A91V is a polymorphism in the perforin gene not causative of an FHLH phenotype

Stadt, Udo zur; Beutel, Karin; Weber, Belinda; Kabisch, H; Schneppenheim, Reinhard; Janka, Gritta

doi:10.1182/blood-2004-02-0733

Cited by 55 publications

(52 citation statements)

References 8 publications

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“…We have previously reported that this amino-acid change was present in seven of 202 controls (3%), suggesting that A91V should be considered a neutral polymorphism. 9 Stadt et al 10 and Santoro et al 15 concurred with our finding, reporting 17.5 and 3.9% of normal controls being A91V heterozygous (both relatively small samples of German and Italian populations respectively). However, recently Trambas et al 13 and Risma et al…”

Section: Discussionsupporting

confidence: 88%

“…A91V is the most common amino-acid substitution identified in perforin, with an allele frequency ranging between 3 and 17% in the general population. 9,10 The role of this substitution in disease pathogenesis remains unclear, and is the subject of continuing debate. [10][11][12] The A91V substitution has generally been regarded as a functionally unimportant polymorphism of the PRF1 gene.…”

Section: Introductionmentioning

confidence: 99%

“…9,10 The role of this substitution in disease pathogenesis remains unclear, and is the subject of continuing debate. [10][11][12] The A91V substitution has generally been regarded as a functionally unimportant polymorphism of the PRF1 gene. However, recent data suggest that A91V results in conformational change that may impair processing of perforin protein to the active form, 13 and expression of this human mutant perforin in cell lines leads to reduced cytotoxicity compared to wild-type perforin.…”

Section: Introductionmentioning

confidence: 99%

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Perforin polymorphism A91V and susceptibility to B-precursor childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group

Mehta

Kumar

et al. 2006

Leukemia

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Perforin plays a key role in the cytotoxicity of natural killer and cytotoxic T cells. Genetic mutations in the perforin gene (PRF1) give rise to approximately 30% cases of familial hemophagocytic lymphohistiocytosis. A frequent polymorphism, A91V (C to T transition at position 272), may impair processing of perforin protein to the active form, and has been suggested to increase susceptibility to childhood acute lymphoblastic leukemia (ALL). To investigate the role of A91V in ALL, we genotyped 2272 children with de novo ALL registered on the Pediatric Oncology Group ALL Classification study P9900 and 655 normal controls. Allele frequencies in the controls showed a very low frequency of the variant allele in blacks, 0.7% compared to 4% in white controls. In light of this, analysis was restricted to a comparison of white cases and controls only. Overall genotype frequencies were similar in white ALL cases and normal white controls (P ¼ 0.58), indicating that in contrast to the previous report, A91V polymorphism is not associated with increased risk of childhood ALL. PRF1 A91V frequency was significantly increased in children with BCR-ABL positive ALL (24 vs 8.5%; P ¼ 0.0048); however, this observation includes a relatively small number of cases and needs further exploration.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Perforin polymorphism A91V and susceptibility to B-precursor childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group

Mehta

Kumar

et al. 2006

Leukemia

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“…It has been reported at a relatively high frequency of between 3 and 17% in Caucasian subjects. [72][73][74] Interestingly, A91V seems to be at a very low frequency of 0.7% in African-American subjects, 72 Sub-Saharan Africans 75 and there are no reported cases of the polymorphism in Japan, thus reinforcing the Mediterranean origin of the mutation. However, the predicted frequency of A91V homozygosity (B1/700 individuals, on the basis of occurrence of the homozygotes in various population studies) is vastly in excess of the frequency of FHL2 cases, that is, 0.002%…”

