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

TY - JOUR

T1 - Immune deficiency-related enteropathy-lymphocytopenia-alopecia syndrome results from tetratricopeptide repeat domain 7A deficiency

AU - Lemoine, Roxane

AU - Pachlopnik-Schmid, Jana

AU - Farin, Henner F

AU - Bigorgne, Amélie

AU - Debré, Marianne

AU - Sepulveda, Fernando

AU - Héritier, Sébastien

AU - Lemale, Julie

AU - Talbotec, Cécile

AU - Rieux-Laucat, Frédéric

AU - Ruemmele, Frank

AU - Morali, Alain

AU - Cathebras, Pascal

AU - Nitschke, Patrick

AU - Bole-Feysot, Christine

AU - Blanche, Stéphane

AU - Brousse, Nicole

AU - Picard, Capucine

AU - Clevers, Hans

AU - Fischer, Alain

AU - de Saint Basile, Geneviève

N1 - Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

PY - 2014/12

Y1 - 2014/12

N2 - 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.

AB - 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.

KW - Adolescent

KW - Adult

KW - Alopecia

KW - Child

KW - Child, Preschool

KW - Colon

KW - Duodenum

KW - Female

KW - Humans

KW - Infant

KW - Inflammatory Bowel Diseases

KW - Lymphopenia

KW - Male

KW - Middle Aged

KW - Mutation, Missense

KW - Proteins

KW - Pyloric Antrum

KW - Young Adult

KW - rho-Associated Kinases

KW - rhoA GTP-Binding Protein

U2 - 10.1016/j.jaci.2014.07.019

DO - 10.1016/j.jaci.2014.07.019

M3 - Article

C2 - 25174867

SN - 0091-6749

VL - 134

SP - 1354-1364.e6

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

IS - 6

ER -