title: The -346T polymorphism of the SH2D1A gene is a risk factor for development of autoimmunity/lymphoproliferation in males with defective Fas function.
abstract: Inherited defects decreasing function of the Fas death receptor cause autoimmune lymphoproliferative syndrome (ALPS) and its variant Dianzani autoimmune lymphoproliferative disease (DALD). Since a deleterious mutation of the SH2D1A gene protects MRLlpr/lpr mice from ALPS development, we investigated the role of SH2D1A, located in the X chromosome, in 51 patients with ALPS or DALD by mutational screening of coding and regulative sequences. Allelic frequency of the -346C>T polymorphism was different in male patients and controls (-346T: 61% vs 36%, p = 0.01), with similar frequencies in ALPS and DALD. By contrast, no differences were found among females or between the controls and patients with multiple sclerosis (229 males, 157 females). Further analyses showed that -346C was a methylation site in CD8(+) T and natural killer cells, and SH2D1A expression was higher in -346T than in -346C males. Finally, in vitro-activated T cells from -346T males produced lower amounts of interferon-γ than those from -346C males. These data suggest that -346T is a predisposing factor for ALPS and DALD in males possibly because of its effect on SAP expression influencing the T-cell response.
authors.affiliation: Interdisciplinary Research Center of Autoimmune Diseases (IRCAD) and Department of Health Sciences, A. Avogadro, University of Eastern Piedmont, Novara, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Boggio
authors.forename: Matteo
authors.initials: M
authors.lastname: Melensi
authors.forename: Sara
authors.initials: S
authors.lastname: Bocca
authors.forename: Annalisa
authors.initials: A
authors.lastname: Chiocchetti
authors.forename: Cristoforo
authors.initials: C
authors.lastname: Comi
authors.forename: Nausicaa
authors.initials: N
authors.lastname: Clemente
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Orilieri
authors.forename: Maria Felicia
authors.initials: MF
authors.lastname: Soluri
authors.forename: Sandra
authors.initials: S
authors.lastname: D'Alfonso
authors.forename: Rosella
authors.initials: R
authors.lastname: Mechelli
authors.forename: Giovanna
authors.initials: G
authors.lastname: Gentile
authors.forename: Alessandro
authors.initials: A
authors.lastname: Poggi
authors.forename: Marco
authors.initials: M
authors.lastname: Salvetti
authors.forename: Ugo
authors.initials: U
authors.lastname: Ramenghi
authors.forename: Umberto
authors.initials: U
authors.lastname: Dianzani
mesh_terms: D000483:Alleles; D056735:Autoimmune Lymphoproliferative Syndrome / Q000235:genetics*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016022:Case-Control Studies; D002648:Child; D041321:Chromosomes, Human, X / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D012737:Sex Factors; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D019014:fas Receptor / Q000235:genetics*
chemical_list: C491901:FAS protein, human; D047908:Intracellular Signaling Peptides and Proteins; C114953:SH2D1A protein, human; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D019014:fas Receptor; D007371:Interferon-gamma