Section: A91v Polymorphism Of Perforinmentioning

confidence: 99%

Perforin deficiency and susceptibility to cancer

et al. 2010

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Cytotoxic lymphocytes (CLs) are the killer cells that destroy intracellular pathogen-infected and transformed cells, predominantly through the cytotoxic granule-mediated death pathway. Soluble cytotoxic granule components, including pore-forming perforin and pro-apoptotic serine proteases, granzymes, synergize to induce unscheduled apoptosis of the target cell. A complete loss of CL function results in an aggressive immunoregulatory disorder, familial hemophagocytic lymphohistiocytosis, whereas a partial loss of function seems to be a factor strongly predisposing to hematological malignancies. This review discusses the pathological manifestations of CL deficiencies due to impaired perforin function and describes novel aspects of perforin biology. Cell Death and Differentiation (2010) 17, 607-615; doi:10.1038/cdd.2009; published online 15 January 2010Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, collectively called cytotoxic lymphocytes (CLs), kill virusinfected and transformed cells through a number of contactdependent mechanisms. 1,2 Engagement of death receptors by membrane-bound members of the TNF superfamily of death ligands is critical for maintaining lymphoid homeostasis in the host. By contrast, studies of gene deficiencies indicate that defects of the granule exocytosis pathway result in a failure to eliminate infected cells or those that pose a risk of subsequent malignancy. Although cytotoxic granules contain diverse toxins that together contribute to apoptosis induction, this review will deal exclusively with the critical role of the pore-forming protein perforin (PRF) as an essential enabler of target-cell apoptosis, and its more recently described role as a potential 'extrinsic' tumor suppressor.Perforin is a 67-kDa pore-forming protein that is stored and released from the secretory granules (SGs) of CLs along with a number of pro-apoptotic serine protease granzymes that display broad substrate specificities. 3 Following exocytic release, PRF and the granzymes are exposed to the neutral pH and calciumrich environment of the immune synapse. 4 After binding calcium through their C2 domains, PRF monomers acquire the ability to bind generic lipids in the target cell membrane, 5 and then coalesce into large transmembrane pores that permit the granzymes to access key death substrates in the cytosol. [6][7][8] Although the diverse apoptotic pathways triggered by granzymes have been extensively studied and are now understood in considerable detail, it is only of late that insights into the molecular and cellular functions of PRF have been even partly addressed.In this review, we will re-examine the pathological consequences of PRF deficiency, both in mice and humans. In doing so, important differences in PRF biology between these species will be described. We will discuss the pathogenic effect of a number of recently described missense mutations of human PRF. In particular, although the complete absence of PRF function typically results in an aggressive, fatal immunoregulatory disorder of ea...

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“…Biallelic mutations of PRF1 were first described in familial HLH (Stepp et al, 1999;G€ oransdotter Ericson et al, 2001;Clementi et al, 2002;Feldmann et al, 2002;Kogawa et al, 2002;Ueda et al, 2003;Molleran Lee et al, 2004). Inherited PRF1 mutations were subsequently described in various types of haematological malignancies, including lymphomas (Zur Stadt et al, 2004;Clementi et al, 2005;Santoro et al, 2005;Mehta et al, 2006). Patients with ALK-positive ALCL were shown to have a higher probability than healthy subjects of being carriers of monoallelic germline variants of the PRF1 gene, such as in HLH (Cannella et al, 2007), suggesting a possible similar underlying pathophysiology.…”

Section: Analysis Of Hlh-associated Alcl In Children ª 2014 John Wilementioning

confidence: 99%

Clinical analysis and prognostic significance of haemophagocytic lymphohistiocytosis-associated anaplastic large cell lymphoma in children

et al. 2014

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SummaryHaemophagocytic lymphohistiocytosis (HLH) has been rarely described in children treated for an anaplastic large-cell lymphoma (ALCL). We evaluated the incidence, the clinical and histological characteristics and the prognosis of HLH associated-ALCL. The medical, biological, cytological and histological data of patients treated for ALK-positive ALCL in the paediatric department of a single institution between 1975 and 2008 were analysed and assessed for HLH according to diagnosis criteria of the Histiocyte Society. Data concerning a series of 50 consecutive children with ALCL were reviewed. HLH-associated ALCL was observed in 12% of the patients. Lung involvement was significantly more frequent in HLH-associated ALCL patients than in the group without HLH (P = 0Á004), as well as central nervous system (CNS) and bone marrow involvement (P = 0Á001 and P = 0Á007 respectively). The histological subtype in children with HLHassociated ALCL did not differ from that of the group without HLH. There was no significant difference between the two groups in 5-year EFS and OS (P = 0Á91 and P > 0Á99 respectively). In conclusion, HLH is not rare in paediatric ALCL. Despite a high incidence of visceral, CNS and bone marrow involvement, HLH does not seem to exert a significant impact on outcome in children treated for ALCL.

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A91V is a polymorphism in the perforin gene not causative of an FHLH phenotype

Cited by 55 publications

References 8 publications

Perforin polymorphism A91V and susceptibility to B-precursor childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group

Perforin polymorphism A91V and susceptibility to B-precursor childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group

Perforin deficiency and susceptibility to cancer

Clinical analysis and prognostic significance of haemophagocytic lymphohistiocytosis-associated anaplastic large cell lymphoma in children

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