title: Functionally defective germline variants of sialic acid acetylesterase in autoimmunity.
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 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.
authors.affiliation: Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Ira
authors.initials: I
authors.lastname: Surolia
authors.forename: Stephan P
authors.initials: SP
authors.lastname: Pirnie
authors.forename: Vasant
authors.initials: V
authors.lastname: Chellappa
authors.forename: Kendra N
authors.initials: KN
authors.lastname: Taylor
authors.forename: Annaiah
authors.initials: A
authors.lastname: Cariappa
authors.forename: Jesse
authors.initials: J
authors.lastname: Moya
authors.forename: Haoyuan
authors.initials: H
authors.lastname: Liu
authors.forename: Daphne W
authors.initials: DW
authors.lastname: Bell
authors.forename: David R
authors.initials: DR
authors.lastname: Driscoll
authors.forename: Sven
authors.initials: S
authors.lastname: Diederichs
authors.forename: Khaleda
authors.initials: K
authors.lastname: Haider
authors.forename: Ilka
authors.initials: I
authors.lastname: Netravali
authors.forename: Sheila
authors.initials: S
authors.lastname: Le
authors.forename: Roberto
authors.initials: R
authors.lastname: Elia
authors.forename: Ethan
authors.initials: E
authors.lastname: Dow
authors.forename: Annette
authors.initials: A
authors.lastname: Lee
authors.forename: Jan
authors.initials: J
authors.lastname: Freudenberg
authors.forename: Philip L
authors.initials: PL
authors.lastname: De Jager
authors.forename: Yves
authors.initials: Y
authors.lastname: Chretien
authors.forename: Ajit
authors.initials: A
authors.lastname: Varki
authors.forename: Marcy E
authors.initials: ME
authors.lastname: MacDonald
authors.forename: Tammy
authors.initials: T
authors.lastname: Gillis
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Behrens
authors.forename: Donald
authors.initials: D
authors.lastname: Bloch
authors.forename: Deborah
authors.initials: D
authors.lastname: Collier
authors.forename: Joshua
authors.initials: J
authors.lastname: Korzenik
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Podolsky
authors.forename: David
authors.initials: D
authors.lastname: Hafler
authors.forename: Mandakolathur
authors.initials: M
authors.lastname: Murali
authors.forename: Bruce
authors.initials: B
authors.lastname: Sands
authors.forename: John H
authors.initials: JH
authors.lastname: Stone
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.forename: Shiv
authors.initials: S
authors.lastname: Pillai
mesh_terms: D000107:Acetylation; D000115:Acetylesterase / Q000235:genetics* / Q000378:metabolism; D000483:Alleles; D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D001172:Arthritis, Rheumatoid / Q000201:enzymology / Q000235:genetics; D001327:Autoimmune Diseases / Q000201:enzymology* / Q000235:genetics*; D015551:Autoimmunity / Q000235:genetics*; D001402:B-Lymphocytes / Q000378:metabolism; D055162:Biocatalysis; D002265:Carboxylic Ester Hydrolases / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D002460:Cell Line; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology / Q000235:genetics; D005060:Europe / Q000208:ethnology; D005091:Exons / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D051379:Mice; D019158:N-Acetylneuraminic Acid / Q000378:metabolism*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D018401:Sample Size; D017422:Sequence Analysis, DNA
chemical_list: D000974:Antibodies, Antinuclear; D002265:Carboxylic Ester Hydrolases; D000115:Acetylesterase; C046298:sialate O-acetylesterase; D019158:N-Acetylneuraminic Acid