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1. Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype

Author

Toubiana, J., Okada, S., Hiller, J., Oleastro, M., Lagos Gomez, M., Aldave Becerra, J. C., Ouachee-Chardin, M., Fouyssac, F., Girisha, K. M., Etzioni, A., Van Montfrans, J., Camcioglu, Y., Kerns, L. A., Belohradsky, B., Blanche, S., Bousfiha, A., Rodriguez-Gallego, C., Meyts, I., Kisand, K., Reichenbach, J., Renner, E. D., Rosenzweig, S., Grimbacher, B., van de Veerdonk, F. L., Traidl-Hoffmann, C., Picard, C., Marodi, L., Morio, T., Kobayashi, M., Lilic, D., Milner, J. D., Holland, S., Casanova, J. -L., Puel A, Cypowyj S, Thumerelle C, Toulon A, Bustamante J, Tahuil N, SALHI, DALILA, Boiu S, Chopra C, Di Giovanni D, Bezrodnik L, Boutros J, Thomas C, Lacuesta G, Jannier S, Korganow AS, Paillard C, Boutboul, Bué M, Marie-Cardine A, Bayart S, Migaud M, Weiss, Karmochkine M, Garcia-Martinez JM, Stephan JL, Bensaid P, Jeannoel GP, Witte T, Baumann U, Harrer T, Navarrete C, ACOSTA HUGHES, BENJAMIN, Firinu, Pignata C, Picco P, Mendoza D, Lugo Reyes SO, Torres Lozano C, Ortega-Cisneros M, Cortina M, Mesdaghi M, Nabavi M, Español T, Martínez-Saavedra MT, Rezaei N, Zoghi S, Pac M, Barlogis V, Revon-Rivière G, Haimi-Cohen Y, Spiegel R, Miron D, Bouchaib J, Blancas-Galicia L, Toth B, Drexel B, Rohrlich PS, Lesens O, Hoernes M, Drewe E, Abinum M, Sawalle-Belohradsky J, Kindle G, Depner M, Milani L, Nikopensius T, Remm M, Talas UG, Tucker M, Willis M, Leonard S, Meuwissen H, Ferdman RM, CORBO UGULINO, WALLACE, Desai MM, Taur P, Badolato R, Soltesz B, Schnopp C, Jansson AF, Ayvaz D, Shabashova N, Chernyshova L, Bondarenko A, Moshous D, Neven B, Boubidi C, Ailal F, Giardino G, Del Giacco S, Bougnoux ME, Imai K, Okawa T, Mizoguchi Y, Ozaki Y, Takeuchi M, Hayakawa A, Lögering B, Reich K, Buhl T, Eyerich K, Schaller M, Arkwright PD, Gennery AR, Cant AJ, Warris A, Henriet S, Mekki N, Barbouche R, Ben Mustapha I, Bodemer, Polak M, Grimprel E, Burgel PR, Fischer A, Hermine O, Debré M, Kocacyk D, Dhalla F, Patel SY, Moens L, Haerynck F, Dullaers, Hoste L, Sanal O, Kilic SS, Roesler J, Lanternier F, Lortholary O, Fieschi C, Church JA, Roifman C, Yuenyongviwat A, Peterson P, Boisson-Dupuis S, Abel L, Marciano BE, Netea MG., Toubiana, J., Okada, S., Hiller, J., Oleastro, M., Lagos Gomez, M., Aldave Becerra, J. C., Ouachee-Chardin, M., Fouyssac, F., Girisha, K. M., Etzioni, A., Van Montfrans, J., Camcioglu, Y., Kerns, L. A., Belohradsky, B., Blanche, S., Bousfiha, A., Rodriguez-Gallego, C., Meyts, I., Kisand, K., Reichenbach, J., Renner, E. D., Rosenzweig, S., Grimbacher, B., van de Veerdonk, F. L., Traidl-Hoffmann, C., Picard, C., Marodi, L., Morio, T., Kobayashi, M., Lilic, D., Milner, J. D., Holland, S., Casanova, J. -L., Puel, A, Cypowyj, S, Thumerelle, C, Toulon, A, Bustamante, J, Tahuil, N, Salhi, Dalila, Boiu, S, Chopra, C, Di Giovanni, D, Bezrodnik, L, Boutros, J, Thomas, C, Lacuesta, G, Jannier, S, Korganow, A, Paillard, C, Boutboul, Bué, M, Marie-Cardine, A, Bayart, S, Migaud, M, Weiss, Karmochkine, M, Garcia-Martinez, Jm, Stephan, Jl, Bensaid, P, Jeannoel, Gp, Witte, T, Baumann, U, Harrer, T, Navarrete, C, ACOSTA HUGHES, Benjamin, Firinu, Pignata, C, Picco, P, Mendoza, D, Lugo Reyes, So, Torres Lozano, C, Ortega-Cisneros, M, Cortina, M, Mesdaghi, M, Nabavi, M, Español, T, Martínez-Saavedra, Mt, Rezaei, N, Zoghi, S, Pac, M, Barlogis, V, Revon-Rivière, G, Haimi-Cohen, Y, Spiegel, R, Miron, D, Bouchaib, J, Blancas-Galicia, L, Toth, B, Drexel, B, Rohrlich, P, Lesens, O, Hoernes, M, Drewe, E, Abinum, M, Sawalle-Belohradsky, J, Kindle, G, Depner, M, Milani, L, Nikopensius, T, Remm, M, Talas, Ug, Tucker, M, Willis, M, Leonard, S, Meuwissen, H, Ferdman, Rm, CORBO UGULINO, Wallace, Desai, Mm, Taur, P, Badolato, R, Soltesz, B, Schnopp, C, Jansson, Af, Ayvaz, D, Shabashova, N, Chernyshova, L, Bondarenko, A, Moshous, D, Neven, B, Boubidi, C, Ailal, F, Giardino, G, Del Giacco, S, Bougnoux, Me, Imai, K, Okawa, T, Mizoguchi, Y, Ozaki, Y, Takeuchi, M, Hayakawa, A, Lögering, B, Reich, K, Buhl, T, Eyerich, K, Schaller, M, Arkwright, Pd, Gennery, Ar, Cant, Aj, Warris, A, Henriet, S, Mekki, N, Barbouche, R, Ben Mustapha, I, Bodemer, Polak, M, Grimprel, E, Burgel, Pr, Fischer, A, Hermine, O, Debré, M, Kocacyk, D, Dhalla, F, Patel, Sy, Moens, L, Haerynck, F, Dullaers, Hoste, L, Sanal, O, Kilic, S, Roesler, J, Lanternier, F, Lortholary, O, Fieschi, C, Church, Ja, Roifman, C, Yuenyongviwat, A, Peterson, P, Boisson-Dupuis, S, Abel, L, Marciano, Be, and Netea, Mg.

