المؤلفون: Parlato, Marianna, Charbit-Henrion, Fabienne, Pan, Jie, Romano, Claudio, Duclaux-Loras, Rémi, Le Du, Marie-Helene, Warner, Neil, FRANCALANCI, PAOLA, Bruneau, Julie, Bras, Marc, Zarhrate, Mohammed, Bègue, Bernadette, Guegan, Nicolas, Rakotobe, Sabine, Kapel, Nathalie, De Angelis, Paola, Griffiths, Anne M, Fiedler, Karoline, Crowley, Eileen, Ruemmele, Frank, Muise, Aleixo M, Cerf-Bensussan, Nadine

المساهمون: Parlato, Marianna, Charbit-Henrion, Fabienne, Pan, Jie, Romano, Claudio, Duclaux-Loras, Rémi, Le Du, Marie-Helene, Warner, Neil, Francalanci, Paola, Bruneau, Julie, Bras, Marc, Zarhrate, Mohammed, Bègue, Bernadette, Guegan, Nicola, Rakotobe, Sabine, Kapel, Nathalie, De Angelis, Paola, Griffiths, Anne M, Fiedler, Karoline, Crowley, Eileen, Ruemmele, Frank, Muise, Aleixo M, Cerf-Bensussan, Nadine

مصطلحات موضوعية: inflammatory bowel diseases, intestinal phosphatase alkaline, monogenic disease, Molecular Medicine

الوصف: Herein, we report the first identification of biallelic-inherited mutations in ALPI as a Mendelian cause of inflammatory bowel disease in two unrelated patients. ALPI encodes for intestinal phosphatase alkaline, a brush border metalloenzyme that hydrolyses phosphate from the lipid A moiety of lipopolysaccharides and thereby drastically reduces Toll-like receptor 4 agonist activity. Prediction tools and structural modelling indicate that all mutations affect critical residues or inter-subunit interactions, and heterologous expression in HEK293T cells demonstrated that all ALPI mutations were loss of function. ALPI mutations impaired either stability or catalytic activity of ALPI and rendered it unable to detoxify lipopolysaccharide-dependent signalling. Furthermore, ALPI expression was reduced in patients' biopsies, and ALPI activity was undetectable in ALPI-deficient patient's stool. Our findings highlight the crucial role of ALPI in regulating host-microbiota interactions and restraining host inflammatory responses. These results indicate that ALPI mutations should be included in screening for monogenic causes of inflammatory bowel diseases and lay the groundwork for ALPI-based treatments in intestinal inflammatory disorders.

وصف الملف: ELETTRONICO

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/29567797; info:eu-repo/semantics/altIdentifier/wos/WOS:000429322500007; volume:10; issue:4, Article Number: e8483; firstpage:1; lastpage:12; numberofpages:12; journal:EMBO MOLECULAR MEDICINE; http://hdl.handle.net/11570/3134617Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85044270984

الإتاحة: https://doi.org/10.15252/emmm.201708483Test
http://hdl.handle.net/11570/3134617Test

المؤلفون: Parlato, Marianna, Charbit-Henrion, Fabienne, Pan, Jie, Romano, Claudio, Duclaux-Loras, Rémi, Le Du, Marie Helene, Warner, Neil, Francalanci, Paola, Bruneau, Julie, Bras, Marc, Zarhrate, Mohammed, Bègue, Bernadette, Guegan, Nicolas, Rakotobe, Sabine, Kapel, Nathalie, De Angelis, Paola, Griffiths, Anne M., Fiedler, Karoline, Crowley, Eileen, Ruemmele, Frank, Muise, Aleixo M., Cerf-Bensussan, Nadine

المصدر: Paediatrics Publications

مصطلحات موضوعية: inflammatory bowel diseases, intestinal phosphatase alkaline, monogenic disease

الوصف: Herein, we report the first identification of biallelic-inherited mutations in ALPI as a Mendelian cause of inflammatory bowel disease in two unrelated patients. ALPI encodes for intestinal phosphatase alkaline, a brush border metalloenzyme that hydrolyses phosphate from the lipid A moiety of lipopolysaccharides and thereby drastically reduces Toll-like receptor 4 agonist activity. Prediction tools and structural modelling indicate that all mutations affect critical residues or inter-subunit interactions, and heterologous expression in HEK293T cells demonstrated that all ALPI mutations were loss of function. ALPI mutations impaired either stability or catalytic activity of ALPI and rendered it unable to detoxify lipopolysaccharide-dependent signalling. Furthermore, ALPI expression was reduced in patients’ biopsies, and ALPI activity was undetectable in ALPI-deficient patient's stool. Our findings highlight the crucial role of ALPI in regulating host–microbiota interactions and restraining host inflammatory responses. These results indicate that ALPI mutations should be included in screening for monogenic causes of inflammatory bowel diseases and lay the groundwork for ALPI-based treatments in intestinal inflammatory disorders.

