TTC7A mutations disrupt intestinal epithelial apicobasal polarity

Amélie E Bigorgne; Henner F Farin; Roxane Lemoine; Nizar Mahlaoui; Nathalie Lambert; Marine Gil; Ansgar Schulz; Pierre Philippet; Patrick Schlesser; Tore G Abrahamsen; Knut Oymar; E Graham Davies; Christian Lycke Ellingsen; Emmanuelle Leteurtre; Brigitte Moreau-Massart; Dominique Berrebi; Christine Bole-Feysot; Patrick Nischke; Nicole Brousse; Alain Fischer; Hans Clevers; Geneviève de Saint Basile

doi:10.1172/JCI71471

TTC7A mutations disrupt intestinal epithelial apicobasal polarity

Amélie E Bigorgne, Henner F Farin, Roxane Lemoine, Nizar Mahlaoui, Nathalie Lambert, Marine Gil, Ansgar Schulz, Pierre Philippet, Patrick Schlesser, Tore G Abrahamsen, Knut Oymar, E Graham Davies, Christian Lycke Ellingsen, Emmanuelle Leteurtre, Brigitte Moreau-Massart, Dominique Berrebi, Christine Bole-Feysot, Patrick Nischke, Nicole Brousse, Alain FischerHans Clevers, Geneviève de Saint Basile

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

149 Citations (Scopus)

Abstract

Multiple intestinal atresia (MIA) is a rare cause of bowel obstruction that is sometimes associated with a combined immunodeficiency (CID), leading to increased susceptibility to infections. The factors underlying this rare disease are poorly understood. We characterized the immunological and intestinal features of 6 unrelated MIA-CID patients. All patients displayed a profound, generalized lymphocytopenia, with few lymphocytes present in the lymph nodes. The thymus was hypoplastic and exhibited an abnormal distribution of epithelial cells. Patients also had profound disruption of the epithelial barrier along the entire gastrointestinal tract. Using linkage analysis and whole-exome sequencing, we identified 10 mutations in tetratricopeptide repeat domain–7A (TTC7A), all of which potentially abrogate TTC7A expression. Intestinal organoid cultures from patient biopsies displayed an inversion of apicobasal polarity of the epithelial cells that was normalized by pharmacological inhibition of Rho kinase. Our data indicate that TTC7A deficiency results in increased Rho kinase activity, which disrupts polarity, growth, and differentiation of intestinal epithelial cells, and which impairs immune cell homeostasis, thereby promoting MIA-CID development.

Original language	English
Pages (from-to)	328-37
Number of pages	10
Journal	Journal of Clinical Investigation
Volume	124
Issue number	1
DOIs	https://doi.org/10.1172/JCI71471
Publication status	Published - Jan 2014

Keywords

Base Sequence
Cell Polarity
Cells, Cultured
Child
Consanguinity
DNA Mutational Analysis
Epithelial Cells
Exome
Female
Genetic Association Studies
Genetic Linkage
Humans
Infant
Intestinal Atresia
Intestinal Mucosa
Lymph Nodes
Lymphopenia
Male
Pedigree
Proteins
Severe Combined Immunodeficiency
Thymus Gland
rho-Associated Kinases

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10.1172/JCI71471

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Bigorgne, A. E., Farin, H. F., Lemoine, R., Mahlaoui, N., Lambert, N., Gil, M., Schulz, A., Philippet, P., Schlesser, P., Abrahamsen, T. G., Oymar, K., Davies, E. G., Ellingsen, C. L., Leteurtre, E., Moreau-Massart, B., Berrebi, D., Bole-Feysot, C., Nischke, P., Brousse, N., ... de Saint Basile, G. (2014). TTC7A mutations disrupt intestinal epithelial apicobasal polarity. Journal of Clinical Investigation, 124(1), 328-37. https://doi.org/10.1172/JCI71471

@article{ed4c17d31e4e4a25a318cad56214c836,

title = "TTC7A mutations disrupt intestinal epithelial apicobasal polarity",

abstract = "Multiple intestinal atresia (MIA) is a rare cause of bowel obstruction that is sometimes associated with a combined immunodeficiency (CID), leading to increased susceptibility to infections. The factors underlying this rare disease are poorly understood. We characterized the immunological and intestinal features of 6 unrelated MIA-CID patients. All patients displayed a profound, generalized lymphocytopenia, with few lymphocytes present in the lymph nodes. The thymus was hypoplastic and exhibited an abnormal distribution of epithelial cells. Patients also had profound disruption of the epithelial barrier along the entire gastrointestinal tract. Using linkage analysis and whole-exome sequencing, we identified 10 mutations in tetratricopeptide repeat domain–7A (TTC7A), all of which potentially abrogate TTC7A expression. Intestinal organoid cultures from patient biopsies displayed an inversion of apicobasal polarity of the epithelial cells that was normalized by pharmacological inhibition of Rho kinase. Our data indicate that TTC7A deficiency results in increased Rho kinase activity, which disrupts polarity, growth, and differentiation of intestinal epithelial cells, and which impairs immune cell homeostasis, thereby promoting MIA-CID development.",

keywords = "Base Sequence, Cell Polarity, Cells, Cultured, Child, Consanguinity, DNA Mutational Analysis, Epithelial Cells, Exome, Female, Genetic Association Studies, Genetic Linkage, Humans, Infant, Intestinal Atresia, Intestinal Mucosa, Lymph Nodes, Lymphopenia, Male, Pedigree, Proteins, Severe Combined Immunodeficiency, Thymus Gland, rho-Associated Kinases",

author = "Bigorgne, {Am{\'e}lie E} and Farin, {Henner F} and Roxane Lemoine and Nizar Mahlaoui and Nathalie Lambert and Marine Gil and Ansgar Schulz and Pierre Philippet and Patrick Schlesser and Abrahamsen, {Tore G} and Knut Oymar and Davies, {E Graham} and Ellingsen, {Christian Lycke} and Emmanuelle Leteurtre and Brigitte Moreau-Massart and Dominique Berrebi and Christine Bole-Feysot and Patrick Nischke and Nicole Brousse and Alain Fischer and Hans Clevers and {de Saint Basile}, Genevi{\`e}ve",

year = "2014",

month = jan,

doi = "10.1172/JCI71471",

language = "English",

volume = "124",

pages = "328--37",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "The American Society for Clinical Investigation",

