Abstract
Sialic acid acetylesterase (SIAE) is an enzyme that negatively regulates B lymphocyte antigen receptor signalling and is required for the maintenance of immunological tolerance in mice1,2. Heterozygous loss-of-function germline rare variants and a homozygous defective polymorphic variant of SIAE were identified in 24/923 subjects of European origin with relatively common autoimmune disorders and in 2/648 controls of European origin. All heterozygous loss-of-function SIAE mutations tested were capable of functioning in a dominant negative manner. A homozygous secretion-defective polymorphic variant of SIAE was catalytically active, lacked the ability to function in a dominant negative manner, and was seen in eight autoimmune subjects but in no control subjects. The odds ratio for inheriting defective SIAE alleles was 8.6 in all autoimmune subjects, 8.3 in subjects with rheumatoid arthritis, and 7.9 in subjects with type I diabetes. Functionally defective SIAE rare and polymorphic variants represent a strong genetic link to susceptibility in relatively common human autoimmune disorders.
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References
Cariappa, A. et al. B cell antigen receptor signal strength and peripheral B cell development are regulated by a 9-O-acetyl sialic acid esterase. J. Exp. Med. 206, 125–138 (2009)
Pillai, S., Cariappa, A. & Pirnie, S. P. Esterases and autoimmunity: the sialic acid acetylesterase pathway and the regulation of peripheral B cell tolerance. Trends Immunol. 30, 488–493 (2009)
Nassir, R. et al. An ancestry informative marker set for determining continental origin: validation and extension using human genome diversity panels. BMC Genet. 10, 39 (2009)
Tian, C. et al. European population genetic substructure: further definition of ancestry informative markers for distinguishing among diverse European ethnic groups. Mol. Med. 15, 371–383 (2009)
Altshuler, D., Daly, M. J. & Lander, E. S. Genetic mapping in human disease. Science 322, 881–888 (2008)
Gregersen, P. K. & Behrens, T. W. Genetics of autoimmune diseases–disorders of immune homeostasis. Nature Rev. Genet. 7, 917–928 (2006)
Cohen, J. C. et al. Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science 305, 869–872 (2004)
Lee-Kirsch, M. A. et al. Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 are associated with systemic lupus erythematosus. Nature Genet. 39, 1065–1067 (2007)
Nejentsev, S., Walker, N., Riches, D., Egholm, M. & Todd, J. A. Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science 324, 387–389 (2009)
Xavier, R. J. & Podolsky, D. K. Unravelling the pathogenesis of inflammatory bowel disease. Nature 448, 427–434 (2007)
Hauser, S. L. et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N. Engl. J. Med. 358, 676–688 (2008)
Jessani, N. et al. Class assignment of sequence-unrelated members of enzyme superfamilies by activity-based protein profiling. Angew. Chem. Int. Edn Engl. 44, 2400–2403 (2005)
Kwak, E. L. et al. Epidermal growth factor receptor kinase domain mutations in esophageal and pancreatic adenocarcinomas. Clin. Cancer Res. 12, 4283–4287 (2006)
Bell, D. W. et al. Common nonsense mutations in RAD52. Cancer Res. 59, 3883–3888 (1999)
Shukla, A. K. & Schauer, R. Fluorimetric determination of unsubstituted and 9(8)-O-acetylated sialic acids in erythrocyte membranes. Hoppe-Seyler's Z. Physiol. Chem. 363, 255–262 (1982)
Krishna, M. & Varki, A. 9-O-Acetylation of sialomucins: a novel marker of murine CD4 T cells that is regulated during maturation and activation. J. Exp. Med. 185, 1997–2013 (1997)
Acknowledgements
We thank M. Cohen for coordinating the recall of inflammatory bowel disease patients, and K. Pedrick and E. Chung for their contributions. These studies were supported by grants from the Alliance for Lupus Research, the Center for the Study of Inflammatory Bowel Disease at MGH, and the NIH (AI 064930, AI 076505, and AR 058481) to S.P. and a grant to M.E.M. (NS 32765). P.K.G. acknowledges NIH support for NARAC (AR 044422 and AR 022263) and MADGC (AI 068759). The NIDDK is acknowledged for making samples available from the EDIC collection of its DNA repository. D.W.B. acknowledges the Intramural program of the National Human Genome Research Institute at NIH.
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S.P. was responsible for overall study design and writing the manuscript. S.P. and A.C. initiated this study. S.P.P., H.L., J.M., D.R.D., D.W.B., S.L., T.G., M.E.M., K.N.T., R.E., A.C., E.D. and S.P. contributed to sequencing and sequence analysis. I.S. cloned the full-length human SIAE. I.S., V.C., S.D. and I.N. performed mutagenesis, and I.S., S.P.P., K.H., V.C., K.N.T. and A.C. performed functional analyses. V.C. performed association studies, dominant negative analyses and metabolic labelling studies. J.F., A.L. and P.K.G. performed the Principal Components Analysis, and M.M., P.K.G., J.H.S., T.W.B., B.S., D.K.P., J.K., D.H., P.L.D.J., D.C. and D.B. provided annotated clinical material. A.V. provided advice on enzymology. Statistical analyses were performed by Y.C., I.N. and S.P.
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Surolia, I., Pirnie, S., Chellappa, V. et al. Functionally defective germline variants of sialic acid acetylesterase in autoimmunity. Nature 466, 243–247 (2010). https://doi.org/10.1038/nature09115
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DOI: https://doi.org/10.1038/nature09115
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