وصف الملف: application/pdf

العلاقة: https://ir.lib.uwo.ca/paedpub/1008Test; https://ir.lib.uwo.ca/context/paedpub/article/2016/viewcontent/17.355.pdfTest

الإتاحة: https://doi.org/10.15252/emmm.201708483Test
https://ir.lib.uwo.ca/paedpub/1008Test
https://ir.lib.uwo.ca/context/paedpub/article/2016/viewcontent/17.355.pdfTest

المؤلفون: Parlato, Marianna, Charbit-Henrion, Fabienne, Pan, Jie, Romano, Claudio, Duclaux-Loras, Rémi, Le Du, Marie-Helene, Warner, Neil, Francalanci, Paola, Bruneau, Julie, Bras, Marc, Zarhrate, Mohammed, Bègue, Bernadette, Guegan, Nicolas, Rakotobe, Sabine, Kapel, Nathalie, de Angelis, Paola, Griffiths, Anne M., Fiedler, Karoline, Crowley, Eileen, Ruemmele, Frank, Muise, Aleixo M., Cerf-Bensussan, Nadine

المساهمون: Laboratory of Intestinal Immunity (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), GENIUS Group, Service de Gastroentérologie, d'hépatologie et nutrition pédiatrique CHU Necker, Hôpital Necker - Enfants Malades AP-HP, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), The Hospital for sick children Toronto (SickKids), University of Messina, Department of Pathology, University of Alabama at Birmingham Birmingham (UAB), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), IRCCS Ospedale Pediatrico Bambino Gesù = Bambino Gesù Children’s Hospital, Université Paris Descartes - Paris 5 (UPD5), Service de pathologie CHU Necker, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Necker - Enfants Malades AP-HP, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Plateforme de bioinformatique (UNIV Paris Descartes), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière AP-HP, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Toronto, Université Sorbonne Paris Cité (USPC), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010)

المصدر: ISSN: 1757-4676.

مصطلحات موضوعية: INTGEN, B3S, inflammatory bowel diseases, intestinal phosphatase alkaline, monogenic disease, [SDV]Life Sciences [q-bio]

الوصف: International audience ; Herein, we report the first identification of biallelic-inherited mutations inALPIas a Mendelian cause of inflammatory bowel disease in two unrelated patients.ALPIencodes for intestinal phosphatase alkaline, a brush border metalloenzyme that hydrolyses phosphate from the lipid A moiety of lipopolysaccharides and thereby drastically reduces Toll-like receptor 4 agonist activity. Prediction tools and structural modelling indicate that all mutations affect critical residues or inter-subunit interactions, and heterologous expression in HEK293T cells demonstrated that allALPImutations were loss of function.ALPImutations impaired either stability or catalytic activity of ALPI and rendered it unable to detoxify lipopolysaccharide-dependent signalling. Furthermore, ALPI expression was reduced in patients' biopsies, and ALPI activity was undetectable in ALPI-deficient patient's stool. Our findings highlight the crucial role of ALPI in regulating host-microbiota interactions and restraining host inflammatory responses. These results indicate thatALPImutations should be included in screening for monogenic causes of inflammatory bowel diseases and lay the groundwork for ALPI-based treatments in intestinal inflammatory disorders.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/29567797; hal-02183255; https://hal.science/hal-02183255Test; PUBMED: 29567797; PUBMEDCENTRAL: PMC5887907

الإتاحة: https://doi.org/10.15252/emmm.201708483Test
https://hal.science/hal-02183255Test

المؤلفون: Parlato, Marianna, Charbit-Henrion, Fabienne, Pan, Jie, Romano, Claudio, Duclaux-Loras, Rémi, Le Du, Marie-Helene, Warner, Neil, Francalanci, Paola, Bruneau, Julie, Bras, Marc, Zarhrate, Mohammed, Bègue, Bernadette, Guegan, Nicolas, Rakotobe, Sabine, Kapel, Nathalie, de Angelis, Paola, Griffiths, Anne M., Fiedler, Karoline, Crowley, Eileen, Ruemmele, Frank, Muise, Aleixo M., Cerf-Bensussan, Nadine

