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Hans D. Ochs - One of the best experts on this subject based on the ideXlab platform.
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Immune Dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome: A systematic review.
Autoimmunity reviews, 2020Co-Authors: Jae Hyon Park, Hans D. Ochs, Ciriaco A. Piccirillo, Keum Hwa Lee, Bokyoung Jeon, Joon Suk Lee, Heon Yung Gee, Seeun Seo, Dongil Geum, Michael EisenhutAbstract:Abstract Background Immune Dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a monogenic disorder characterized by early onset fatal multi-system autoimmunity due to loss-of-function mutations in the gene encoding the forkhead box P3 (FOXP3) transcription factor which is crucial for the development, maturation, and maintenance of CD4+ regulatory T (T-reg) cells. Various autoImmune phenomena such as enteropathy, endocrinopathies, cytopenias, renal disease, and skin manifestations are characteristic findings in patients affected by IPEX syndrome. Objectives In this systematic review, we focus on both clinical and demographic characteristics of IPEX patients, highlighting possible genotype-phenotype correlations and address prognostic factors for disease outcome. Methods We performed a literature search to systematically investigate the case reports of IPEX which were published before August 7th, 2017. Results A total of 75 articles (195 patients) were identified. All IPEX patients included had FOXP3 mutations which were most frequently located in the forkhead domain (n = 68, 34.9%) followed by the leucine-zipper domain (n = 30, 15.4%) and repressor domain (n = 36, 18.4%). Clinical manifestations were as follows: enteropathy (n = 191, 97.9%), skin manifestations (n = 121, 62.1%), endocrinopathy (n = 104, 53.3%), hematologic abnormalities (n = 75, 38.5%), infections (n = 78, 40.0%), other Immune-related complications (n = 43, 22.1%), and renal involvement (n = 32, 16.4%). Enteropathic presentations (P = 0.017), eczema (P = 0.030), autoImmune hemolytic anemia (P = 0.022) and food allergy (P = 0.009) were associated with better survival, while thrombocytopenia (P = 0.034), septic shock (P = 0.045) and mutations affecting the repressor domain (P = 0.021), intron 7 (P = 0.033) or poly A sequence (P = 0.025) were associated with increased risk of death. Immunosuppressive therapy alone was significantly associated with increased cumulative survival compared to patients who received no treatment (P = 0.041). Conclusions We report the most comprehensive summary of demographic and clinical profiles derived from a total of 195 IPEX patients with deleterious mutations in FOXP3. Analysis of our findings provides new insights into genotype/phenotype correlations, and clinical and genetic factors associated with increased risk of death and response to treatment strategies.
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Immune Dysregulation polyendocrinopathy enteropathy x linked forkhead box protein 3 mutations and lack of regulatory t cells
The Journal of Allergy and Clinical Immunology, 2007Co-Authors: Troy R Torgerson, Hans D. OchsAbstract:The rare X-linked disorder Immune Dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) and its murine counterpart scurfy have provided important new insights into the essential role of regulatory T cells (Treg) in maintaining tolerance to self-antigens. Mutations of the FOXP3 gene, identified in patients with IPEX, have helped pinpoint key structural domains of the protein that are essential for its function as a transcriptional regulator. Ongoing work using these and associated models has begun to elucidate factors important for the development, function, and competitive fitness of Treg. This improved understanding is beginning to lead to the identification of other defects that may be present in patients who have the clinical phenotype of IPEX but only wild-type FOXP3. It has also led to improved treatment options for IPEX including immunosuppressive drugs and bone marrow transplantation. We are hopeful that the knowledge gained about mechanisms that regulate FOXP3 expression and Treg function will have a major effect on how other autoImmune and allergic disorders are approached.
