title: Immune deficiency-related enteropathy-lymphocytopenia-alopecia syndrome results from tetratricopeptide repeat domain 7A deficiency.
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.
authors.affiliation: INSERM, Unité U1163, Laboratoire Homéostasie normale et pathologique du système immunitaire, Hôpital Necker Enfants-Malades, Paris, France; Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France; Unité d'Immunologie et Hématologie Pédiatrique, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants-Malades, Paris, France.
authors.forename: Roxane
authors.initials: R
authors.lastname: Lemoine
authors.affiliation: INSERM, Unité U1163, Laboratoire Homéostasie normale et pathologique du système immunitaire, Hôpital Necker Enfants-Malades, Paris, France; Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France; Unité d'Immunologie et Hématologie Pédiatrique, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants-Malades, Paris, France.
authors.forename: Jana
authors.initials: J
authors.lastname: Pachlopnik-Schmid
authors.affiliation: Hubrecht Institute for Developmental Biology and Stem Cell Research and University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Henner F
authors.initials: HF
authors.lastname: Farin
authors.affiliation: INSERM, Unité U1163, Laboratoire Homéostasie normale et pathologique du système immunitaire, Hôpital Necker Enfants-Malades, Paris, France; Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France; Unité d'Immunologie et Hématologie Pédiatrique, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants-Malades, Paris, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Bigorgne
authors.affiliation: Unité d'Immunologie et Hématologie Pédiatrique, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants-Malades, Paris, France.
authors.forename: Marianne
authors.initials: M
authors.lastname: Debré
authors.affiliation: INSERM, Unité U1163, Laboratoire Homéostasie normale et pathologique du système immunitaire, Hôpital Necker Enfants-Malades, Paris, France; Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France; Unité d'Immunologie et Hématologie Pédiatrique, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants-Malades, Paris, France.
authors.forename: Fernando
authors.initials: F
authors.lastname: Sepulveda
authors.affiliation: Unité d'Immunologie et Hématologie Pédiatrique, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants-Malades, Paris, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Héritier
authors.affiliation: Unité de Nutrition et Gastroentérologie Pédiatriques, Hôpital Trousseau, Paris, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Lemale
authors.affiliation: Service de gastroentérologie, hépatologie et nutrition pédiatriques, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Talbotec
authors.affiliation: INSERM, Unité U1163, Laboratoire Homéostasie normale et pathologique du système immunitaire, Hôpital Necker Enfants-Malades, Paris, France; Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France; Unité d'Immunologie et Hématologie Pédiatrique, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants-Malades, Paris, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Rieux-Laucat
authors.affiliation: Service de gastroentérologie, hépatologie et nutrition pédiatriques, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Frank
authors.initials: F
authors.lastname: Ruemmele
authors.affiliation: Unité d'Hépato-Gastro-Entérologie et Nutrition Pédiatriques, Hôpital d'Enfants, CHU Nancy Brabois-F 54500 Vandoeuvre les Nancy et Unité INSERM U954, Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Morali
authors.affiliation: Service de Médecine Interne, CHU de Saint Etienne, Saint Etienne, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Cathebras
authors.affiliation: Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Nitschke
authors.affiliation: Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Bole-Feysot
authors.affiliation: INSERM, Unité U1163, Laboratoire Homéostasie normale et pathologique du système immunitaire, Hôpital Necker Enfants-Malades, Paris, France; Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Blanche
authors.affiliation: Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France; Laboratoire d'Anatomie Pathologique, Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Paris, France.
authors.forename: Nicole
authors.initials: N
authors.lastname: Brousse
authors.affiliation: Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France; Unité d'Immunologie et Hématologie Pédiatrique, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants-Malades, Paris, France; Centre d'Etudes des Déficits Immunitaires, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.affiliation: Hubrecht Institute for Developmental Biology and Stem Cell Research and University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Clevers
authors.affiliation: INSERM, Unité U1163, Laboratoire Homéostasie normale et pathologique du système immunitaire, Hôpital Necker Enfants-Malades, Paris, France; Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France; Unité d'Immunologie et Hématologie Pédiatrique, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants-Malades, Paris, France; College de France, Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.affiliation: INSERM, Unité U1163, Laboratoire Homéostasie normale et pathologique du système immunitaire, Hôpital Necker Enfants-Malades, Paris, France; Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France; Unité d'Immunologie et Hématologie Pédiatrique, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants-Malades, Paris, France; Centre d'Etudes des Déficits Immunitaires, Assistance Publique-Hôpitaux de Paris, Paris, France. Electronic address: genevieve.de-saint-basile@inserm.fr.
authors.forename: Geneviève
authors.initials: G
authors.lastname: de Saint Basile
mesh_terms: D000293:Adolescent; D000328:Adult; D000505:Alopecia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D003106:Colon / Q000473:pathology; D004386:Duodenum / Q000473:pathology; D005260:Female; D006801:Humans; D007223:Infant; D015212:Inflammatory Bowel Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D011506:Proteins / Q000235:genetics* / Q000276:immunology*; D011706:Pyloric Antrum / Q000473:pathology; D055815:Young Adult; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000276:immunology; D020742:rhoA GTP-Binding Protein / Q000276:immunology
chemical_list: D011506:Proteins; C583818:TTC7A protein, human; C066737:RHOA protein, human; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein
keywords: Inflammatory bowel disease; RhoA kinase; cell homeostasis; cytoskeleton; gut organoid; immune deficiency; lymphocytes; tetratricopeptide repeat domain 7A deficiency