{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T02:21:50Z","timestamp":1784514110333,"version":"3.55.0"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,12,15]],"date-time":"2021-12-15T00:00:00Z","timestamp":1639526400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Rare autosomal-recessive variants in tetratricopeptide repeat domain 7A (\n                    <jats:italic>TTC7A<\/jats:italic>\n                    ) gene have been shown to cause intestinal and immune disorders of variable severity. Missense mutations in\n                    <jats:italic>TTC7A<\/jats:italic>\n                    gene, usually retaining most of the functional motifs, is associated with relative milder clinical presentations. In this study, we reported a patient who was suffering from severe multiple intestinal atresia (MIA) with combined immunodeficiency (CID) that led to the pyloric diaphragm, ileum atresia, colon stenosis, and multiple episodes of sepsis. In spite of several surgeries and supportive treatment, the patient died of severe sepsis and multiple organ failure at age of 3 months. The whole exome sequencing (WES) of peripheral blood samples identified a novel homozygous\n                    <jats:italic>TTC7A<\/jats:italic>\n                    missense mutation (c. 206T&amp;gt;C, p. L69P), inherited from his parents with consanguineous marriage.\n                    <jats:italic>In silico<\/jats:italic>\n                    analysis revealed that a hydrogen bond present between Gly65 and Leu69 in the wild-type TTC7A was disrupted by the Leu69Pro mutation. Moreover, this homozygous missense mutation led to a reduced TTC7A expression in lymphocytes and intestinal tissues, accompanied by impeded lymphocyte development. Further studies demonstrated that the PI4K-FAM126A-EFR3A pathway was impaired in colon tissues. Our data strongly support the linkage of severe MIA-CID with the missense mutation in\n                    <jats:italic>TTC7A<\/jats:italic>\n                    gene. More knowledge of the TTC7A protein functions will have important therapeutic implications for patients with MIA-CID.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2021.759308","type":"journal-article","created":{"date-parts":[[2021,12,15]],"date-time":"2021-12-15T00:12:11Z","timestamp":1639527131000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":18,"title":["A Novel Homozygous TTC7A Missense Mutation Results in Familial Multiple Intestinal Atresia and Combined Immunodeficiency"],"prefix":"10.3389","volume":"12","author":[{"given":"Wenjun","family":"Mou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shen","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruolan","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Libing","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weihong","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingbin","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianxin","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinghua","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chanjuan","family":"Hao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingang","family":"Gui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinshi","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,12,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmgh.2018.12.001","article-title":"TTC7A: Steward of Intestinal Health","volume":"7","author":"Jardine","year":"2019","journal-title":"Cell Mol Gastroenterol Hepatol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1097\/MOP.0000000000000159","article-title":"Multiple Intestinal Atresia With Combined Immune Deficiency","volume":"26","author":"Notarangelo","year":"2014","journal-title":"Curr Opin Pediatr"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-08-595397","article-title":"Hypomorphic Mutation in TTC7A Causes Combined Immunodeficiency With Mild Structural Intestinal Defects","volume":"125","author":"Woutsas","year":"2015","journal-title":"Blood"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2017.11.014","article-title":"Missense Mutation of TTC7A Mimicking Tricho-Hepato-Enteric (SD\/THE) Syndrome in a Patient With Very-Early Onset Inflammatory Bowel Disease","volume":"61","author":"Neves","year":"2018","journal-title":"Eur J Med Genet"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3317","article-title":"HISAT: A Fast Spliced Aligner With Low Memory Requirements","volume":"12","author":"Kim","year":"2015","journal-title":"Nat Methods"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3122","article-title":"StringTie Enables Improved Reconstruction of a Transcriptome From RNA-Seq Reads","volume":"33","author":"Pertea","year":"2015","journal-title":"Nat Biotechnol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"3767","DOI":"10.1038\/s41467-019-11783-9","article-title":"Tuberculous Meningitis in Children is Characterized by Compartmentalized Immune Responses and Neural Excitotoxicity","volume":"10","author":"Rohlwink","year":"2019","journal-title":"Nat Commun"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated Estimation of Fold Change and Dispersion for RNA-Seq Data With Deseq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa970","article-title":"KEGG: Integrating Viruses and Cellular Organisms","volume":"49","author":"Kanehisa","year":"2021","journal-title":"Nucleic Acids Res"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq1018","article-title":"Reactome: A Database of Reactions, Pathways and Biological Processes","volume":"39","author":"Croft","year":"2011","journal-title":"Nucleic Acids