Faculty Collaboration Database

Mutations in tetratricopeptide repeat domain 7A result in a severe form of very early onset inflammatory bowel disease. Gastroenterology 2014 Apr;146(4):1028-39

Date

01/15/2014

Pubmed ID

24417819

Pubmed Central ID

PMC4002656

DOI

10.1053/j.gastro.2014.01.015

Scopus ID

2-s2.0-84896492362 (requires institutional sign-in at Scopus site)   163 Citations

Abstract

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.

Author List

Avitzur Y, Guo C, Mastropaolo LA, Bahrami E, Chen H, Zhao Z, Elkadri A, Dhillon S, Murchie R, Fattouh R, Huynh H, Walker JL, Wales PW, Cutz E, Kakuta Y, Dudley J, Kammermeier J, Powrie F, Shah N, Walz C, Nathrath M, Kotlarz D, Puchaka J, Krieger JR, Racek T, Kirchner T, Walters TD, Brumell JH, Griffiths AM, Rezaei N, Rashtian P, Najafi M, Monajemzadeh M, Pelsue S, McGovern DP, Uhlig HH, Schadt E, Klein C, Snapper SB, Muise AM

Author

Abdul Aziz Elkadri MD Associate Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

1-Phosphatidylinositol 4-Kinase
Age of Onset
Apoptosis
Cell Adhesion
Cell Line
Child, Preschool
DNA Mutational Analysis
Enterocolitis
Enterocytes
Exome
Female
Genetic Association Studies
Genetic Predisposition to Disease
Heterozygote
Humans
Infant
Infant, Newborn
Inflammatory Bowel Diseases
Intestinal Atresia
Lymphocytes
Male
Mutation
Pedigree
Phenotype
Prognosis
Protein Binding
Proteins
RNA Interference
Severity of Illness Index
Signal Transduction
Transfection