Subjects
Male, 0301 basic medicine, Pediatrics, Clinical Trials and Observations, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], medicine.disease_cause, Biochemistry, Gastroenterology, Cohort Studies, STAT5 Transcription Factor, Medicine, Chronic mucocutaneous candidiasis, Child, Hematology, biology, Progressive multifocal leukoencephalopathy, Candidiasis, Chronic Mucocutaneous, Candidiasis, Orvostudományok, Middle Aged, Phenotype, STAT1 Transcription Factor, Staphylococcus aureus, Child, Preschool, Female, STAT3 Transcription Factor, Adult, Heterozygote, medicine.medical_specialty, Adolescent, Aged, Genetic Predisposition to Disease, Humans, Infant, Young Adult, Genetic Association Studies, Mutation, Immunology, Cell Biology, Chronic Mucocutaneous, Klinikai orvostudományok, Herpesviridae, Mycobacterium tuberculosis, 03 medical and health sciences, Internal medicine, Journal Article, ddc:610, Preschool, Key Points AD STAT1 GOF is the most common genetic cause of inherited CMC and is not restricted to a specific age or ethnic group. STAT1 GOF underlies a variety of infectious and autoimmune features, as well as carcinomas and aneurysms associated with a poor outcome, Type 1 diabetes, Cytopenia, business.industry, medicine.disease, biology.organism_classification, 030104 developmental biology, business
Abstract

