Structure of the human perforin gene. A simple gene organization with interesting potential regulatory sequences.

Lichtenheld, Mathias G.; Podack, E R

doi:10.4049/jimmunol.143.12.4267

Cited by 65 publications

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Expression of cytotoxic molecules in intestinal T-cell lymphomas

Daum

Foss²,

Anagnostopoulos³

et al. 1997

J. Pathol.

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Intestinal T‐cell lymphoma (ITCL) represents a subgroup of peripheral T‐cell lymphomas which is thought to arise from αβ intraepithelial T‐lymphocytes. Since these lymphocytes may contain cytotoxic molecules, the question of whether this also holds true for ITCL arises. Twenty ITCL cases were examined for the presence of granzyme B, perforin, and T‐cell‐restricted intracellular antigen (TIA‐1)/granule membrane protein of 17 kD (GMP‐17). Two molecules with restricted expression in cytotoxic cells, granzyme B and perforin, were detected by immunocytochemistry and by in situ hybridization with an isotopically labelled RNA probe, respectively. Immunocytochemistry was also performed with the antibody 2G9, which recognizes two molecules, one expressed by cytotoxic cells (TIA‐1) and the other found in granulocytes and cytotoxic cells (GMP‐17). Granzyme B, TIA‐1/GMP‐17, and perforin were found in the neoplastic cells of 16/19 cases, 19/20 cases, and 16/17 cases, respectively, of ITCL, but not in the tumour cells of the control group, which consisted of intestinal B‐cell lymphomas (five cases) and CD8‐negative peripheral nodal T‐cell lymphomas (six cases). At least one of these molecules was expressed in the tumour cells of all ITCL cases. 2G9 proved to be the most sensitive immunohistological marker, since reactivity with this antibody was not only observed in the highest number of cases, but also found in high numbers of neoplastic cells in positive cases. In conclusion, ITCL appears to show cytotoxic differentiation in all cases. In conjunction with immunophenotypic and genotypic data, our results support a uniform derivation of this tumour from intraepithelial αβ cytotoxic T‐lymphocytes. © 1997 John Wiley & Sons, Ltd.

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Expression of cytotoxic molecules in intestinal T-cell lymphomas

Daum

Foss²,

Anagnostopoulos³

et al. 1997

J. Pathol.

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Novel perforin mutation in a patient with hemophagocytic lymphohistiocytosis and CD45 abnormal splicing

McCormick

Flower

Ströbel³

et al. 2002

American J of Med Genetics Pt A

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Hemophagocytic lymphohistiocytosis (HLH) composes a group of rare heterogenous disorders characterized by uncontrolled accumulation and infiltration of activated T lymphocytes and macrophages. Cytotoxic T and natural killer cell activity is significantly reduced or absent in these patients. Mutations in the important mediator of lymphocyte cytotoxicity perforin were identified in a number of HLH individuals. Here we report a novel missense mutation thr435met in the conserved Ca(2+) binding domain of perforin in a patient with HLH. Prediction of the 3-dimensional structure of the thr435met perforin mutant using comparative molecular modeling indicates that the protein's ability to bind Ca(2+), and therefore its cytolytic function, would be strongly compromised. In addition, this patient exhibited abnormal CD45 splicing caused by a C77G mutation in the gene encoding CD45 (PTPRC). Our findings suggest a combined role for perforin mutation and abnormal CD45 splicing as significant contributory factors in the pathogenesis of HLH.

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Mutation spectrum in children with primary hemophagocytic lymphohistiocytosis: molecular and functional analyses ofPRF1, UNC13D, STX11, andRAB27A

et al. 2005

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Communicated by Jurgen HorstFamilial hemophagocytic lymphohistiocytosis (FHL) is an autosomal-recessive disease that affects young children. It presents as a severe hyperinflammatory syndrome with activated macrophages and T lymphocytes. Mutations in the perforin 1 gene (PRF1) were found in FHL-2 in 15-50% of all cases. Defective granule exocytosis caused by mutations in the hMunc13-4 gene (UNC13D) has been described in FHL-3. FHL-4 patients have mutations in STX11, a t-SNARE involved in intracellular trafficking. We analyzed a large group of 63 unrelated patients with FHL of different geographic origins (Turkey:32; Germany:23; others:8) for mutations in STX11, PRF1, and UNC13D. We identified mutations in 38 samples (20 in PRF1, 12 in UNC13D, and six in STX11). Of 32 patients from Turkey, 14 had mutations in PRF1, six had mutations in UNC13D, and six had mutations in STX11. The mutation Trp374X in PRF1 was found in 12 patients from Turkey and was associated with a very early onset of the disease below the age of 3 months in all cases. In contrast, three of 23 and four of 23 patients from Germany, and three of eight and two of eight from other origins showed mutations in PRF1 and UNC13D, respectively, but none in STX11. Thus, FHL-2, FHL-3, and FHL-4 account for 80% of the HLH cases of Turkish origin, and for 30% of German patients. Furthermore, we identified mutations in RAB27A in three patients with FHL-related Griscelli syndrome type 2. In functional studies using a mammalian two-hybrid system we found that missense mutations Ala87Pro in Rab27a and Leu403Pro in hMunc13-4 each prevented the formation of a stable hMunc13-4/Rab27a complex in vitro. Our findings demonstrate extensive genetic and allelic heterogeneity in FHL and delineate an approach for functionally characterizing missense mutations in RAB27A and UNC13D. Hum Mutat 27(1), [62][63][64][65][66][67][68] 2006.

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Structure of the human perforin gene. A simple gene organization with interesting potential regulatory sequences.

Cited by 65 publications

References 0 publications

Expression of cytotoxic molecules in intestinal T-cell lymphomas

Expression of cytotoxic molecules in intestinal T-cell lymphomas

Novel perforin mutation in a patient with hemophagocytic lymphohistiocytosis and CD45 abnormal splicing

Mutation spectrum in children with primary hemophagocytic lymphohistiocytosis: molecular and functional analyses ofPRF1, UNC13D, STX11, andRAB27A

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