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

ABSTRACT: 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.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.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.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.

SUBMITTER: Avitzur Y

PROVIDER: S-EPMC4002656 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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

Avitzur Yaron Y Guo Conghui C Mastropaolo Lucas A LA Bahrami Ehsan E Chen Hannah H Zhao Zhen Z Elkadri Abdul A Dhillon Sandeep S Murchie Ryan R Fattouh Ramzi R Huynh Hien H Walker Jennifer L JL Wales Paul W PW Cutz Ernest E Kakuta Yoichi Y Dudley Joel J Kammermeier Jochen J Powrie Fiona F Shah Neil N Walz Christoph C Nathrath Michaela M Kotlarz Daniel D Puchaka Jacek J Krieger Jonathan R JR Racek Tomas T Kirchner Thomas T Walters Thomas D TD Brumell John H JH Griffiths Anne M AM Rezaei Nima N Rashtian Parisa P Najafi Mehri M Monajemzadeh Maryam M Pelsue Stephen S McGovern Dermot P B DP Uhlig Holm H HH Schadt Eric E Klein Christoph C Snapper Scott B SB Muise Aleixo M AM

Gastroenterology 20140111 4

<h4>Background & aims</h4>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.<h4>Methods</h4>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 we ...[more]

PMID: 24417819

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Project description:The gastrointestinal tract contains the largest lymphoid organ to react with pathogenic microorganisms and suppress excess inflammation. Patients with primary immunodeficiency diseases (PIDs) can suffer from refractory diarrhea. In this study, we present two siblings who began to suffer from refractory diarrhea with a poor response to aggressive antibiotic and immunosuppressive treatment after surgical release of neonatal intestinal obstruction. Their lymphocyte proliferation was low, but superoxide production and IL-10 signaling were normal. Candidate genetic approach targeted to genes involved in PIDs with inflammatory bowel disease (IBD)-like manifestation was unrevealing. Whole-genome sequencing revealed novel heterozygous mutations Glu75Lys and nucleotide 520-521 CT deletion in the tetratricopeptide repeat domain 7A (TTC7A) gene. A Medline search identified 49 patients with TTC7A mutations, of whom 20 survived. Their phenotypes included both multiple intestinal atresia (MIA) and combined T and/or B immunodeficiency (CID) in 16, both IBD and CID in 14, isolated MIA in 8, MIA, IBD, and CID complex in 8, and isolated IBD in 3. Of these 98 mutant alleles over-through the coding region clustering on exon 2 (40 alleles), exon 7 (12 alleles), and exon 20 (10 alleles), 2 common hotspot mutations were c.211 G>A (p.E71K in exon 2) in 26 alleles and AAGT deletion in exon 7 (+3) in 10 alleles. Kaplan-Meier analysis showed that those with biallelic missense mutations (p = 0.0168), unaffected tetratricopeptide repeat domains (p = 0.0311), and developing autoimmune disorders (p = 0.001) had a relatively better prognosis. Hematopoietic stem cell transplantation (HSCT) restored immunity and seemed to decrease the frequency of infections; however, refractory diarrhea persisted. Clinical improvement was reported upon intestinal and liver transplantation in a child with CID and MIA of unknown genetic etiology. In conclusion, patients with TTC7A mutations presenting with the very early onset of refractory diarrhea had limit improvement by HSCT or/and tailored immunosuppressive therapy in the absence of suitable intestine donors. We suggest that MIA-CID-IBD disorder caused by TTC7A mutations should also be included in the PID classification of "immunodeficiencies affecting cellular and humoral immunity" to allow for prompt recognition and optimal treatment.

Dataset Information

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

Publications

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

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