Contains fulltext : 172671.pdf (Publisher’s version ) (Closed access) Since their discovery in patients with autosomal dominant (AD) chronic mucocutaneous candidiasis (CMC) in 2011, heterozygous STAT1 gain-of-function (GOF) mutations have increasingly been identified worldwide. The clinical spectrum associated with them needed to be delineated. We enrolled 274 patients from 167 kindreds originating from 40 countries from 5 continents. Demographic data, clinical features, immunological parameters, treatment, and outcome were recorded. The median age of the 274 patients was 22 years (range, 1-71 years); 98% of them had CMC, with a median age at onset of 1 year (range, 0-24 years). Patients often displayed bacterial (74%) infections, mostly because of Staphylococcus aureus (36%), including the respiratory tract and the skin in 47% and 28% of patients, respectively, and viral (38%) infections, mostly because of Herpesviridae (83%) and affecting the skin in 32% of patients. Invasive fungal infections (10%), mostly caused by Candida spp. (29%), and mycobacterial disease (6%) caused by Mycobacterium tuberculosis, environmental mycobacteria, or Bacille Calmette-Guerin vaccines were less common. Many patients had autoimmune manifestations (37%), including hypothyroidism (22%), type 1 diabetes (4%), blood cytopenia (4%), and systemic lupus erythematosus (2%). Invasive infections (25%), cerebral aneurysms (6%), and cancers (6%) were the strongest predictors of poor outcome. CMC persisted in 39% of the 202 patients receiving prolonged antifungal treatment. Circulating interleukin-17A-producing T-cell count was low for most (82%) but not all of the patients tested. STAT1 GOF mutations underlie AD CMC, as well as an unexpectedly wide range of other clinical features, including not only a variety of infectious and autoimmune diseases, but also cerebral aneurysms and carcinomas that confer a poor prognosis.

Published
2016
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2. A randomized controlled trial of genotypic HIV drug resistance testing in HIV-1-infected children: the PERA (PENTA 8) trial

Author

Green, H, Gibb, D, Compagnucci, A, Giacomet, V, de Rossi, A, Harper, L, Saïdi, Y, Castelli-Gattinara, G, Pillay, D, Babiker, A, Aboulker, J, Lyall, H, Bacheler, LT, Walker, A, Debré, M, Rosso, R, Burger, D, Della Negra, M, Dunn, D, and Giaquinto, C

Abstract

OBJECTIVE: To evaluate the longer-term utility of genotypic resistance testing in HIV-1-infected children with virological failure. METHODS: Children aged 3 months-18 years switching antiretroviral therapy (ART) with HIV-1 RNA > 2,000 copies/ml were randomized between genotypic testing (Virtual Phenotype) and no testing at baseline and subsequent virological failures. Children were followed to at least 96 weeks. RESULTS: One hundred and seventy eligible children, from 24 clinical centres in six countries, were randomized to resistance testing (n = 87) or no testing (n = 83) between June 2000-July 2003. At baseline, mean HIV-1 RNA and CD4+ T-cell percentage were 4.7 log10 copies/ml and 20%, respectively. Children had taken ART for a mean of 5 years; 24% had received all three classes, 53% nucleoside reverse transcriptase inhibitors (NRTIs)+protease inhibitors (PIs), 9% NRTIs+non-nucleoside reverse transcriptase inhibitors (NNRTIs) and 14% NRTIs only. There was no difference between the arms in the drug classes or the individual PIs/NNRTIs prescribed. However, 49% in the resistance test arm (RT) versus 19% in the no-test arm (NT) continued at least one NRTI from their failing regimen; 56% versus 19% were prescribed didanosine+stavudine as their NRTI backbone. Adjusting for baseline HIV-1 RNA, mean reductions in HIV-1 RNA at 48 weeks were 1.51 log10 copies/ml in the RT arm and 1.23 in the NT arm (P = 0.3); the difference between the arms was smaller at week 96 (RT: 1.50, NT: 1.47; P = 0.9). CONCLUSION: In this first paediatric trial of resistance testing, we observed a substantial difference in NRTI-prescribing behaviour across arms. However statistically significant evidence of a long-term virological or immunological benefit was not observed. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN14367816.