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Immune Dysregulation polyendocrinopathy enteropathy x linked inheritance model for autoaggression
Advances in Experimental Medicine and Biology, 2007Co-Authors: Hans D. Ochs, Troy R TorgersonAbstract:Patients with the rare X-linked syndrome, Immune Dysregulation, polyendocrinopathy, enteropathy (IPEX) may present early in life with type I diabetes, hyperthyroidism, chronic enteropathy, villous atrophy, dermatitis, autoImmune hemolytic anemia, and antibody- induced neutropenia and thrombocytopenia. Of the reported families with IPEX, most affected boys died before the age of 3 years of malabsorbtion, failure to thrive, infections, or other complications. Characteristic findings at autopsy include lymphocytic infiltrates affecting the lungs, endocrine organs, such as pancreas and thyroid and skin, and increased lymphoid elements in lymph nodes and spleen. Although symptomatic therapy with immunosuppressive drugs provides some beneficial effects, the only curative treatment is hematopoietic stem cell transplantation.
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successful use of the new Immune suppressor sirolimus in ipex Immune Dysregulation polyendocrinopathy enteropathy x linked syndrome
The Journal of Pediatrics, 2005Co-Authors: L Bindl, Hans D. Ochs, Olivier Goulet, Lucia Perroni, Troy Torgerson, Nelly Youssef, Frank M. RuemmeleAbstract:IPEX (Immune-Dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome is an autoImmune disorder with an often lethal outcome in spite of immunosuppressive therapy. We report the successful use of sirolimus in 3 patients with IPEX. The efficacy of sirolimus is probably due to its different mode of action compared to calcineurin-dependent agents.
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Immune Dysregulation polyendocrinopathy enteropathy and x linked inheritance ipex a syndrome of systemic autoimmunity caused by mutations of foxp3 a critical regulator of t cell homeostasis
Current Opinion in Rheumatology, 2003Co-Authors: Eleonora Gambineri, Troy R Torgerson, Hans D. OchsAbstract:Immune Dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX) is one of a group of clinical syndromes that present with multisystem autoImmune disease suggesting a phenotype of Immune Dysregulation. Clinically, IPEX manifests most commonly with diarrhea, insulin-dependent di
Troy R Torgerson - One of the best experts on this subject based on the ideXlab platform.
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the immunogenetics of Immune Dysregulation polyendocrinopathy enteropathy x linked ipex syndrome
Journal of Medical Genetics, 2012Co-Authors: Eva Dhennezel, Troy R Torgerson, Khalid Bin Dhuban, Ciriaco A. PiccirilloAbstract:Immune Dysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome is a rare disorder in humans caused by germ-line mutations in the FOXP3 gene, a master transcriptional regulator for the development of CD4 regulatory T (Treg) cells. This T cell subset has global inhibitory functions that maintain Immune homeostasis and mediate self-tolerance. Treg developmental deficiency or dysfunction is a hallmark of IPEX. It leads to severe, multi-organ, autoImmune phenomena including enteropathy, chronic dermatitis, endocrinopathy and other organ-specific diseases such as anaemia, thrombocytopenia, hepatitis and nephritis. In this review, the genetic, immunological and clinical characteristics of IPEX syndrome are described, and the impact of heritable mutations on the function of Treg cells highlighted.
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Immune Dysregulation polyendocrinopathy enteropathy x linked forkhead box protein 3 mutations and lack of regulatory t cells
The Journal of Allergy and Clinical Immunology, 2007Co-Authors: Troy R Torgerson, Hans D. OchsAbstract:The rare X-linked disorder Immune Dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) and its murine counterpart scurfy have provided important new insights into the essential role of regulatory T cells (Treg) in maintaining tolerance to self-antigens. Mutations of the FOXP3 gene, identified in patients with IPEX, have helped pinpoint key structural domains of the protein that are essential for its function as a transcriptional regulator. Ongoing work using these and associated models has begun to elucidate factors important for the development, function, and competitive fitness of Treg. This improved understanding is beginning to lead to the identification of other defects that may be present in patients who have the clinical phenotype of IPEX but only wild-type FOXP3. It has also led to improved treatment options for IPEX including immunosuppressive drugs and bone marrow transplantation. We are hopeful that the knowledge gained about mechanisms that regulate FOXP3 expression and Treg function will have a major effect on how other autoImmune and allergic disorders are approached.
