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 - Publisher Copyright:
© 2014 American Academy of Allergy, Asthma & Immunology.
PY - 2014/12/1
Y1 - 2014/12/1
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.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.MethodsWe 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.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.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.MethodsWe 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.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 - cell homeostasis
KW - cytoskeleton
KW - gut organoid
KW - immune deficiency
KW - Inflammatory bowel disease
KW - lymphocytes
KW - RhoA kinase
KW - tetratricopeptide repeat domain 7A deficiency
UR - http://www.scopus.com/inward/record.url?scp=84919599348&partnerID=8YFLogxK
U2 - 10.1016/j.jaci.2014.07.019
DO - 10.1016/j.jaci.2014.07.019
M3 - Article
C2 - 25174867
AN - SCOPUS:84919599348
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 -