Published
2016

3. Neurocognition and quality of life after reinitiating antiretroviral therapy in children randomized to planned treatment interruption

Author

Ananworanich, J, Melvin, D, Amador, Jt, Childs, T, Medin, G, Boscolo, V, Compagnucci, A, Kanjanavanit, S, Montero, S, Gibb, Dm, PENTA 11 Study Group including Aboulker, J, Babiker, A, Belfrage, E, Bernardi, S, Bologna, R, Burger, D, Butler, K, Castelli Gattinara, G, Castro, H, Clayden, P, Cressey, T, Darbyshire, Jh, Debré, M, de Groot, R, della Negra, M, di Biagio, A, De Rossi, A, Duicelescu, D, Faye, A, Giaquinto, C, Giacomet, V, Grosch Wörner, I, Hainault, M, Klein, N, Lallemant, M, Levy, J, Lyall, H, Marczynska, M, Marques, L, Mardarescu, M, Mellado Peña MJ, Nadal, D, Nastouli, E, Naver, L, Niehues, T, Peckham, C, Pillay, D, Popieska, J, Ramos Amador JT, Rojo Conejo, P, Rosado, L, Rosso, R, Rudin, C, Scherpbier, Hj, Sharland, M, Stevanovic, M, Thorne, C, Tovo, Pier Angelo, Tudor Williams, G, Turkova, A, Valerius, N, Volokha, A, Walker, As, Welch, S, Wintergerst, U, Aboulker, Jp, Burger, Dm, Green, H, Harper, L, Mofenson, L, Moye, J, Saïdi, Y, Cressey, Tr, Jacqz Aigrain, E, Khoo, S, Regazzi, M, Tréluyer, Jm, Ngo Giang Huong, N, Muñoz Fernandez MA, Hill, C, Lepage, P, Pozniak, A, Vella, S, Chêne, G, Vesikari, T, Hadjou, G, Léonardo, S, Riault, Y, Bleier, J, Buck, L, Duong, T, Farrelly, L, Forcat, S, Harrison, L, Horton, J, Johnson, D, Taylor, C, Chalermpantmetagul, S, Peongjakta, R, Khamjakkaew, W, Than in at, K, Chailert, S, Jourdain, G, Le Coeur, S, Floret, D, Costanzo, P, Le Thi TT, Monpoux, F, Mellul, S, Caranta, I, Boudjoudi, N, Firtion, G, Denon, M, Charlemaine, E, Picard, F, Hellier, E, Heuninck, C, Damond, F, Alexandre, G, Tricoire, J, Antras, M, Lachendowier, C, Nicot, F, Krivine, A, Rivaux, D, Notheis, G, Strotmann, G, Schlieben, S, Rampon, O, Zanchetta, M, Ginocchio, F, Viscoli, C, Martino, A, Pontrelli, G, Baldassar, S, Concato, C, Mazza, A, Rossetti, G, Dobosz, S, Oldakowska, A, Popielska, J, Kaflik, M, Stanczak, J, Stanczack, G, Dyda, T, Kruk, M, González Tomé MI, Delgado García, R, Fernandez Gonzalez MT, Mellado Peña, M, Martín Fontelos, P, Garcia Mellado MI, Medina, Af, Ascencion, B, Garcia Bermejo, I, Navarro Gomez DM, Saavedra, J, Prieto, C, Jimenez, Jl, Garcia Torre, A, de José Gómez MI, García Rodriguez MC, Moreno Pérez, D, Núñez Cuadros, E, Asensi Botet, F, Otero Reigada, C, Pérez Tamarit MD, Vilalta, R, Molina Moreno JM, Rainer, T, Schupbach, J, Rutishauser, M, Bunupuradah, T, Butterworth, O, Phasomsap, C, Prasitsuebsai, W, Chuanjaroen, T, Jupimai, T, Ubolyam, S, Phanuphak, P, Puthanakit, T, Pancharoen, C, Mai, C, Namwong, T, Punsakoon, W, Payakachat, S, Chutima, D, Raksasang, M, Foster, C, Hamadache, D, Campbell, S, Newbould, C, Monrose, C, Abdulla, A, Walley, A, Patel, D, Kaye, S, Seery, P, Rankin, A, Wildfire, A, Novelli, V, Shingadia, D, Moshal, K, Flynn, J, Clapson, M, Allen, A, Spencer, L, Rackstraw, C, Ward, B, Parkes, K, Depala, M, Jacobsen, M, Poulsom, H, Barkley, L, Miah, J, Lurie, P, Keane, C, Mcmaster, P, Phipps, M, Orendi, J, Farmer, C, Liebeschuetz, S, Sodeinde, O, Wong, S, Bostock, V, Heath, Y, Scott, S, Gandhi, K, Lewis, P, Daglish, J, Miles, K, Summerhill, L, Subramaniam, B, Weiner, L, Famiglietti, M, Rana, S, Yu, P, Roa, J, Puga, A, Haerry, A., AII - Amsterdam institute for Infection and Immunity, Paediatric Infectious Diseases / Rheumatology / Immunology, and Global Health