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Immune Dysregulation polyendocrinopathy enteropathy x linked inheritance model for autoaggression
Advances in Experimental Medicine and Biology, 2007Co-Authors: Hans D. Ochs, Troy R TorgersonAbstract:Patients with the rare X-linked syndrome, Immune Dysregulation, polyendocrinopathy, enteropathy (IPEX) may present early in life with type I diabetes, hyperthyroidism, chronic enteropathy, villous atrophy, dermatitis, autoImmune hemolytic anemia, and antibody- induced neutropenia and thrombocytopenia. Of the reported families with IPEX, most affected boys died before the age of 3 years of malabsorbtion, failure to thrive, infections, or other complications. Characteristic findings at autopsy include lymphocytic infiltrates affecting the lungs, endocrine organs, such as pancreas and thyroid and skin, and increased lymphoid elements in lymph nodes and spleen. Although symptomatic therapy with immunosuppressive drugs provides some beneficial effects, the only curative treatment is hematopoietic stem cell transplantation.
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Immune Dysregulation polyendocrinopathy enteropathy and x linked inheritance ipex a syndrome of systemic autoimmunity caused by mutations of foxp3 a critical regulator of t cell homeostasis
Current Opinion in Rheumatology, 2003Co-Authors: Eleonora Gambineri, Troy R Torgerson, Hans D. OchsAbstract:Immune Dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX) is one of a group of clinical syndromes that present with multisystem autoImmune disease suggesting a phenotype of Immune Dysregulation. Clinically, IPEX manifests most commonly with diarrhea, insulin-dependent di
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Immune Dysregulation polyendocrinopathy enteropathy and x linked inheritance ipex a syndrome of systemic autoimmunity caused by mutations of foxp3 a critical regulator of t cell homeostasis
Current Opinion in Rheumatology, 2003Co-Authors: Eleonora Gambineri, Troy R Torgerson, Hans D. OchsAbstract:Immune Dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX) is one of a group of clinical syndromes that present with multisystem autoImmune disease suggesting a phenotype of Immune Dysregulation. Clinically, IPEX manifests most commonly with diarrhea, insulin-dependent diabetes mellitus, thyroid disorders, and eczema. FOXP3, the gene responsible for IPEX, maps to chromosome Xp11.23-Xq13.3 and encodes a putative DNA-binding protein of the forkhead family. Recent data indicate that FOXP3 is expressed primarily in the CD4+CD25+ regulatory T-cell subset, where it may function as a transcriptional repressor and key modulator of regulatory T-cell fate and function. This review describes the clinical features of IPEX and the structure, function, and known mutations of FOXP3 that provide important insights into its role in maintenance of Immune homeostasis.
Rosa Bacchetta - One of the best experts on this subject based on the ideXlab platform.
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Gene/Cell Therapy Approaches for Immune Dysregulation Polyendocri- nopathy Enteropathy X-Linked Syndrome
2016Co-Authors: Laura Passerini, Matthew H. Porteus, Francesca Santoni R. De Sio, Rosa BacchettaAbstract:Abstract: Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) syndrome is a rare autoImmune disease due to mutations in the gene encoding for Forkhead box P3 (FOXP3), a transcription factor fundamental for the function of thymus-derived (t) regulatory T (Treg) cells. The dysfunction of Treg cells results in the development of dev-astating autoImmune manifestations affecting multiple organs, eventually leading to premature death in infants, if not promptly treated by hematopoietic stem cell transplantation (HSCT). Novel gene therapy strategies can be developed for IPEX syndrome as more definitive cure than allogeneic HSCT. Here we describe the therapeutic approaches, alternative to HSCT, currently under development. We described that effector T cells can be converted in regulatory T cells by LV-mediated FOXP3-gene transfer in differentiated T lymphocytes. Despite FOXP3 mutations mainly affect a highly specific T cell subset, manipulation of stem cells could be required for long-term remission of the disease. Therefore, we believe that a more comprehensive strategy should aim at correcting FOXP3-mutated stem cells. Potentials and hurdles of both strategies will be highlighted here
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From IPEX syndrome to FOXP3 mutation: a lesson on Immune Dysregulation
Annals of the New York Academy of Sciences, 2016Co-Authors: Rosa Bacchetta, Federica Barzaghi, Maria Grazia RoncaroloAbstract:Immune Dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare disorder that increasingly has gained attention as a model of genetic autoimmunity. Numerous papers documenting the key clinical and molecular characteristics of IPEX have provided a detailed understanding of this devastating disease. IPEX is a primary immunodeficiency caused by mutations in the gene FOXP3, which encodes an essential transcription factor required for maintenance of thymus-derived regulatory T (tTreg) cells. tTreg cell dysfunction is the main pathogenic event leading to multiorgan autoimmunity in IPEX. In addition to the traditional clinical presentation (i.e., severe enteropathy, type 1 diabetes, and eczema), IPEX may encompass other variable and distinct clinical manifestations. As IPEX awareness and characterization have increased, so has identification of FOXP3 mutations, with at least 70 to date. Thus, while FOXP3 is the unifying gene, IPEX is a complex and diverse clinical continuum of disorders. Despite understanding IPEX pathogenesis, new treatment options have remained elusive, although early diagnosis led to hematopoietic stem cell transplantation (HSCT) and immunosuppression treatment and improved patient outcomes. Here, we review current knowledge about IPEX syndrome and highlight findings that could lead to novel targeted treatments.
