Mutations in Tetratricopeptide Repeat Domain 7A Result in a Severe Form of Very Early Onset Inflammatory Bowel Disease

Abstract

Background & Aims Very early onset inflammatory bowel diseases (VEOIBD), including infant disorders, are a diverse group of diseases found in children less than 6 years of age. They have been associated with several gene variants. We aimed to identify genes that cause VEOIBD. Methods We performed whole-exome sequencing of DNA from 1 infants 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 the mutations in 2 unrelated families, each with 2 affected siblings. TTC7A interacts with EFR3 homolog B (EFR3B) to regulate phosphatidylinositol 4-kinase (PI4KA) 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. PI4KA 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. Conclusion 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 PI4KA–TTC7A–EFR3B pathway are involved in the pathogenesis of VEOIBD.

Paneth cell defects in Crohn’s disease patients promote dysbiosis

“…While it is possible that the sample size was too small to detect a correlation, it is also possible that additional genes involved in the development of CD in these patients also affect the development of Type I Paneth cell phenotype. Compared to adult CD, genetics plays a more important pathogenic role in pediatric CD, in particular those with very early onset disease (42)(43)(44), although in mouse models the Paneth cell antimicrobial function is independent of Nod2 (45). Thus, it is possible that additional CD susceptibility genes may cause the Paneth cell defect.…”

Stem cell transplantation for tetratricopeptide repeat domain 7A deficiency: long-term follow-up

“…The composition of the plasma membrane in particular levels of phosphorylated PI (PI-4P) are crucial for preserving epithelial cell polarity and survival. [1][2][3] The clinical spectrum of the disease varies from multiple intestinal atresias (MIA) to severe autoimmune enterocolitis clinically evident by infantile-onset intestinal obstruction/failure, bleeding, and diarrhea. 1,[4][5][6] Furthermore, the disease can be associated with severe immunodeficiency or autoimmune phenomena owing to the central role of TTC7A in thymic architecture.…”

“…Overall, 52 cases with genetically confirmed TTC7A deficiency were reported in the 1306 LETTERS 1,[6][7][8] Most of the reported patients were treated symptomatically and managed with supportive medical and surgical care. One reported case was referred for combined small intestine and HSCT but was lost to follow-up.…”

Hypomorphic mutation in TTC7A causes combined immunodeficiency with mild structural intestinal defects

“…1 Traditional anthracycline-or platinum-based chemotherapy is associated with complete response (CR) rates of ,20%, and median survival after transformation is ,12 months. 2 Although stem cell transplantation has been shown to improve outcomes in RS, 3 fewer than 15% of patients are able to proceed to transplantation because of primary refractory disease. 4 Ibrutinib, a Bruton's tyrosine kinase inhibitor, has shown remarkable efficacy in relapsed/refractory CLL.…”