Variations of the perforin gene in patients with autoimmunity/lymphoproliferation and defective Fas function.
Mutations decreasing function of the Fas death receptor cause the autoimmune lymphoproliferative syndrome (ALPS) with autoimmune manifestations, spleen/lymph node enlargement, and expansion of CD4/CD8-negative T cells. Dianzani Autoimmune Lymphoproliferative Disease (DALD) is a variant lacking this expansion. Perforin is involved in cell-mediated cytotoxicity and its biallelic mutations cause familial hemophagocytic lymphohistiocytosis (HLH). We previously described an ALPS patient carrying heterozygous mutations of the Fas and perforin genes and suggested that they concurred in ALPS. This work extends the analysis to 14 ALPS, 28 DALD, and 816 controls, and detects an N252S amino acid substitution in 2 ALPS, and an A91V amino acid substitution in 6 DALD. N252S conferred an OR = 62.7 (P = .0016) for ALPS and A91V conferred an OR = 3 (P = .016) for DALD. Copresence of A91V and variations of the osteopontin gene previously associated with DALD conferred an OR = 17 (P = .0007) for DALD. In one N252S patient, NK activity was strikingly defective in early childhood, but became normal in late childhood. A91V patients displayed lower NK activity than controls. These data suggest that perforin variations are a susceptibility factor for ALPS/DALD development in subjects with defective Fas function and may influence disease expression.
Clementi
Rita
R
Pediatric Haematology-Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, University of Pavia, Pavia, Italy.
Chiocchetti
Annalisa
A
Cappellano
Giuseppe
G
Cerutti
Elisa
E
Ferretti
Massimo
M
Orilieri
Elisabetta
E
Dianzani
Irma
I
Ferrarini
Marina
M
Bregni
Marco
M
Danesino
Cesare
C
Bozzi
Valeria
V
Putti
Maria Caterina
MC
Cerutti
Franco
F
Cometa
Angela
A
Locatelli
Franco
F
Maccario
Rita
R
Ramenghi
Ugo
U
Dianzani
Umberto
U
D019943:Amino Acid Substitution; D001327:Autoimmune Diseases / Q000235:genetics*; D003602:Cytotoxicity, Immunologic; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D018655:Lymphocyte Count; D008232:Lymphoproliferative Disorders / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000235:genetics*; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000235:genetics*; D019014:fas Receptor / Q000502:physiology*
D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D019014:fas Receptor; D054353:Perforin