المساهمون: Laboratory of Intestinal Immunity (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), GENIUS Group, Service de Gastroentérologie, d'hépatologie et nutrition pédiatrique CHU Necker, Hôpital Necker - Enfants Malades AP-HP, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), The Hospital for sick children Toronto (SickKids), University of Messina, Department of Pathology, University of Alabama at Birmingham Birmingham (UAB), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), IRCCS Ospedale Pediatrico Bambino Gesù = Bambino Gesù Children’s Hospital, Université Paris Descartes - Paris 5 (UPD5), Service de pathologie CHU Necker, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Necker - Enfants Malades AP-HP, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Plateforme de bioinformatique (UNIV Paris Descartes), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière AP-HP, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Toronto, Université Sorbonne Paris Cité (USPC), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010)

المصدر: ISSN: 1757-4676.

مصطلحات موضوعية: INTGEN, B3S, inflammatory bowel diseases, intestinal phosphatase alkaline, monogenic disease, [SDV]Life Sciences [q-bio]

الوصف: International audience ; Herein, we report the first identification of biallelic-inherited mutations inALPIas a Mendelian cause of inflammatory bowel disease in two unrelated patients.ALPIencodes for intestinal phosphatase alkaline, a brush border metalloenzyme that hydrolyses phosphate from the lipid A moiety of lipopolysaccharides and thereby drastically reduces Toll-like receptor 4 agonist activity. Prediction tools and structural modelling indicate that all mutations affect critical residues or inter-subunit interactions, and heterologous expression in HEK293T cells demonstrated that allALPImutations were loss of function.ALPImutations impaired either stability or catalytic activity of ALPI and rendered it unable to detoxify lipopolysaccharide-dependent signalling. Furthermore, ALPI expression was reduced in patients' biopsies, and ALPI activity was undetectable in ALPI-deficient patient's stool. Our findings highlight the crucial role of ALPI in regulating host-microbiota interactions and restraining host inflammatory responses. These results indicate thatALPImutations should be included in screening for monogenic causes of inflammatory bowel diseases and lay the groundwork for ALPI-based treatments in intestinal inflammatory disorders.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/29567797; hal-02183255; https://hal.science/hal-02183255Test; PUBMED: 29567797; PUBMEDCENTRAL: PMC5887907

الإتاحة: https://doi.org/10.15252/emmm.201708483Test
https://hal.science/hal-02183255Test

المؤلفون: Parlato, Marianna, Charbit-Henrion, Fabienne, Pan, Jie, Romano, Claudio, Duclaux-Loras, Rémi, Le Du, Marie-Helene, Warner, Neil, Francalanci, Paola, Bruneau, Julie, Bras, Marc, Zarhrate, Mohammed, Bègue, Bernadette, Guegan, Nicolas, Rakotobe, Sabine, Kapel, Nathalie, de Angelis, Paola, Griffiths, Anne M., Fiedler, Karoline, Crowley, Eileen, Ruemmele, Frank, Muise, Aleixo M., Cerf-Bensussan, Nadine

المساهمون: Laboratory of Intestinal Immunity (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), GENIUS Group, Service de Gastroentérologie, d'hépatologie et nutrition pédiatrique CHU Necker, Hôpital Necker - Enfants Malades AP-HP, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), The Hospital for sick children Toronto (SickKids), University of Messina, Department of Pathology, University of Alabama at Birmingham Birmingham (UAB), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), IRCCS Ospedale Pediatrico Bambino Gesù = Bambino Gesù Children’s Hospital, Université Paris Descartes - Paris 5 (UPD5), Service de pathologie CHU Necker, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Necker - Enfants Malades AP-HP, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Plateforme de bioinformatique (UNIV Paris Descartes), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière AP-HP, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Toronto, Université Sorbonne Paris Cité (USPC), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010)

المصدر: ISSN: 1757-4676.