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Bigorgne, AE, Farin, HF, Lemoine, R, Mahlaoui, N, Lambert, N, Gil, M, Schulz, A, Philippet, P, Schlesser, P, Abrahamsen, TG, Oymar, K, Davies, EG, Ellingsen, CL, Leteurtre, E, Moreau-Massart, B, Berrebi, D, Bole-Feysot, C, Nischke, P, Brousse, N, Fischer, A, Clevers, H & de Saint Basile, G 2014, 'TTC7A mutations disrupt intestinal epithelial apicobasal polarity', Journal of Clinical Investigation, vol. 124, no. 1, pp. 328-37. https://doi.org/10.1172/JCI71471

TY - JOUR

T1 - TTC7A mutations disrupt intestinal epithelial apicobasal polarity

AU - Bigorgne, Amélie E

AU - Farin, Henner F

AU - Lemoine, Roxane

AU - Mahlaoui, Nizar

AU - Lambert, Nathalie

AU - Gil, Marine

AU - Schulz, Ansgar

AU - Philippet, Pierre

AU - Schlesser, Patrick

AU - Abrahamsen, Tore G

AU - Oymar, Knut

AU - Davies, E Graham

AU - Ellingsen, Christian Lycke

AU - Leteurtre, Emmanuelle

AU - Moreau-Massart, Brigitte

AU - Berrebi, Dominique

AU - Bole-Feysot, Christine

AU - Nischke, Patrick

AU - Brousse, Nicole

AU - Fischer, Alain

AU - Clevers, Hans

AU - de Saint Basile, Geneviève

PY - 2014/1

Y1 - 2014/1

N2 - Multiple intestinal atresia (MIA) is a rare cause of bowel obstruction that is sometimes associated with a combined immunodeficiency (CID), leading to increased susceptibility to infections. The factors underlying this rare disease are poorly understood. We characterized the immunological and intestinal features of 6 unrelated MIA-CID patients. All patients displayed a profound, generalized lymphocytopenia, with few lymphocytes present in the lymph nodes. The thymus was hypoplastic and exhibited an abnormal distribution of epithelial cells. Patients also had profound disruption of the epithelial barrier along the entire gastrointestinal tract. Using linkage analysis and whole-exome sequencing, we identified 10 mutations in tetratricopeptide repeat domain–7A (TTC7A), all of which potentially abrogate TTC7A expression. Intestinal organoid cultures from patient biopsies displayed an inversion of apicobasal polarity of the epithelial cells that was normalized by pharmacological inhibition of Rho kinase. Our data indicate that TTC7A deficiency results in increased Rho kinase activity, which disrupts polarity, growth, and differentiation of intestinal epithelial cells, and which impairs immune cell homeostasis, thereby promoting MIA-CID development.

AB - Multiple intestinal atresia (MIA) is a rare cause of bowel obstruction that is sometimes associated with a combined immunodeficiency (CID), leading to increased susceptibility to infections. The factors underlying this rare disease are poorly understood. We characterized the immunological and intestinal features of 6 unrelated MIA-CID patients. All patients displayed a profound, generalized lymphocytopenia, with few lymphocytes present in the lymph nodes. The thymus was hypoplastic and exhibited an abnormal distribution of epithelial cells. Patients also had profound disruption of the epithelial barrier along the entire gastrointestinal tract. Using linkage analysis and whole-exome sequencing, we identified 10 mutations in tetratricopeptide repeat domain–7A (TTC7A), all of which potentially abrogate TTC7A expression. Intestinal organoid cultures from patient biopsies displayed an inversion of apicobasal polarity of the epithelial cells that was normalized by pharmacological inhibition of Rho kinase. Our data indicate that TTC7A deficiency results in increased Rho kinase activity, which disrupts polarity, growth, and differentiation of intestinal epithelial cells, and which impairs immune cell homeostasis, thereby promoting MIA-CID development.

KW - Base Sequence

KW - Cell Polarity

KW - Cells, Cultured

KW - Child

KW - Consanguinity

KW - DNA Mutational Analysis

KW - Epithelial Cells

KW - Exome

KW - Female

KW - Genetic Association Studies

KW - Genetic Linkage

KW - Humans

KW - Infant

KW - Intestinal Atresia

KW - Intestinal Mucosa

KW - Lymph Nodes

KW - Lymphopenia

KW - Male

KW - Pedigree

KW - Proteins

KW - Severe Combined Immunodeficiency

KW - Thymus Gland

KW - rho-Associated Kinases

U2 - 10.1172/JCI71471

DO - 10.1172/JCI71471

M3 - Article

C2 - 24292712

SN - 0021-9738

VL - 124

SP - 328

EP - 337

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 1

ER -

TTC7A mutations disrupt intestinal epithelial apicobasal polarity

Abstract

Keywords

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