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gene cell therapy approaches for Immune Dysregulation polyendocrinopathy enteropathy x linked syndrome
Current Gene Therapy, 2014Co-Authors: Laura Passerini, Matthew H. Porteus, Francesca Santoni R. De Sio, Rosa BacchettaAbstract:Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) syndrome is a rare autoImmune disease due to mutations in the gene encoding for Forkhead box P3 (FOXP3), a transcription factor fundamental for the function of thymus-derived (t) regulatory T (Treg) cells. The dysfunction of Treg cells results in the development of devastating autoImmune manifestations affecting multiple organs, eventually leading to premature death in infants, if not promptly treated by hematopoietic stem cell transplantation (HSCT). Novel gene therapy strategies can be developed for IPEX syndrome as more definitive cure than allogeneic HSCT. Here we describe the therapeutic approaches, alternative to HSCT, currently under development. We described that effector T cells can be converted in regulatory T cells by LV-mediated FOXP3-gene transfer in differentiated T lymphocytes. Despite FOXP3 mutations mainly affect a highly specific T cell subset, manipulation of stem cells could be required for long-term remission of the disease. Therefore, we believe that a more comprehensive strategy should aim at correcting FOXP3-mutated stem cells. Potentials and hurdles of both strategies will be highlighted here.
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Immune Dysregulation polyendocrinopathy enteropathy x linked syndrome a paradigm of immunodeficiency with autoimmunity
Frontiers in Immunology, 2012Co-Authors: Federica Barzaghi, Laura Passerini, Rosa BacchettaAbstract:Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) syndrome is a rare monogenic primary immunodeficiency (PID) due to mutations of FOXP3, a key transcription factor for naturally occurring (n) regulatory T (Treg) cells. The dysfunction of Treg cells is the main pathogenic event leading to the multi-organ autoimmunity that characterizes IPEX syndrome, a paradigm of genetically determined PID with autoimmunity. IPEX has a severe early onset and can become rapidly fatal within the first year of life regardless of the type and site of the mutation. The initial presenting symptoms are severe enteritis and/or type 1 diabetes mellitus, alone or in combination with eczema and elevated serum IgE. Other autoImmune symptoms, such as hypothyroidism, cytopenia, hepatitis, nephropathy, arthritis, and alopecia, can develop in patients who survive the initial acute phase. The current therapeutic options for IPEX patients are limited. Supportive and replacement therapies combined with pharmacological immunosuppression are required to control symptoms at onset. However, these procedures can allow only a reduction of the clinical manifestations without a permanent control of the disease. The only known effective cure for IPEX syndrome is haematopoietic stem cell transplantation, but it is always limited by the availability of a suitable donor and the lack of specific guidelines for bone marrow transplant in the context of this disease. This review aims to summarize the clinical histories and genomic mutations of the IPEX patients described in the literature to date. We will focus on the clinical and immunological features that allow differential diagnosis of IPEX syndrome and distinguish it from other PID with autoimmunity. The efficacy of the current therapies will be reviewed, and possible innovative approaches, based on the latest highlights of the pathogenesis to treat this severe primary autoImmune disease of childhood, will be discussed.