Subjects
0301 basic medicine, Male, Pediatrics, medicine.medical_specialty, antiretroviral therapy, children, HIV, neurocognition, neurodevelopment, quality of life, treatment interruption, Immunology and Allergy, Immunology, Infectious Diseases, Adolescent, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Antiretroviral Therapy, HIV Infections, Standard score, 03 medical and health sciences, 0302 clinical medicine, Cognition, Acquired immunodeficiency syndrome (AIDS), Antiretroviral Therapy, Highly Active, Memory span, Medicine, Humans, Highly Active, 030212 general & internal medicine, Child, Wechsler Intelligence Scale for Children, business.industry, Wechsler Adult Intelligence Scale, medicine.disease, 030112 virology, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], Treatment Outcome, Anti-Retroviral Agents, Test score, Mann–Whitney U test, Quality of Life, Female, business, Neurocognitive
Abstract

Item does not contain fulltext OBJECTIVE: Understanding the effects of antiretroviral treatment (ART) interruption on neurocognition and quality of life (QoL) are important for managing unplanned interruptions and planned interruptions in HIV cure research. DESIGN: Children previously randomized to continuous (continuous ART, n = 41) vs. planned treatment interruption (PTI, n = 47) in the Pediatric European Network for Treatment of AIDS (PENTA) 11 study were enrolled. At study end, PTI children resumed ART. At 1 and 2 years following study end, children were assessed by the coding, symbol search and digit span subtests of Wechsler Intelligence Scale for Children (6-16 years old) or Wechsler Adult Intelligence Scale (>/=17 years old) and by Pediatrics QoL questionnaires for physical and psychological QoL. Transformed scaled scores for neurocognition and mean standardized scores for QoL were compared between arms by t-test and Mann-Whitney U test, respectively. Scores indicating clinical concern were compared (

Published
2016

4. FRI0509 Chromosome 22Q11.2 Deletion Syndrome (Digeorge Syndrome) and Autoimmunity: A French Retrospective Pediatric Study of 15 Cases

Author

Freychet, C., primary, Debré, M., additional, Bader Meunier, B., additional, Lemelle, I., additional, Pagnier, A., additional, Taque, S., additional, Munzer, M., additional, Jeziorski, E., additional, Hatchuel, Y., additional, Launay, D., additional, Quartier, P., additional, Mahlaoui, N., additional, and Stephan, J.L., additional

Published
2015
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5. Correction to: A 1-Year Prospective French Nationwide Study of Emergency Hospital Admissions in Children and Adults with Primary Immunodeficiency.

