Genotype phenotype study of familial haemophagocytic lymphohistiocytosis due to perforin mutations

Trizzino, Antonino; Stadt, Udo zur; Ueda, Ikuyo; Risma, Kimberly A.; Janka, Gritta; Ishii, Eiichi; Beutel, Karin; Sümegi, János; Cannella, Sonia; Pende, Daniela; Mian, Amir; Ji, Henter; Griffiths, Gillian M.; Santoro, Alessandra; Filipovich, Alexandra H.; Aricò, Maurizio

doi:10.1136/jmg.2007.052670

Cited by 121 publications

(112 citation statements)

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“…[13] The prevalence and characteristics of PRF1 mutation may be different in different populations. [11,12] In this study, we found 11 novel mutations in 8 of 77 Chinese patients with lymphoma. We collected nails and/or hair follicles from 4 patients with PRF1 mutations.…”

Section: Discussionmentioning

confidence: 68%

“…[8] In addition to familial hemophagocytic lymphohistiocytosis due to PRF1 mutations, human lymphomas were also found to harbor PRF1 mutations in some cases. [9,10] The presence of PRF1 gene mutations may be different in different geographic regions and ethnic groups,[11,12] and little is known about the mutations in Chinese populations. Here we report our findings of mutations in the PRF1 gene and the association with EBV infection in Chinese patients with lymphoma.…”

Section: Introductionmentioning

confidence: 99%

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Perforin gene mutations in 77 Chinese patients with lymphomas

Ding

Yang

2013

World Journal of Emergency Medicine

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BACKGROUND:Perforin gene (PRF1) mutations have been reported in patients with lymphoma, but the prevalence and characteristics of PRF1 mutation have not been identified in Chinese patients with lymphoma.METHODS:Seventy-seven patients with lymphoma, including 6 patients with Hodgkin lymphoma and 71 patients with non-Hodgkin lymphoma, were recruited. DNA samples from peripheral blood were used for PRF1 mutation detection by the PCR-sequencing method.RESULTS:Eleven novel PRF1 mutations were found in 8 of the 77 patients with lymphoma. Biallelic or compound monoallelic missense mutations in 3 patients indicated the severe impairment of perforin function, monoallelic missense mutations in 3 patients possibly contributed a genetic predisposition to malignancies, and synonymous mutations in 2 patients showed unknown significance.CONCLUSIONS:The frequency of EBV infection was similar in lymphoma patients with PRF1 mutations and those without the mutations. The same PRF1 mutations were also found in DNA samples from nails or hair follicles from 4 patients with PRF1 mutations, suggesting that these mutations may be of germ-line origin.

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Section: Discussionmentioning

confidence: 68%

Section: Introductionmentioning

confidence: 99%

Perforin gene mutations in 77 Chinese patients with lymphomas

Ding

Yang

2013

World Journal of Emergency Medicine

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“…58,[67][68][69] For example, the W374X mutation of PRF1 is common among patients of Turkish descent, a frameshift mutation 50delT leading to premature termination of PRF is virtually unique to patients of Central African descent 70 and the frameshift 1090.91delCT and 207delC originated from and are unique to SouthWestern Japan. 67,71 A number of disease incidents were also reported in other parts of Europe, but many of these patients were of Mediterranean origin.…”

Section: Genetics and Geoepidemiology Of Fhlmentioning

confidence: 99%

“…83,84 The most detrimental PRF1 mutations associated with minimal or no protein expression invariably present during early infancy, with a mean age of onset of 2 months. 3,69 If untreated, this form of FHL is always fatal within a few months or even weeks. By contrast, compound heterozygous PRF1 missense muta-tions are predominantly detected in older patients 3,69 and encode partially active PRF, which might enable patients to survive for a significant period of time before developing FHL.…”

Section: Perforin Deficiency and Human Cancermentioning

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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“…Perforin protein is relevant for cellular cytotoxicity mechanisms and its defect results in impaired antiviral defense and dysregulation of the apoptotic mechanisms causing FHL2. The most detrimental PRF1 mutations associated with minimal or no protein expression invariably present during early infancy, with a mean age of onset of 2 months, [2]. However, there have been reports of FHL2 cases with an age at onset in teens and adulthood [3][4][5].…”

Section: Introductionmentioning

confidence: 99%