PubMed ID:
20555325
Public Release Type:
Journal
Publication Year: 2010
Affiliation: Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
DOI:
https://doi.org/10.1038/nature09115
Authors:
Behrens TW,
Bell DW,
Bloch D,
Cariappa A,
Chellappa V,
Chretien Y,
Collier D,
De Jager PL,
Diederichs S,
Dow E,
Driscoll DR,
Elia R,
Freudenberg J,
Gillis T,
Gregersen PK,
Hafler D,
Haider K,
Korzenik J,
Lee A,
Le S,
Liu H,
MacDonald ME,
Moya J,
Murali M,
Netravali I,
Pillai S,
Pirnie SP,
Podolsky DK,
Sands B,
Stone JH,
Surolia I,
Taylor KN,
Varki A
Request IDs:
10140
Studies:
Diabetes Control and Complications Trial
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 mice. 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.