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 lympho-histiocytosis (HLH). We previously described an ALPS patient carrying het-erozygous 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, R., Chiocchetti, A., Cappellano, G., Cerutti, E., Ferretti, M., Orilieri, E., Dianzani, I., Ferrarini, M., Bregni, M., Danesino, C., Bozzi, V., Putti, M. C., Cerutti, F., Cometa, A., Locatelli, F., Maccario, R., Ramenghi, U., Dianzani, U., Variations of the perforin gene in patients with autoimmunity/lymphoproliferation and defective Fas function, <<BLOOD>>, 2006; 108 (9): 3079-3084. [doi:10.1182/blood-2006-02-001412] [https://hdl.handle.net/10807/258975]

Variations of the perforin gene in patients with autoimmunity/lymphoproliferation and defective Fas function

Locatelli, Franco;
2006

Abstract

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 lympho-histiocytosis (HLH). We previously described an ALPS patient carrying het-erozygous 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.
2006
Inglese
Clementi, R., Chiocchetti, A., Cappellano, G., Cerutti, E., Ferretti, M., Orilieri, E., Dianzani, I., Ferrarini, M., Bregni, M., Danesino, C., Bozzi, V., Putti, M. C., Cerutti, F., Cometa, A., Locatelli, F., Maccario, R., Ramenghi, U., Dianzani, U., Variations of the perforin gene in patients with autoimmunity/lymphoproliferation and defective Fas function, <<BLOOD>>, 2006; 108 (9): 3079-3084. [doi:10.1182/blood-2006-02-001412] [https://hdl.handle.net/10807/258975]
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10807/258975
Citazioni
  • ???jsp.display-item.citation.pmc??? 19
  • Scopus 54
  • ???jsp.display-item.citation.isi??? 46
social impact