Res"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx1064","article-title":"WikiPathways: A Multifaceted Pathway Database Bridging Metabolomics to Other Omics Research","volume":"46","author":"Slenter","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118","article-title":"Clusterprofiler: An R Package for Comparing Biological Themes Among Gene Clusters","volume":"16","author":"Yu","year":"2012","journal-title":"OMICS"},{"key":"B13","doi-asserted-by":"publisher","first-page":"656","DOI":"10.1016\/j.jaci.2013.06.013","article-title":"Whole-Exome Sequencing Identifies Tetratricopeptide Repeat Domain 7A (TTC7A) Mutations for Combined Immunodeficiency With Intestinal Atresias","volume":"132","author":"Chen","year":"2013","journal-title":"J Allergy Clin Immunol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"970","DOI":"10.1016\/j.jaci.2018.04.022","article-title":"Reference Values for Peripheral Blood Lymphocyte Subsets of Healthy Children in China","volume":"142","author":"Ding","year":"2018","journal-title":"J Allergy Clin Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2014.01.015","article-title":"Mutations in Tetratricopeptide Repeat Domain 7A Result in a Severe Form of Very Early Onset Inflammatory Bowel Disease","volume":"146","author":"Avitzur","year":"2014","journal-title":"Gastroenterology"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3271","article-title":"The Leukodystrophy Protein FAM126A (Hyccin) Regulates PtdIns(4)P Synthesis at the Plasma Membrane","volume":"18","author":"Baskin","year":"2016","journal-title":"Nat Cell Biol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1354","DOI":"10.1016\/j.jaci.2014.07.019","article-title":"Immune Deficiency-Related Enteropathy-Lymphocytopenia-Alopecia Syndrome Results From Tetratricopeptide Repeat Domain 7A Deficiency","volume":"134","author":"Lemoine","year":"2014","journal-title":"J\u00a0Allergy Clin Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.01066","article-title":"Novel Mutations of the Tetratricopeptide Repeat Domain 7a Gene and Phenotype\/Genotype Comparison","volume":"8","author":"Lien","year":"2017","journal-title":"Front Immunol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"e10939","DOI":"10.1097\/MD.0000000000010939","article-title":"Congenital Intestinal Atresias With Multiple Episodes of Sepsis: A Case Report and Review of Literature","volume":"97","author":"Mandia","year":"2018","journal-title":"Med (Baltimore)"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12729","article-title":"Newborn Screening for Severe Combined Immunodeficiency and T-Cell Lymphopenia","volume":"287","author":"Puck","year":"2019","journal-title":"Immunol Rev"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-01-696385","article-title":"Stem Cell Transplantation for Tetratricopeptide Repeat Domain 7A Deficiency: Long-Term Follow-Up","volume":"128","author":"Kammermeier","year":"2016","journal-title":"Blood"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1111\/pai.12501","article-title":"Prospective Neonatal Screening for Severe T- and B-Lymphocyte Deficiencies in Seville","volume":"27","author":"de Felipe","year":"2016","journal-title":"Pediatr Allergy Immunol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1186\/1479-5876-11-188","article-title":"Utilization of TREC and KREC Quantification for the Monitoring of Early T- and B-Cell Neogenesis in Adult Patients After Allogeneic Hematopoietic Stem Cell Transplantation","volume":"11","author":"Mensen","year":"2013","journal-title":"J Transl Med"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1136\/bcr.05.2010.3031","article-title":"Hereditary Multiple Intestinal Atresia (HMIA) With Severe Combined Immunodeficiency (SCID): A Case Report of Two Siblings and Review of the Literature on MIA, HMIA and HMIA With Immunodeficiency Over the Last 50 Years","author":"Ali","year":"2011","journal-title":"BMJ Case Rep"},{"key":"B25","doi-asserted-by":"publisher","first-page":"2045","DOI":"10.1053\/j.gastro.2018.03.067","article-title":"Advances in Evaluation of Chronic Diarrhea in Infants","volume":"154","author":"Thiagarajah","year":"2018","journal-title":"Gastroenterology"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2003-04-1187","article-title":"Donor Immune Reconstitution After Liver-Small Bowel Transplantation for Multiple Intestinal Atresia With Immunodeficiency","volume":"103","author":"Gilroy","year":"2004","journal-title":"Blood"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.arcped.2018.05.006","article-title":"TTC7A Mutation Must be Considered in Patients With Repeated Intestinal Atresia Associated With Early Inflammatory Bowel Disease: Two New Case Reports and a Literature Review","volume":"25","author":"Fayard","year":"2018","journal-title":"Arch Pediatr"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1172\/JCI71471","article-title":"TTC7A Mutations Disrupt Intestinal Epithelial Apicobasal Polarity","volume":"124","author":"Bigorgne","year":"2014","journal-title":"J Clin Invest"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.759308\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,15]],"date-time":"2021-12-15T00:12:14Z","timestamp":1639527134000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.759308\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,15]]},"references-count":28,"alternative-id":["10.3389\/fimmu.2021.759308"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.759308","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-635099\/v1","asserted-by":"object"}]},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,15]]},"article-number":"759308"}}