مصطلحات موضوعية: INTGEN, B3S, inflammatory bowel diseases, intestinal phosphatase alkaline, monogenic disease, [SDV]Life Sciences [q-bio]

الوصف: International audience ; Herein, we report the first identification of biallelic-inherited mutations inALPIas a Mendelian cause of inflammatory bowel disease in two unrelated patients.ALPIencodes for intestinal phosphatase alkaline, a brush border metalloenzyme that hydrolyses phosphate from the lipid A moiety of lipopolysaccharides and thereby drastically reduces Toll-like receptor 4 agonist activity. Prediction tools and structural modelling indicate that all mutations affect critical residues or inter-subunit interactions, and heterologous expression in HEK293T cells demonstrated that allALPImutations were loss of function.ALPImutations impaired either stability or catalytic activity of ALPI and rendered it unable to detoxify lipopolysaccharide-dependent signalling. Furthermore, ALPI expression was reduced in patients' biopsies, and ALPI activity was undetectable in ALPI-deficient patient's stool. Our findings highlight the crucial role of ALPI in regulating host-microbiota interactions and restraining host inflammatory responses. These results indicate thatALPImutations should be included in screening for monogenic causes of inflammatory bowel diseases and lay the groundwork for ALPI-based treatments in intestinal inflammatory disorders.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/29567797; hal-02183255; https://hal.science/hal-02183255Test; PUBMED: 29567797; PUBMEDCENTRAL: PMC5887907

الإتاحة: https://doi.org/10.15252/emmm.201708483Test
https://hal.science/hal-02183255Test

المؤلفون: Parlato, Marianna, Charbit-Henrion, Fabienne, Pan, Jie, Romano, Claudio, Duclaux-Loras, Rémi, Le Du, Marie-Helene, Warner, Neil, Francalanci, Paola, Bruneau, Julie, Bras, Marc, Zarhrate, Mohammed, Bègue, Bernadette, Guegan, Nicolas, Rakotobe, Sabine, Kapel, Nathalie, de Angelis, Paola, Griffiths, Anne M., Fiedler, Karoline, Crowley, Eileen, Ruemmele, Frank, Muise, Aleixo M., Cerf-Bensussan, Nadine

المساهمون: Laboratory of Intestinal Immunity (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), GENIUS Group, Service de Gastroentérologie, d'hépatologie et nutrition pédiatrique CHU Necker, Hôpital Necker - Enfants Malades AP-HP, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), The Hospital for sick children Toronto (SickKids), University of Messina, Department of Pathology, University of Alabama at Birmingham Birmingham (UAB), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), IRCCS Ospedale Pediatrico Bambino Gesù = Bambino Gesù Children’s Hospital, Université Paris Descartes - Paris 5 (UPD5), Service de pathologie CHU Necker, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Necker - Enfants Malades AP-HP, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Plateforme de bioinformatique (UNIV Paris Descartes), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière AP-HP, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Toronto, Université Sorbonne Paris Cité (USPC), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010)

المصدر: ISSN: 1757-4676.

مصطلحات موضوعية: INTGEN, B3S, inflammatory bowel diseases, intestinal phosphatase alkaline, monogenic disease, [SDV]Life Sciences [q-bio]

الوصف: International audience ; Herein, we report the first identification of biallelic-inherited mutations inALPIas a Mendelian cause of inflammatory bowel disease in two unrelated patients.ALPIencodes for intestinal phosphatase alkaline, a brush border metalloenzyme that hydrolyses phosphate from the lipid A moiety of lipopolysaccharides and thereby drastically reduces Toll-like receptor 4 agonist activity. Prediction tools and structural modelling indicate that all mutations affect critical residues or inter-subunit interactions, and heterologous expression in HEK293T cells demonstrated that allALPImutations were loss of function.ALPImutations impaired either stability or catalytic activity of ALPI and rendered it unable to detoxify lipopolysaccharide-dependent signalling. Furthermore, ALPI expression was reduced in patients' biopsies, and ALPI activity was undetectable in ALPI-deficient patient's stool. Our findings highlight the crucial role of ALPI in regulating host-microbiota interactions and restraining host inflammatory responses. These results indicate thatALPImutations should be included in screening for monogenic causes of inflammatory bowel diseases and lay the groundwork for ALPI-based treatments in intestinal inflammatory disorders.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/29567797; hal-02183255; https://hal.science/hal-02183255Test; PUBMED: 29567797; PUBMEDCENTRAL: PMC5887907

الإتاحة: https://doi.org/10.15252/emmm.201708483Test
https://hal.science/hal-02183255Test

