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Autoimmune Lymphoproliferative Syndrome and Perforin
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     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45 [G45R] and the replacement of glycine with serine at position 149 [G149S]) were later found in this patient (our unpublished data), casting doubt about the pathogenicity of the N252S variant.4 In addition, this Prf1 variant is found in 18 percent of healthy controls and 10 percent of patients with ALPS type I (our unpublished data).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 1). 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.

    Figure 1. Pedigree of the Patient.

    The Fas mutation was inherited from the patient's healthy father, whereas the Prf1 N252S variant was found in all members of this family.

    Frédéric Rieux-Laucat, Ph.D.

    Fran?oise Le Deist, M.D., Ph.D.

    Geneviève De Saint Basile, M.D., Ph.D.

    INSERM Unité 429

    75015 Paris, France

    rieux@necker.fr

    References

    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.

    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.

    Stepp SE, Dufourcq-Lagelouse R, Le Deist F, et al. Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science 1999;286:1957-1959.

    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.

    The authors reply: 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.

    Rita Clementi, M.D.

    Policinico San Matteo

    27100 Pavia, Italy

    Marina Ferrarini, M.D.

    Marco Bregni, M.D.

    Istituto Scientifico San Raffaele

    20132 Milan, Italy

    marco.bregni@hsr.it

    References

    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.

    Stepp SE, Dufourcq-Lagelouse R, Le Deist F, et al. Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science 1999;286:1957-1959.

    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.

    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.