TTC7A mutations disrupt intestinal epithelial apicobasal polarity
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 intest...
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| Veröffentlicht in: | The Journal of clinical investigation 2014-01, Vol.124 (1), p.328-337 |
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| creator | Bigorgne, Amélie E Farin, Henner F Lemoine, Roxane Mahlaoui, Nizar Lambert, Nathalie Gil, Marine Schulz, Ansgar Philippet, Pierre Schlesser, Patrick Abrahamsen, Tore G Oymar, Knut Davies, E Graham Ellingsen, Christian Lycke Leteurtre, Emmanuelle Moreau-Massart, Brigitte Berrebi, Dominique Bole-Feysot, Christine Nischke, Patrick Brousse, Nicole Fischer, Alain Clevers, Hans de Saint Basile, Geneviève |
| description | 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. |
| doi_str_mv | 10.1172/jci71471 |
| format | Article |
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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.</description><identifier>ISSN: 0021-9738</identifier><identifier>EISSN: 1558-8238</identifier><identifier>DOI: 10.1172/jci71471</identifier><identifier>PMID: 24292712</identifier><language>eng</language><publisher>United States: American Society for Clinical Investigation</publisher><subject>Base Sequence ; Biomedical research ; Biopsy ; Cell Polarity ; Cells, Cultured ; Child ; Chromosomes ; Complications and side effects ; Consanguinity ; Data processing ; Development and progression ; DNA Mutational Analysis ; Epithelial Cells - physiology ; Exome ; Female ; Gene mutations ; Genes ; Genetic aspects ; Genetic Association Studies ; Genetic Linkage ; Glycerol ; Humans ; Infant ; Integrated software ; Intestinal Atresia - genetics ; Intestinal Atresia - immunology ; Intestinal Atresia - mortality ; Intestinal Atresia - pathology ; Intestinal Mucosa - pathology ; Lymph Nodes - pathology ; Lymphocytopenia ; Lymphopenia - genetics ; Lymphopenia - immunology ; Lymphopenia - pathology ; Male ; Mutation ; Patient outcomes ; Patients ; Pedigree ; Proteins - genetics ; Proteins - metabolism ; rho-Associated Kinases - metabolism ; Risk factors ; Severe Combined Immunodeficiency - genetics ; Severe Combined Immunodeficiency - immunology ; Severe Combined Immunodeficiency - mortality ; Severe Combined Immunodeficiency - pathology ; Studies ; Thymus Gland - abnormalities ; Thymus Gland - pathology</subject><ispartof>The Journal of clinical investigation, 2014-01, Vol.124 (1), p.328-337</ispartof><rights>COPYRIGHT 2014 American Society for Clinical Investigation</rights><rights>Copyright American Society for Clinical Investigation Jan 2014</rights><rights>Copyright © 2014, American Society for Clinical Investigation 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c569t-14a697d156d6dd1d6e077801839c07a5114b82376844bf04a2eb540fe656a8c33</citedby><cites>FETCH-LOGICAL-c569t-14a697d156d6dd1d6e077801839c07a5114b82376844bf04a2eb540fe656a8c33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3871247/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3871247/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27903,27904,53769,53771</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24292712$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bigorgne, Amélie E</creatorcontrib><creatorcontrib>Farin, Henner F</creatorcontrib><creatorcontrib>Lemoine, Roxane</creatorcontrib><creatorcontrib>Mahlaoui, Nizar</creatorcontrib><creatorcontrib>Lambert, Nathalie</creatorcontrib><creatorcontrib>Gil, Marine</creatorcontrib><creatorcontrib>Schulz, Ansgar</creatorcontrib><creatorcontrib>Philippet, Pierre</creatorcontrib><creatorcontrib>Schlesser, Patrick</creatorcontrib><creatorcontrib>Abrahamsen, Tore G</creatorcontrib><creatorcontrib>Oymar, Knut</creatorcontrib><creatorcontrib>Davies, E Graham</creatorcontrib><creatorcontrib>Ellingsen, Christian