Functionally defective germline variants of sialic acid acetylesterase in autoimmunity

Ira Surolia, Stephan P. Pirnie, Vasant Chellappa, Kendra N. Taylor, Annaiah Cariappa, Jesse Moya, Haoyuan Liu, Daphne W. Bell, David R. Driscoll, Sven Diederichs, Khaleda Haider, Ilka Netravali, Sheila Le, Roberto Elia, Ethan Dow, Annette Lee, Jan Freudenberg, Philip L. De Jager, Yves Chretien, Ajit VarkiMarcy E. MacDonald, Tammy Gillis, Timothy W. Behrens, Donald Bloch, Deborah Collier, Joshua Korzenik, Daniel K. Podolsky, David Hafler, Mandakolathur Murali, Bruce Sands, John H. Stone, Peter K. Gregersen, Shiv Pillai

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Abstract

Sialic acid acetylesterase (SIAE) is an enzyme that negatively regulatesBlymphocyte 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-offunction SIAE mutations tested were capable of functioning in a dominant negativemanner. Ahomozygous 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.

Original languageEnglish (US)
Pages (from-to)243-247
Number of pages5
JournalNature
Volume466
Issue number7303
DOIs
StatePublished - Jul 8 2010

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Surolia, I., Pirnie, S. P., Chellappa, V., Taylor, K. N., Cariappa, A., Moya, J., Liu, H., Bell, D. W., Driscoll, D. R., Diederichs, S., Haider, K., Netravali, I., Le, S., Elia, R., Dow, E., Lee, A., Freudenberg, J., De Jager, P. L., Chretien, Y., ... Pillai, S. (2010). Functionally defective germline variants of sialic acid acetylesterase in autoimmunity. Nature, 466(7303), 243-247. https://doi.org/10.1038/nature09115