Frank M. Ruemmele - One of the best experts on this subject based on the ideXlab platform.
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Cutaneous manifestations of Immune Dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome.
The British journal of dermatology, 2008Co-Authors: M. Halabi-tawil, Frank M. Ruemmele, Frédéric Rieux-laucat, O. Goulet, Nicole Brousse, Sylvie Fraitag, Bénédicte Neven, Y. De Prost, Anne-marie Fischer, C. BodemerAbstract:Summary Background Immune Dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare disorder characterized by neonatal autoImmune enteropathy, diabetes and thyroiditis, food allergies and skin rash. IPEX syndrome is caused by mutations in FOXP3, a master control gene of regulatory T cells (Tregs), resulting in absent or dysfunctional Tregs. Data in the literature are scarce and the cutaneous manifestations are rarely depicted. Objectives To evaluate the frequency and characteristics of cutaneous manifestations found in IPEX. Methods Retrospective single-centre study of a case series of IPEX. Patients’ data were retrieved from medical files and numerous parameters concerning general and cutaneous characteristics of the disease were recorded. Results Ten children with IPEX were studied. Cutaneous involvement was present in seven of 10 chidren; age at onset was 0–4 months, median 1·5. All patients presented with atopic dermatitis (AD). Three presented more psoriasiform lesions. Eczema was severe; most affected areas were lower limbs, trunk and face. Pruritus was present in four of seven, and painful fissurary cheilitis in four of seven. Hyper-IgE was found in seven of 10 and hypereosinophilia in five of 10. Skin biopsies showed eczematiform or psoriasiform features. Affected patients were improved by dermocorticoids; no clear improvement was obtained with immunosuppressive regimens. Other features were urticaria secondary to food allergies and staphylococcal sepsis, mostly Staphylococcus aureus and catheter related. Conclusions AD seems to be a frequent finding in IPEX syndrome, which is characterized by Treg anomalies. This hints to a possible role of Tregs in AD, which is then discussed in this study.
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Clinical and molecular aspects of autoImmune enteropathy and Immune Dysregulation, polyendocrinopathy autoImmune enteropathy X-linked syndrome.
Current opinion in gastroenterology, 2008Co-Authors: Frank M. Ruemmele, Nicolette Moes, Natacha Patey-mariaud De Serre, Frédéric Rieux-laucat, Olivier GouletAbstract:Purpose of review AutoImmune enteropathy (AIE) is a distinct cause of severe and persistent inflammatory diarrhea in children. Recent research data allowed us to gain a first insight in the pathogenesis of AIE. On the basis of this data, we will discuss new aspects of AIE emphasizing new diagnostic and therapeutic possibilities. Recent findings With the discovery of disease-causing mutations in the FOXP3 gene in patients with AIE, a dramatic advance in the understanding of AIE was made. Subsequent studies indicated that FOXP3 is a key transcription factor indispensable for regulatory functions of T cells pointing to a critical role of regulatory T-cell homeostasis in the development of AIE. Abnormal FOXP3 expression results in defective regulatory functions of T cells, which in turn cause a systemic T-cell-mediated autoaggressive disorder, now called Immune Dysregulation, polyendocrinopathy autoImmune enteropathy X-linked syndrome. Upon systematic review, we describe different phenotypes of Immune Dysregulation polyendocrinopathy autoImmune enteropathy X-linked syndrome, as well as Immune Dysregulation polyendocrinopathy autoImmune enteropathy X-linked-like forms of AIE, which are FOXP3 independent. No genotype–phenotype correlation could be established so far. Summary On the basis of the profound Immune Dysregulation in AIE, new, most often T-cell-oriented treatment strategies were developed. The recent molecular advances in the understanding of AIE give a clear rational for the use of immunosuppression (combining steroids and tacrolimus or rapamycine) to stabilize AIE patients or to perform bone marrow transplantation in those who do not respond to immunomodulation.
