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J Allergy Clin Immunol. 2014 Dec;134(6):1354-1364.e6. doi: 10.1016/j.jaci.2014.07.019. Epub 2014 Aug 28.

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

Author information

1
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.
2
Hubrecht Institute for Developmental Biology and Stem Cell Research and University Medical Centre Utrecht, Utrecht, The Netherlands.
3
Unité d'Immunologie et Hématologie Pédiatrique, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants-Malades, Paris, France.
4
Unité de Nutrition et Gastroentérologie Pédiatriques, Hôpital Trousseau, Paris, France.
5
Service de gastroentérologie, hépatologie et nutrition pédiatriques, Hôpital Necker-Enfants Malades, Paris, France.
6
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.
7
Service de Médecine Interne, CHU de Saint Etienne, Saint Etienne, France.
8
Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France.
9
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.
10
Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France; Laboratoire d'Anatomie Pathologique, Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Paris, France.
11
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.
12
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.
13
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.

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.

KEYWORDS:

Inflammatory bowel disease; RhoA kinase; cell homeostasis; cytoskeleton; gut organoid; immune deficiency; lymphocytes; tetratricopeptide repeat domain 7A deficiency

PMID:
25174867
DOI:
10.1016/j.jaci.2014.07.019
[Indexed for MEDLINE]

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