Correspondence
Autoimmune Lymphoproliferative Syndrome and Perforin
N Engl J Med 2005; 352:306-307January 20, 2005
- Article
To the Editor:
Clementi et al. (Sept. 30 issue)1 describe the occurrence of autoimmune lymphoproliferative syndrome (ALPS) and lymphoma in a patient carrying both a heterozygous Fas mutation and a heterozygous mutation in the perforin gene (Prf1). It is likely that, in addition to Fas mutations, associated genetic defects could contribute to the ALPS phenotype.2 However, the possibility that the described Prf1 variant, which resulted in the replacement of asparagine with serine at position 252 of the perforin protein (N252S), would be such an associated factor is questionable. Although this variant was identified in a patient with hemophagocytic lymphohistiocytosis,3 two additional Prf1 mutations (resulting in the replacement of glycine with arginine at position 45 [G45R] and the replacement of glycine with serine at position 149 [G149S]) were later found in this patient (our unpublished data), casting doubt about the pathogenicity of the N252S variant.4 In addition, this Prf1 variant is found in 18 percent of healthy controls and 10 percent of patients with ALPS type I (our unpublished data). We have also found a heterozygous Fas mutation (resulting in the replacement of glycine with serine at position 237 of Fas), together with the N252S Prf1 polymorphism, in a patient with ALPS and his healthy father (Figure 1Figure 1
Pedigree of the Patient.). The absence of any disease in the father strongly suggests that the heterozygous Prf1 N252S mutation in the patient described by Clementi et al. was not pathogenetic.4 ReferencesFrédéric Rieux-Laucat, Ph.D.
Françoise Le Deist, M.D., Ph.D.
Geneviève De Saint Basile, M.D., Ph.D.
INSERM Unité 429, 75015 Paris, France
rieux@necker.fr 1
Clementi R ,Dagna L ,Dianzani U , et al. Inherited perforin and Fas mutations in a patient with autoimmune lymphoproliferative syndrome and lymphoma. N Engl J Med 2004;351:1419-1424
Full Text | Web of Science | Medline2
Rieux-Laucat F ,Blachere S ,Danielan S , et al. Lymphoproliferative syndrome with autoimmunity: a possible genetic basis for dominant expression of the clinical manifestations. Blood 1999;94:2575-2582
Web of Science | Medline3
Stepp SE ,Dufourcq-Lagelouse R ,Le Deist F , et al. Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science 1999;286:1957-1959
CrossRef | Web of Science | Medline4
Molleran Lee S ,Villanueva J ,Sumegi J , et al. Characterisation of diverse PFR1 mutations leading to decreased natural killer cell activity in North American families with haemophagocytic lymphohistiocytosis. J Med Genet 2004;41:137-144
CrossRef | Web of Science | Medline
Author/Editor Response
Rieux-Laucat et al. question the role of the N252S perforin mutation in ALPS. We argue that it can contribute to ALPS for the following reasons. First, the frequency of N252S cited by Rieux-Laucat et al. is much higher than the published data.1 Moreover, Rieux-Laucat et al. do not mention the ethnic origins and actual numbers of subjects. To date, we have found this variant in 1 of 330 Italian controls (0.3 percent).
Second, we recently found the N252S variant in a second patient with ALPS type III who had a remarkable defect in natural-killer-cell activity. The frequency of N252S in patients with ALPS (2 of 25) and in controls (1 of 330) suggests its association with ALPS in the Italian population (odds ratio, 28.6; 95 percent confidence interval, 1.9 to 830.6).
Third, the unpublished data on two additional perforin mutations in the patient described in the report that Rieux-Laucat et al. cite2 do not rule out a role for N252S, since three causal mutations of a gene in the same patient have been reported in persons with other diseases.3,4 Finally, the detection by Rieux-Laucat et al. of a Fas mutation and N252S in a patient with ALPS and his healthy father supports the possibility, suggested in our report, that other environmental or genetic factors may contribute to ALPS.
4 ReferencesRita Clementi, M.D.
Policinico San Matteo, 27100 Pavia, ItalyMarina Ferrarini, M.D.
Marco Bregni, M.D.
Istituto Scientifico San Raffaele, 20132 Milan, Italy
marco.bregni@hsr. it 1
Molleran Lee S ,Villanueva J ,Sumegi J , et al. Characterisation of diverse PFR1 mutations leading to decreased natural killer cell activity in North American families with haemophagocytic lymphohistiocytosis. J Med Genet 2004;41:137-144
CrossRef | Web of Science | Medline2
Stepp SE ,Dufourcq-Lagelouse R ,Le Deist F , et al. Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science 1999;286:1957-1959
CrossRef | Web of Science | Medline3
Monaghan KG ,Feldman GL ,Barbarotto GM ,Manji S ,Desai TK ,Snow K . Frequency and clinical significance of the S1235R mutation in the cystic fibrosis transmembrane conductance regulator gene: results from a collaborative study. Am J Med Genet 2000;95:361-365
CrossRef | Web of Science | Medline4
Hojo S ,Fujita J ,Miyawaki H ,Obayashi Y ,Takahara J . Bartholomew DW. Severe cystic fibrosis associated with a deltaF508/R347H + D979A compound heterozygous genotype. Clin Genet 1998;53:50-53
CrossRef | Web of Science | Medline
- Citing Articles (4)
Citing Articles
1
Helen C. Su, Michael J. Lenardo. (2008) Genetic Defects of Apoptosis and Primary Immunodeficiency. Immunology and Allergy Clinics of North America 28:2, 329-351
CrossRef2
V. Mateo, M. Menager, G. de Saint-Basile, M.-C. Stolzenberg, B. Roquelaure, N. Andre, B. Florkin, F. le Deist, C. Picard, A. Fischer, F. Rieux-Laucat. (2007) Perforin-dependent apoptosis functionally compensates Fas deficiency in activation-induced cell death of human T lymphocytes. Blood 110:13, 4285-4292
CrossRef3
Ilia Voskoboinik, Mark J. Smyth, Joseph A. Trapani. (2006) Perforin-mediated target-cell death and immune homeostasis. Nature Reviews Immunology 6:12, 940-952
CrossRef4
Nicolas Bidère, Helen C. Su, Michael J. Lenardo. (2006) GENETIC DISORDERS OF PROGRAMMED CELL DEATH IN THE IMMUNE SYSTEM *. Annual Review of Immunology 24:1, 321-352
CrossRef
