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Blood, 1 May 2005, Vol. 105, No. 9, pp. 3442-3448. Prepublished online as a Blood First Edition Paper on January 4, 2005; DOI 10.1182/blood-2004-08-3296. This Article Full Text (PDF) All Versions of this Article: 2004-08-3296v1 105/9/3442    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Ishii, E. Articles by Yasukawa, M. Search for Related Content PubMed PubMed Citation Articles by Ishii, E. Articles by Yasukawa, M. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted August 26, 2004 Accepted December 30, 2004 Genetic subtypes of familial hemophagocytic lymphohistiocytosis: correlations with clinical features and cytotoxic T lymphocyte/natural killer cell functions Eiichi Ishii*, Ikuyo Ueda, Ryutaro Shirakawa, Ken Yamamoto, Hisanori Horiuchi, Shouichi Ohga, Kenji Furuno, Akira Morimoto, Miyoko Imayoshi, Yoshiyasu Ogata, Masafumi Zaitzu, Masahiro Sako, Kenichi Koike, Akifumi Sakata, Hidetoshi Takada, Toshiro Hara, Shinsaku Imashuku, Takehiko Sasazuki, and Masaki Yasukawa Department of Pediatrics, Saga University, Saga, Japan Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan Department of Cardiovascular Medicine, Kyoto University, Kyoto, Japan Department of Pediatrics, Graduate School of Medicine, Kyushu University, Fukuoka, Japan Division of Molecular Population Genetics, Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan Division of Pediatrics, Osaka General Hospital, Osaka, Japan Department of Pediatrics, Shinshu University, Matsumoto, Japan Division of Pediatrics, Okinawa Central Hospital, Okinawa, Japan Research Institute, International Medical Center of Japan, Tokyo, Japan First Department of Internal Medicine, Ehime University, Ehime, Japan * Corresponding author; email: ishiei{at}med.saga-u.ac.jp. Mutations of the perforin (PRF1) and MUNC13-4 genes distinguish two forms of familial hemophagocytic lymphohistiocytosis (FHL2 and FHL3, respectively), but the clinical and biological correlates of these genotypes remain in question. We studied the presenting features and cytotoxic T lymphocyte/natural killer cell (CTL/NK) functions of 35 patients for their relationship to distinct FHL subtypes. FHL2 (n=11) had an earlier onset than either FHL3 (n=8) or the non-FHL2/FHL3 subtype lacking a PRF1 or MUNC13-4 mutation (n=16). Deficient NK cell activity persisted after chemotherapy in all cases of FHL2, while some patients with FHL3 or the non-FHL2/FHL3 subtype showed partial recovery of this activity during remission. Alloantigen-specific CTL-mediated cytotoxicity was deficient in FHL2 patients with PRF1 nonsense mutations, was very low in FHL3 patients, but was only moderately reduced in FHL2 patients with PRF1 missense mutations. These findings correlated well with Western blot analyses showing an absence of perforin in FHL2 cases with PRF1 nonsense mutations and of MUNC13-4 in FHL3 cases, whereas in FHL2 cases with PRF1 missense mutations, mature perforin was present in low amounts. These results suggest an association between the type of genetic mutation in FHL cases and the magnitude of CTL cytolytic activity and age at onset. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. Chia, K. P. Yeo, J. C. Whisstock, M. A. Dunstone, J. A. Trapani, and I. Voskoboinik Temperature sensitivity of human perforin mutants unmasks subtotal loss of cytotoxicity, delayed FHL, and a predisposition to cancer PNAS, June 16, 2009; 106(24): 9809 - 9814. [Abstract] [Full Text] [PDF] R. Urrea Moreno, J. Gil, C. Rodriguez-Sainz, E. Cela, V. LaFay, B. Oloizia, A. B. Herr, J. Sumegi, M. B. Jordan, and K. A. 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Defective cytotoxic lymphocyte degranulation in syntaxin-11 deficient familial hemophagocytic lymphohistiocytosis 4 (FHL4) patients Blood, September 15, 2007; 110(6): 1906 - 1915. [Abstract] [Full Text] [PDF] K. Nagafuji, A. Nonami, T. Kumano, Y. Kikushige, G. Yoshimoto, K. Takenaka, K. Shimoda, S. Ohga, M. Yasukawa, H. Horiuchi, et al. Perforin gene mutations in adult-onset hemophagocytic lymphohistiocytosis Haematologica, July 1, 2007; 92(7): 978 - 981. [Abstract] [Full Text] [PDF] M.-T. Lin, H.-M. Chang, C.-J. Huang, W.-L. Chen, C.-Y. Lin, C.-Y. Lin, and S.-S. Chuang Massive expansion of EBV+ monoclonal T cells with CD5 down regulation in EBV-associated haemophagocytic lymphohistiocytosis J. Clin. Pathol., January 1, 2007; 60(1): 101 - 103. [Abstract] [Full Text] [PDF] A Santoro, S Cannella, G Bossi, F Gallo, A Trizzino, D Pende, F Dieli, G Bruno, J C Stinchcombe, C Micalizzi, et al. 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