Article

Genetic subtypes of familial hemophagocytic lymphohistiocytosis: correlations with clinical features and cytotoxic T lymphocyte/natural killer cell functions

Department of Pediatrics, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan.
Blood (Impact Factor: 10.43). 06/2005; 105(9):3442-8. DOI: 10.1182/blood-2004-08-3296
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ABSTRACT Mutations of the perforin (PRF1) and MUNC13-4 genes distinguish 2 forms of familial hemophagocytic lymphohistiocytosis (FHL2 and FHL3, respectively), but the clinical and biologic correlates of these genotypes remain in question. We studied the presenting features and cytotoxic T lymphocyte/natural killer (CTL/NK) cell 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, whereas 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.

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    • "In patients with mutations in STXBP2, severe chronic inflammatory bowel disease (colitis) and hypogammaglobulinemia were frequently found (Ishii et al. 2005). Mutations in the Munc 13-4 (UNC13D) and Munc 18-2 (STXBP2) genes often cause abnormal platelet function, which causes a tendency to hemorrhage and bleeding during surgical procedures (Ishii et al. 2005; Meeths et al. 2011). Crohn-like colitis has been reported in significant proportion of boys and men with a X-linked inhibitor of apoptosis (XIAP) deficiency caused by mutations in BIRC4 (Speckmann et al. 2013). "
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    • "A second, more common outcome (n = 14) was presynaptic dysfunction, which we have previously defined as reduced expression and/or PRF degradation or truncation in the RBL cells (Voskoboinik et al., 2004). As was observed previously with FHL-associated mutations (Ishii et al., 2005; Voskoboinik et al., 2005b), this group of substitutions invariably led to a marked loss of function (Table S1). Most commonly, presynaptic dysfunction occurred at residues that showed extremely high conservation between species as divergent as humans and fish (for instance, residues 189, 220, 221, 231, or 239), presumably because they are critical for protein folding during its biosynthesis. "
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    • "The study was also approved by the Institutional Review Boards at Kyushu University and Saga University, Japan. As described in our recent report (Ishii et al 2005), all cases were screened for the PRF1 gene, 12 of which were classified as FHL2. Thirty-eight of the remaining 57 cases were tested for MUNC13-4 gene mutations, eight of which were diagnosed as FHL3. "
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