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successful use of the new Immune suppressor sirolimus in ipex Immune Dysregulation polyendocrinopathy enteropathy x linked syndrome
The Journal of Pediatrics, 2005Co-Authors: L Bindl, Hans D. Ochs, Olivier Goulet, Lucia Perroni, Troy Torgerson, Nelly Youssef, Frank M. RuemmeleAbstract:IPEX (Immune-Dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome is an autoImmune disorder with an often lethal outcome in spite of immunosuppressive therapy. We report the successful use of sirolimus in 3 patients with IPEX. The efficacy of sirolimus is probably due to its different mode of action compared to calcineurin-dependent agents.
Alice Y Chan - One of the best experts on this subject based on the ideXlab platform.
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primary Immune regulatory disorders a growing universe of Immune Dysregulation
Current Opinion in Allergy and Clinical Immunology, 2020Co-Authors: Alice Y ChanAbstract:Purpose of review Primary Immune regulatory disorders (PIRD) are a growing subset of diseases referred to as inborn errors of immunity. Unlike classical primary Immune deficiency disorders that typically present with severe, recurrent, or unusual infections, the clinical manifestations of PIRD are dominated by Immune-mediated diseases (autoimmunity, autoinflammation/hyperinflammation, lymphoproliferation, malignancy, and severe atopy). This review introduces the concept of PIRD including clinical phenotypes, treatments, and new PIRD-associated gene defects. Recent findings The number of genetic defects associated with PIRD is rapidly growing. The identified genes often encode proteins that play critical roles in regulating the Immune response to various triggers. Understanding the molecular mechanisms underlying PIRD has shed light on the clinical phenotypes and has helped to identify targeted therapies. In some cases, hematopoietic cell transplant (HCT) has been successfully employed as a cure. Summary It is important to recognize the broad clinical manifestations of PIRD as patients may have symptoms atypical of classical 'immunodeficiency'. Because of their diverse Immune Dysregulation problems, they are often primarily managed by other subspecialists. Immunologists can help connect the diverse Immune-mediated pathologies to a gene defect. This, in turn, can play a significant role in directing clinical management, selecting effective therapy, and deciding on appropriateness of HCT.
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a large crispr induced bystander mutation causes Immune Dysregulation
Communications Biology, 2019Co-Authors: Dimitre R Simeonov, Alexander J Brandt, Alice Y Chan, Jessica T Cortez, Jonathan M Woo, Youjin V Lee, Claudia M B Carvalho, Alyssa C IndartAbstract:A persistent concern with CRISPR-Cas9 gene editing has been the potential to generate mutations at off-target genomic sites. While CRISPR-engineering mice to delete a ~360 bp intronic enhancer, here we discovered a founder line that had marked Immune Dysregulation caused by a 24 kb tandem duplication of the sequence adjacent to the on-target deletion. Our results suggest unintended repair of on-target genomic cuts can cause pathogenic "bystander" mutations that escape detection by routine targeted genotyping assays.
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a large crispr induced bystander mutation causes Immune Dysregulation
Communications biology, 2019Co-Authors: Dimitre R Simeonov, Alice Y Chan, Jessica T Cortez, Claudia M B Carvalho, Alyssa C Indart, Alexander Brandt, Zhongmei Li, Theodore L Roth, James R LupskiAbstract:A persistent concern with CRISPR-Cas9 gene editing has been the potential to generate mutations at off-target genomic sites. While CRISPR-engineering mice to delete a ~360 bp intronic enhancer, here we discovered a founder line that had marked Immune Dysregulation caused by a 24 kb tandem duplication of the sequence adjacent to the on-target deletion. Our results suggest unintended repair of on-target genomic cuts can cause pathogenic “bystander” mutations that escape detection by routine targeted genotyping assays. Dimitre Simeonov, Alexander Brandt et al. report a pathogenic bystander mutation caused by unintended repair of a CRISPR-Cas9-mediated deletion in mice. They generate mice lacking an IL2RA intronic enhancer previously associated with human disease risk and find that one line of edited mice show unexpected disease features due to a bystander mutation.