Author

Coignard-Biehler H, Mahlaoui N, Pilmis B, Barlogis V, Brosselin P, De Vergnes N, Debré M, Malphettes M, Frange P, Catherinot E, Pellier I, Durieu I, Perlat A, Royer B, Quellec AL, Jeziorski E, Fischer A, and Lortholary O

Abstract

The original version of the article contained error regarding the presentation of the institutional authors in the PDF and html versions.

Published
2020
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6. A 1-Year Prospective French Nationwide Study of Emergency Hospital Admissions in Children and Adults with Primary Immunodeficiency.

Author

Coignard-Biehler H, Mahlaoui N, Pilmis B, Barlogis V, Brosselin P, De Vergnes N, Debré M, Malphettes M, Frange P, Catherinot E, Pellier I, Durieu I, Perlat A, Royer B, Le Quellec A, Jeziorski E, Fischer A, Lortholary O, Aaron L, Adoue D, Aguilar C, Aladjidi N, Alcais A, Amoura Z, Arlet P, Armari-Alla C, Bader-Meunier B, Bayart S, Bertrand Y, Bienvenu B, Blanche S, Bodet D, Bonnotte B, Borie R, Boutard P, Briandet C, Brion JP, Brouard J, Cohen-Beaussant S, Costes L, Couderc LJ, Cougoul P, Courteille V, de Saint Basile G, Devoldere C, Deville A, Donadieu J, Dore E, Dulieu F, Edan C, Entz-Werle N, Fieschi C, Forestier A, Fouyssac F, Gajdos V, Galicier L, Gandemer V, Gardembas M, Gaud C, Guillerm G, Hachulla E, Hamidou M, Hermine O, Hoarau C, Humbert S, Jaccard A, Jacquot S, Jais JP, Jaussaud R, Jeandel PY, Kebaili K, Korganow AS, Lambotte O, Lanternier F, Larroche C, Lascaux AS, Le Moigne E, Le Moing V, Lebranchu Y, Lecuit M, Lefevre G, Lemal R, Te VLT, Marie-Cardine A, Silva NM, Masseau A, Massot C, Mazingue F, Merlin E, Michel G, Millot F, Monlibert B, Monpoux F, Moshous D, Mouthon L, Munzer M, Neven B, Nove-Josserand R, Oksenhendler E, Ouachée-Chardin M, Oudot C, Pagnier A, Pasquali JL, Pasquet M, Perel Y, Picard C, Piguet C, Plantaz D, Provot J, Quartier P, Rieux-Laucat F, Roblot P, Roger PM, Rohrlich PS, Rubie H, Salle V, Sarrot-Reynauld F, Servettaz A, Stephan JL, Schleinitz N, Suarez F, Swiader L, Taque S, Thomas C, Tournilhac O, Thumerelle C, Tron F, Vannier JP, and Viallard JF

Subjects
Adult, Child, Communicable Disease Control, Communicable Diseases etiology, Disease Management, France epidemiology, Humans, Incidence, Pre-Exposure Prophylaxis, Primary Immunodeficiency Diseases diagnosis, Primary Immunodeficiency Diseases etiology, Primary Immunodeficiency Diseases therapy, Public Health Surveillance, Treatment Outcome, Emergency Medical Services, Hospitalization, Primary Immunodeficiency Diseases epidemiology
Abstract

