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Functionally defective germline variants of sialic acid acetylesterase in autoimmunity


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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Figure 1: Analysis of SIAE variants from subjects with autoimmunity.
Figure 2: Analysis of SIAE variants from controls
Figure 3: Analysis of SIAE mutants in terms of secretion, in vitro dominant interfering activity, and effect on induced cell surface 9- O -acetylation of sialic acid


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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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Correspondence to Shiv Pillai.

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The authors declare no competing financial interests.

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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).

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