Mutations in tetratricopeptide repeat domain 7A result in a severe form of very early onset inflammatory bowel disease

Yaron Avitzur, Conghui Guo, Lucas A. Mastropaolo, Ehsan Bahrami, Hannah Chen, Zhen Zhao, Abdul Elkadri, Sandeep Dhillon, Ryan Murchie, Ramzi Fattouh, Hien Huynh, Jennifer L. Walker, Paul W. Wales, Ernest Cutz, Yoichi Kakuta, Joel Dudley, Jochen Kammermeier, Fiona Powrie, Neil Shah, Christoph WalzMichaela Nathrath, Daniel Kotlarz, Jacek Puchaka, Jonathan R. Krieger, Tomas Racek, Thomas Kirchner, Thomas D. Walters, John H. Brumell, Anne M. Griffiths, Nima Rezaei, Parisa Rashtian, Mehri Najafi, Maryam Monajemzadeh, Stephen Pelsue, Dermot P.B. McGovern, Holm H. Uhlig, Eric Schadt, Christoph Klein, Scott B. Snapper, Aleixo M. Muise

Research output: Contribution to journalArticlepeer-review

165 Scopus citations


Background & Aims Very early onset inflammatory bowel diseases (VEOIBD), including infant disorders, are a diverse group of diseases found in children younger than 6 years of age. They have been associated with several gene variants. Our aim was to identify the genes that cause VEOIBD. Methods We performed whole exome sequencing of DNA from 1 infant with severe enterocolitis and her parents. Candidate gene mutations were validated in 40 pediatric patients and functional studies were carried out using intestinal samples and human intestinal cell lines. Results We identified compound heterozygote mutations in the Tetratricopeptide repeat domain 7 (TTC7A) gene in an infant from non-consanguineous parents with severe exfoliative apoptotic enterocolitis; we also detected TTC7A mutations in 2 unrelated families, each with 2 affected siblings. TTC7A interacts with EFR3 homolog B to regulate phosphatidylinositol 4-kinase at the plasma membrane. Functional studies demonstrated that TTC7A is expressed in human enterocytes. The mutations we identified in TTC7A result in either mislocalization or reduced expression of TTC7A. Phosphatidylinositol 4-kinase was found to co-immunoprecipitate with TTC7A; the identified TTC7A mutations reduced this binding. Knockdown of TTC7A in human intestinal-like cell lines reduced their adhesion, increased apoptosis, and decreased production of phosphatidylinositol 4-phosphate. Conclusions In a genetic analysis, we identified loss of function mutations in TTC7A in 5 infants with VEOIBD. Functional studies demonstrated that the mutations cause defects in enterocytes and T cells that lead to severe apoptotic enterocolitis. Defects in the phosphatidylinositol 4-kinase-TTC7A-EFR3 homolog B pathway are involved in the pathogenesis of VEOIBD.

Original languageEnglish
Pages (from-to)1028-1039
Number of pages12
Issue number4
StatePublished - Apr 2014
Externally publishedYes


  • Autoimmunity
  • IBD
  • Intestinal Atresia
  • Intestine


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