Somatic FAS mutations are common in patients with genetically undefined autoimmune lymphoproliferative syndrome

Dowdell, Kennichi C.; Niemela, Julie E.; Price, Susan; Davis, Joie; Hornung, Ronald L.; Oliveira, João Bosco; Puck, Jennifer M.; Jaffe, Elaine S.; Pittaluga, Stefania; Cohen, Jeffrey I.; Fleisher, Thomas A.; Rao, V. Koneti

doi:10.1182/blood-2010-01-263145

Cited by 138 publications

(106 citation statements)

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“…However, somatic FAS mutations have also been reported (ALPS-sFAS). 6,[8][9][10][11] Homozygous or compound heterozygous FAS mutations result in a clinically more severe phenotype. Less frequently, FASLG mutations (ALPS-FASLG) [12][13][14][15][16] or CASP10 mutations (ALPS-CASP10) 17 have been detected.…”

Section: Introductionmentioning

confidence: 99%

Deregulation of Fas ligand expression as a novel cause of autoimmune lymphoproliferative syndrome-like disease

et al. 2015

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© F e r r a t a S t o r t i F o u n d a t i o nFor instance, forced expression of the Fas regulating miR146a caused an immune disorder similar to ALPS in transgenic mice. 22 One factor known to regulate expression of both Fas and FasL is interleukin-12 (IL12). [23][24][25][26][27][28][29][30] This cytokine mediates its effects via binding to a heterodimeric receptor composed of the IL12 receptors β1 (IL12RB1) and β2 (IL12RB2) and subsequent activation of JAK/STAT signaling. 31 The IL12 receptor is mainly expressed on T lymphocytes and natural killer (NK) cells. IL12RB1 deficiency is associated with Mendelian susceptibility to mycobacterial diseases. [32][33][34][35] These diseases predispose affected individuals to mycobacterial infections (tuberculosis) due to disturbance of IL12/IL23/IFNg signaling. IL12RB1 also associates with IL23R to form the IL23 receptor. Phagocytic cells release both IL12 and IL23 in response to non-viral infections to induce the secretion of interferon (IFN)g by T and NK cells. This in turn stimulates phagocytes to eliminate intracellular pathogens and activation of IFNg−secreting T helper cells. The IL12 signaling pathway is known to regulate FasL expression on activated T cells and knockout of IL12RB2 predisposes mice to spontaneous autoimmunity, lymphoproliferation and B-cell malignancies. 36 In the present study we identified a patient with a classical ALPS phenotype that was associated with a truncating nonsense mutation in IL12RB1 and loss of IL12/IL23-mediated signaling. Methods Study cohorts and DNA isolationTwenty-six ALPS patients, relatives and healthy controls were enrolled in the study. Written informed consent was obtained from all participants. Experiments were approved by the Ethical Review Boards of Hadassah, the Israeli Ministry of Health and the local Ethics committee of the University of Düsseldorf. Mononuclear cells were derived from peripheral blood by Ficoll (Biochrom, Berlin, Germany) density centrifugation. DNT cells were magnetically selected employing the double-negative T-cell isolation kit (Miltenyi, Bergisch-Gladbach, Germany). Genomic DNA was isolated from whole blood or DNT cells using the DNA blood kit (Qiagen, Hilden, Germany). Whole-exome sequencing and data analysisAfter exclusion of mutations in known ALPS-associated genes by targeted Sanger sequencing (Online Supplementary Methods, Online Supplementary Table S1) whole-exome sequencing was carried out as described elsewhere. 37 In brief, sequencing libraries of 350 bp fragments were generated from sheared genomic DNA. Exome capture was performed using the SeqCap EZ Exome Library 2.0 kit (Roche/Nimblegen, Madison, WI, USA). One hundred base-pair, single-read sequencing was performed on a HiSeq2000 (Illumina, San Diego, CA, USA).Sequencing data were aligned against the human reference genome hg19 (GRCh37, statistics provided in Online Supplementary Table S2) and converted using Samtools. 38 Variation calls were obtained employing GATK, HapMap, OmniArray and dbSNP134 datasets (The Broad Institu...

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Section: Introductionmentioning

confidence: 99%

Deregulation of Fas ligand expression as a novel cause of autoimmune lymphoproliferative syndrome-like disease

et al. 2015

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“…Rarely, ALPS patients have mutations in FASL (,1%) and CASP10 (2% to 3%). 9,10 Approximately one-third of patients with ALPS have yet undetermined genetic defects (ALPS-U). 11 Treatment of patients with ALPS varies significantly, with no consensus on the management.…”

Section: Introductionmentioning

confidence: 99%

Sirolimus is effective in relapsed/refractory autoimmune cytopenias: results of a prospective multi-institutional trial

Bride

Vincent

Smith‐Whitley

et al. 2016

Blood

173

131

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“…Physicians should consider ALPS in these situations and also in Evans's syndrome, which has now been recognized as a heterogeneous syndrome that includes patients with ALPS-FAS. 10 The occurrence of lymphoma in 3 of the adult patients reported highlights the need to consider a diagnosis of ALPS-FAS in lymphoma patients with immune cytopenias or chronic benign lymphoproliferation during infancy. The relapse of immune cytopenias in adulthood should also prompt the physician to consider a diagnosis of ALPS.…”

Section: Discussionmentioning

confidence: 99%

“…during adulthood) has only been described in a few cases. 9,10 Here, we present data on the clinical, biological and molecular aspects of 17 ALPS-FAS patients diagnosed during adulthood. The data were collated by the French national reference centers for hereditary immunodeficiencies and immune cytopenias.…”

Section: Introductionmentioning

confidence: 99%

Diagnosis of autoimmune lymphoproliferative syndrome caused by FAS deficiency in adults

et al. 2012

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Somatic FAS mutations are common in patients with genetically undefined autoimmune lymphoproliferative syndrome

Cited by 138 publications

References 38 publications

Deregulation of Fas ligand expression as a novel cause of autoimmune lymphoproliferative syndrome-like disease

Deregulation of Fas ligand expression as a novel cause of autoimmune lymphoproliferative syndrome-like disease

Sirolimus is effective in relapsed/refractory autoimmune cytopenias: results of a prospective multi-institutional trial

Diagnosis of autoimmune lymphoproliferative syndrome caused by FAS deficiency in adults

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