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 Varki; Marcy 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

doi:10.1038/nature09115

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 mice^1,2. 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 language	English (US)
Pages (from-to)	243-247
Number of pages	5
Journal	Nature
Volume	466
Issue number	7303
DOIs	https://doi.org/10.1038/nature09115
State	Published - 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

Surolia, I, Pirnie, SP, Chellappa, V, Taylor, KN, Cariappa, A, Moya, J, Liu, H, Bell, DW, Driscoll, DR, Diederichs, S, Haider, K, Netravali, I, Le, S, Elia, R, Dow, E, Lee, A, Freudenberg, J, De Jager, PL, Chretien, Y, Varki, A, MacDonald, ME, Gillis, T, Behrens, TW, Bloch, D, Collier, D, Korzenik, J, Podolsky, DK, Hafler, D, Murali, M, Sands, B, Stone, JH, Gregersen, PK & Pillai, S 2010, 'Functionally defective germline variants of sialic acid acetylesterase in autoimmunity', Nature, vol. 466, no. 7303, pp. 243-247. https://doi.org/10.1038/nature09115

@article{b97ea7a48b6d4ad3b18b639f6d447ab5,

title = "Functionally defective germline variants of sialic acid acetylesterase in autoimmunity",

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.",

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

note = "Funding Information: 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.",

year = "2010",

month = jul,

day = "8",

doi = "10.1038/nature09115",

language = "English (US)",

volume = "466",

pages = "243--247",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "7303",

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TY - JOUR

T1 - Functionally defective germline variants of sialic acid acetylesterase in autoimmunity

AU - Surolia, Ira

AU - Pirnie, Stephan P.

AU - Chellappa, Vasant

AU - Taylor, Kendra N.

AU - Cariappa, Annaiah

AU - Moya, Jesse

AU - Liu, Haoyuan

AU - Bell, Daphne W.

AU - Driscoll, David R.

AU - Diederichs, Sven

AU - Haider, Khaleda

AU - Netravali, Ilka

AU - Le, Sheila

AU - Elia, Roberto

AU - Dow, Ethan

AU - Lee, Annette

AU - Freudenberg, Jan

AU - De Jager, Philip L.

AU - Chretien, Yves

AU - Varki, Ajit

AU - MacDonald, Marcy E.

AU - Gillis, Tammy

AU - Behrens, Timothy W.

AU - Bloch, Donald

AU - Collier, Deborah

AU - Korzenik, Joshua

AU - Podolsky, Daniel K.

AU - Hafler, David

AU - Murali, Mandakolathur

AU - Sands, Bruce

AU - Stone, John H.

AU - Gregersen, Peter K.

AU - Pillai, Shiv

N1 - Funding Information: 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.

PY - 2010/7/8

Y1 - 2010/7/8

N2 - 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.

AB - 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.

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Functionally defective germline variants of sialic acid acetylesterase in autoimmunity

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