Purpose: Patients with primary immunodeficiency (PID) are at risk of serious complications. However, data on the incidence and causes of emergency hospital admissions are scarce. The primary objective of the present study was to describe emergency hospital admissions among patients with PID, with a view to identifying "at-risk" patient profiles., Methods: We performed a prospective observational 12-month multicenter study in France via the CEREDIH network of regional PID reference centers from November 2010 to October 2011. All patients with PIDs requiring emergency hospital admission were included., Results: A total of 200 admissions concerned 137 patients (73 adults and 64 children, 53% of whom had antibody deficiencies). Thirty admissions were reported for 16 hematopoietic stem cell transplantation recipients. When considering the 170 admissions of non-transplant patients, 149 (85%) were related to acute infections (respiratory tract infections and gastrointestinal tract infections in 72 (36%) and 34 (17%) of cases, respectively). Seventy-seven percent of the admissions occurred during winter or spring (December to May). The in-hospital mortality rate was 8.8% (12 patients); death was related to a severe infection in 11 cases (8%) and Epstein-Barr virus-induced lymphoma in 1 case. Patients with a central venous catheter (n = 19, 13.9%) were significantly more hospitalized for an infection (94.7%) than for a non-infectious reason (5.3%) (p = 0.04)., Conclusion: Our data showed that the annual incidence of emergency hospital admission among patients with PID is 3.4%. The leading cause of emergency hospital admission was an acute infection, and having a central venous catheter was associated with a significantly greater risk of admission for an infectious episode.

Published
2019
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7. Immune deficiency-related enteropathy-lymphocytopenia-alopecia syndrome results from tetratricopeptide repeat domain 7A deficiency.

Author

Lemoine R, Pachlopnik-Schmid J, Farin HF, Bigorgne A, Debré M, Sepulveda F, Héritier S, Lemale J, Talbotec C, Rieux-Laucat F, Ruemmele F, Morali A, Cathebras P, Nitschke P, Bole-Feysot C, Blanche S, Brousse N, Picard C, Clevers H, Fischer A, and de Saint Basile G

Subjects
Adolescent, Adult, Child, Child, Preschool, Colon pathology, Duodenum pathology, Female, Humans, Infant, Male, Middle Aged, Mutation, Missense, Pyloric Antrum pathology, Young Adult, rho-Associated Kinases antagonists & inhibitors, rho-Associated Kinases immunology, rhoA GTP-Binding Protein immunology, Alopecia genetics, Alopecia immunology, Alopecia pathology, Inflammatory Bowel Diseases genetics, Inflammatory Bowel Diseases immunology, Inflammatory Bowel Diseases pathology, Lymphopenia genetics, Lymphopenia immunology, Lymphopenia pathology, Proteins genetics, Proteins immunology
Abstract

Background: Inflammatory bowel disease (IBD) is one of the most common chronic gastrointestinal diseases, but the underlying molecular mechanisms remain largely unknown. Studies of monogenic diseases can provide insight into the pathogenesis of IBD., Objective: We thought to determine the underlying molecular causes of IBD occurring in 2 unrelated families in association with an immune deficiency., Methods: We performed genetic linkage analysis and candidate gene sequencing on 13 patients from a large consanguineous family affected by early-onset IBD, progressive immune deficiency, and, in some cases, autoimmunity and alopecia, a condition we named enteropathy-lymphocytopenia-alopecia. The candidate gene was also sequenced in an unrelated patient with a similar phenotype. We performed histologic analysis of patients' intestinal biopsy specimens and carried out functional assays on PBMCs. Gut organoids derived from a patient's biopsy specimen were analyzed., Results: We identified biallelic missense mutations in tetratricopeptide repeat domain 7A (TTC7A) in all patients from both families. The resulting TTC7A depletion modified the proliferation, adhesion, and migratory capacities of lymphocytes through inappropriate activation of the RhoA signaling pathway. Normal function was restored by wild-type TTC7A expression or addition of a RhoA kinase inhibitor. The growth and polarity of gut epithelial organoids were also found to be dependent on the RhoA signaling pathway., Conclusions: We show that TTC7A regulates the actin cytoskeleton dynamics in lymphocytes through the RhoA signaling pathway and is required in both lymphocytes and epithelial cells for maintaining equilibrium between cell proliferation, migration, polarization, and cell death. Our study highlights variability in the phenotypic expression resulting from TTC7A deficiency and outlines that impairment of both epithelial cells and lymphocytes cooperatively causes IBD., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Published
2014
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