المؤلفون: Parlato, Marianna, Charbit-Henrion, Fabienne, Pan, Jie, Romano, Claudio, Duclaux-Loras, Rémi, Le Du, Marie-Helene, Warner, Neil, Francalanci, Paola, Bruneau, Julie, Bras, Marc, Zarhrate, Mohammed, Bègue, Bernadette, Guegan, Nicolas, Rakotobe, Sabine, Kapel, Nathalie, de Angelis, Paola, Griffiths, Anne M., Fiedler, Karoline, Crowley, Eileen, Ruemmele, Frank, Muise, Aleixo M., Cerf-Bensussan, Nadine

المساهمون: Laboratory of Intestinal Immunity (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), GENIUS Group, Service de Gastroentérologie, d'hépatologie et nutrition pédiatrique CHU Necker, Hôpital Necker - Enfants Malades AP-HP, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), The Hospital for sick children Toronto (SickKids), University of Messina, Department of Pathology, University of Alabama at Birmingham Birmingham (UAB), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), IRCCS Ospedale Pediatrico Bambino Gesù = Bambino Gesù Children’s Hospital, Université Paris Descartes - Paris 5 (UPD5), Service de pathologie CHU Necker, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Necker - Enfants Malades AP-HP, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Plateforme de bioinformatique (UNIV Paris Descartes), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière AP-HP, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Toronto, Université Sorbonne Paris Cité (USPC), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010)

المصدر: ISSN: 1757-4676.

مصطلحات موضوعية: INTGEN, B3S, inflammatory bowel diseases, intestinal phosphatase alkaline, monogenic disease, [SDV]Life Sciences [q-bio]

الوصف: International audience ; Herein, we report the first identification of biallelic-inherited mutations inALPIas a Mendelian cause of inflammatory bowel disease in two unrelated patients.ALPIencodes for intestinal phosphatase alkaline, a brush border metalloenzyme that hydrolyses phosphate from the lipid A moiety of lipopolysaccharides and thereby drastically reduces Toll-like receptor 4 agonist activity. Prediction tools and structural modelling indicate that all mutations affect critical residues or inter-subunit interactions, and heterologous expression in HEK293T cells demonstrated that allALPImutations were loss of function.ALPImutations impaired either stability or catalytic activity of ALPI and rendered it unable to detoxify lipopolysaccharide-dependent signalling. Furthermore, ALPI expression was reduced in patients' biopsies, and ALPI activity was undetectable in ALPI-deficient patient's stool. Our findings highlight the crucial role of ALPI in regulating host-microbiota interactions and restraining host inflammatory responses. These results indicate thatALPImutations should be included in screening for monogenic causes of inflammatory bowel diseases and lay the groundwork for ALPI-based treatments in intestinal inflammatory disorders.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/29567797; hal-02183255; https://hal.science/hal-02183255Test; PUBMED: 29567797; PUBMEDCENTRAL: PMC5887907

الإتاحة: https://doi.org/10.15252/emmm.201708483Test
https://hal.science/hal-02183255Test

المؤلفون: Parlato, Marianna, Charbit-Henrion, Fabienne, Pan, Jie, Romano, Claudio, DUCLAUX-LORAS, Rémi, Le Du, Marie-Helene, Warner, Neil, Francalanci, Paola, Bruneau, Julie, Bras, Marc, Zarhrate, Mohammed, Bègue, Bernadette, Guegan, Nicolas, Rakotobe, Sabine, Kapel, Nathalie, De Angelis, Paola, Griffiths, Anne M., Fiedler, Karoline, Crowley, Eileen, Ruemmele, Frank, Muise, Aleixo M., Cerf-Bensussan, Nadine

المساهمون: Laboratory of Intestinal Immunity (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), GENIUS Group, Service de Gastroentérologie, d'hépatologie et nutrition pédiatrique CHU Necker, CHU Necker - Enfants Malades AP-HP, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), The Hospital for sick children Toronto (SickKids), University of Messina, Department of Pathology, University of Alabama at Birmingham Birmingham (UAB), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Children's Hospital Bambino Gesù IRCCS Rome, Université Paris Descartes - Paris 5 (UPD5), Service de pathologie CHU Necker, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades AP-HP, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Plateforme de bioinformatique (UNIV Paris Descartes), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière AP-HP, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Toronto, Université Sorbonne Paris Cité (USPC)

المصدر: ISSN: 1757-4676.

