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 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.
Surolia
Ira
I
Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
Pirnie
Stephan P
SP
Chellappa
Vasant
V
Taylor
Kendra N
KN
Cariappa
Annaiah
A
Moya
Jesse
J
Liu
Haoyuan
H
Bell
Daphne W
DW
Driscoll
David R
DR
Diederichs
Sven
S
Haider
Khaleda
K
Netravali
Ilka
I
Le
Sheila
S
Elia
Roberto
R
Dow
Ethan
E
Lee
Annette
A
Freudenberg
Jan
J
De Jager
Philip L
PL
Chretien
Yves
Y
Varki
Ajit
A
MacDonald
Marcy E
ME
Gillis
Tammy
T
Behrens
Timothy W
TW
Bloch
Donald
D
Collier
Deborah
D
Korzenik
Joshua
J
Podolsky
Daniel K
DK
Hafler
David
D
Murali
Mandakolathur
M
Sands
Bruce
B
Stone
John H
JH
Gregersen
Peter K
PK
Pillai
Shiv
S
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
D000974:Antibodies, Antinuclear; D002265:Carboxylic Ester Hydrolases; D000115:Acetylesterase; C046298:sialate O-acetylesterase; D019158:N-Acetylneuraminic Acid