Lycke</creatorcontrib><creatorcontrib>Leteurtre, Emmanuelle</creatorcontrib><creatorcontrib>Moreau-Massart, Brigitte</creatorcontrib><creatorcontrib>Berrebi, Dominique</creatorcontrib><creatorcontrib>Bole-Feysot, Christine</creatorcontrib><creatorcontrib>Nischke, Patrick</creatorcontrib><creatorcontrib>Brousse, Nicole</creatorcontrib><creatorcontrib>Fischer, Alain</creatorcontrib><creatorcontrib>Clevers, Hans</creatorcontrib><creatorcontrib>de Saint Basile, Geneviève</creatorcontrib><title>TTC7A mutations disrupt intestinal epithelial apicobasal polarity</title><title>The Journal of clinical investigation</title><addtitle>J Clin Invest</addtitle><description>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.</description><subject>Base Sequence</subject><subject>Biomedical research</subject><subject>Biopsy</subject><subject>Cell Polarity</subject><subject>Cells, Cultured</subject><subject>Child</subject><subject>Chromosomes</subject><subject>Complications and side effects</subject><subject>Consanguinity</subject><subject>Data processing</subject><subject>Development and progression</subject><subject>DNA Mutational Analysis</subject><subject>Epithelial Cells - physiology</subject><subject>Exome</subject><subject>Female</subject><subject>Gene mutations</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Genetic Association Studies</subject><subject>Genetic Linkage</subject><subject>Glycerol</subject><subject>Humans</subject><subject>Infant</subject><subject>Integrated software</subject><subject>Intestinal Atresia - genetics</subject><subject>Intestinal Atresia - immunology</subject><subject>Intestinal Atresia - mortality</subject><subject>Intestinal Atresia - pathology</subject><subject>Intestinal Mucosa - pathology</subject><subject>Lymph Nodes - pathology</subject><subject>Lymphocytopenia</subject><subject>Lymphopenia - genetics</subject><subject>Lymphopenia - immunology</subject><subject>Lymphopenia - pathology</subject><subject>Male</subject><subject>Mutation</subject><subject>Patient outcomes</subject><subject>Patients</subject><subject>Pedigree</subject><subject>Proteins - genetics</subject><subject>Proteins - metabolism</subject><subject>rho-Associated Kinases - metabolism</subject><subject>Risk factors</subject><subject>Severe Combined Immunodeficiency - genetics</subject><subject>Severe Combined Immunodeficiency - immunology</subject><subject>Severe Combined Immunodeficiency - mortality</subject><subject>Severe Combined Immunodeficiency - pathology</subject><subject>Studies</subject><subject>Thymus Gland - 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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. 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| ispartof | The Journal of clinical investigation, 2014-01, Vol.124 (1), p.328-337 |
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| subjects | Base Sequence Biomedical research Biopsy Cell Polarity Cells, Cultured Child Chromosomes Complications and side effects Consanguinity Data processing Development and progression DNA Mutational Analysis Epithelial Cells - physiology Exome Female Gene mutations Genes Genetic aspects Genetic Association Studies Genetic Linkage Glycerol Humans Infant Integrated software Intestinal Atresia - genetics Intestinal Atresia - immunology Intestinal Atresia - mortality Intestinal Atresia - pathology Intestinal Mucosa - pathology Lymph Nodes - pathology Lymphocytopenia Lymphopenia - genetics Lymphopenia - immunology Lymphopenia - pathology Male Mutation Patient outcomes Patients Pedigree Proteins - genetics Proteins - metabolism rho-Associated Kinases - metabolism Risk factors Severe Combined Immunodeficiency - genetics Severe Combined Immunodeficiency - immunology Severe Combined Immunodeficiency - mortality Severe Combined Immunodeficiency - pathology Studies Thymus Gland - abnormalities Thymus Gland - pathology |
| title | TTC7A mutations disrupt intestinal epithelial apicobasal polarity |
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