مصطلحات موضوعية: monogenic disease, intestinal phosphatase alkaline, inflammatory bowel diseases, B3S, INTGEN, [SDV]Life Sciences [q-bio]

الوصف: International audience ; Herein, we report the first identification of biallelic-inherited mutations inALPIas a Mendelian cause of inflammatory bowel disease in two unrelated patients.ALPIencodes for intestinal phosphatase alkaline, a brush border metalloenzyme that hydrolyses phosphate from the lipid A moiety of lipopolysaccharides and thereby drastically reduces Toll-like receptor 4 agonist activity. Prediction tools and structural modelling indicate that all mutations affect critical residues or inter-subunit interactions, and heterologous expression in HEK293T cells demonstrated that allALPImutations were loss of function.ALPImutations impaired either stability or catalytic activity of ALPI and rendered it unable to detoxify lipopolysaccharide-dependent signalling. Furthermore, ALPI expression was reduced in patients' biopsies, and ALPI activity was undetectable in ALPI-deficient patient's stool. Our findings highlight the crucial role of ALPI in regulating host-microbiota interactions and restraining host inflammatory responses. These results indicate thatALPImutations should be included in screening for monogenic causes of inflammatory bowel diseases and lay the groundwork for ALPI-based treatments in intestinal inflammatory disorders.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/29567797; hal-02183255; https://hal.archives-ouvertes.fr/hal-02183255Test; PUBMED: 29567797; PUBMEDCENTRAL: PMC5887907

الإتاحة: https://doi.org/10.15252/emmm.201708483Test
https://hal.archives-ouvertes.fr/hal-02183255Test

المؤلفون: Parlato, Marianna, Charbit-Henrion, Fabienne, Pan, Jie, Romano, Claudio, Duclaux-Loras, Rémi, Le Du, Marie-Helene, Warner, Neil, Francalanci, Paola, Bruneau, Julie, Bras, Marc, Zarhrate, Mohammed, Bègue, Bernadette, Guegan, Nicolas, Rakotobe, Sabine, Kapel, Nathalie, de Angelis, Paola, Griffiths, Anne M., Fiedler, Karoline, Crowley, Eileen, Ruemmele, Frank, Muise, Aleixo M., Cerf-Bensussan, Nadine

المساهمون: Laboratory of Intestinal Immunity (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), GENIUS Group, Service de Gastroentérologie, d'hépatologie et nutrition pédiatrique CHU Necker, Hôpital Necker - Enfants Malades AP-HP, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), The Hospital for sick children Toronto (SickKids), University of Messina, Department of Pathology, University of Alabama at Birmingham Birmingham (UAB), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), IRCCS Ospedale Pediatrico Bambino Gesù = Bambino Gesù Children’s Hospital, Université Paris Descartes - Paris 5 (UPD5), Service de pathologie CHU Necker, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Necker - Enfants Malades AP-HP, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Plateforme de bioinformatique (UNIV Paris Descartes), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière AP-HP, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Toronto, Université Sorbonne Paris Cité (USPC), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010)

المصدر: ISSN: 1757-4676.

مصطلحات موضوعية: INTGEN, B3S, inflammatory bowel diseases, intestinal phosphatase alkaline, monogenic disease, [SDV]Life Sciences [q-bio]

الوصف: International audience ; Herein, we report the first identification of biallelic-inherited mutations inALPIas a Mendelian cause of inflammatory bowel disease in two unrelated patients.ALPIencodes for intestinal phosphatase alkaline, a brush border metalloenzyme that hydrolyses phosphate from the lipid A moiety of lipopolysaccharides and thereby drastically reduces Toll-like receptor 4 agonist activity. Prediction tools and structural modelling indicate that all mutations affect critical residues or inter-subunit interactions, and heterologous expression in HEK293T cells demonstrated that allALPImutations were loss of function.ALPImutations impaired either stability or catalytic activity of ALPI and rendered it unable to detoxify lipopolysaccharide-dependent signalling. Furthermore, ALPI expression was reduced in patients' biopsies, and ALPI activity was undetectable in ALPI-deficient patient's stool. Our findings highlight the crucial role of ALPI in regulating host-microbiota interactions and restraining host inflammatory responses. These results indicate thatALPImutations should be included in screening for monogenic causes of inflammatory bowel diseases and lay the groundwork for ALPI-based treatments in intestinal inflammatory disorders.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/29567797; hal-02183255; https://hal.science/hal-02183255Test; PUBMED: 29567797; PUBMEDCENTRAL: PMC5887907

الإتاحة: https://doi.org/10.15252/emmm.201708483Test
https://hal.science/hal-02183255Test