothelial selectins: in vivo induction by a myasthenogenic T cell epitope and immunomodulation by a dual altered peptide ligand. Int Immunol 12(12):1651–1658. https://doi.org/10.1093/intimm/12.12.1651 CrossRefPubMedGoogle Scholar
- 32.Sakatsume M, Igarashi K, Winestock KD, Garotta G, Larner AC, Finbloom DS (1995) The Jak kinases differentially associate with the alpha and beta (accessory factor) chains of the interferon gamma receptor to form a functional receptor unit capable of activating STAT transcription factors. J Biol Chem 270(29):17528–17534. https://doi.org/10.1074/jbc.270.29.17528 CrossRefPubMedGoogle Scholar
- 37.Kotenko SV, Izotova LS, Pollack BP, Mariano TM, Donnelly RJ, Muthukumaran G, Cook JR, Garotta G, Silvennoinen O, Ihle JN, Pestka S (1995) Interaction between the components of the interferon gamma receptor complex. J Biol Chem 270(36):20915–20921. https://doi.org/10.1074/jbc.270.36.20915 CrossRefPubMedGoogle Scholar
- 38.Balasa B, Deng C, Lee J, Bradley LM, Dalton DK, Christadoss P, Sarvetnick N (1997) Interferon gamma (IFN-gamma) is necessary for the genesis of acetylcholine receptor-induced clinical experimental autoimmune myasthenia gravis in mice. J Exp Med 186(3):385–391. https://doi.org/10.1084/jem.186.3.385 CrossRefPubMedPubMedCentralGoogle Scholar
- 39.Zhang GX, Navikas V, Link H (1997) Cytokines and the pathogenesis of myasthenia gravis. Muscle Nerve 20(5):543–551. https://doi.org/10.1002/(SICI)1097-4598(199705)20:5<543::AID-MUS2>3.0.CO;2-9 CrossRefPubMedGoogle Scholar