+ Site Statistics
References:
54,258,434
Abstracts:
29,560,870
PMIDs:
28,072,757
+ Search Articles
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ PDF Full Text
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Translate
+ Recently Requested

Novel Mutations of the Tetratricopeptide Repeat Domain 7A Gene and Phenotype/Genotype Comparison



Novel Mutations of the Tetratricopeptide Repeat Domain 7A Gene and Phenotype/Genotype Comparison



Frontiers in Immunology 8: 1066



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.

(PDF emailed within 0-6 h: $19.90)

Accession: 060030023

Download citation: RISBibTeXText

PMID: 28936210

DOI: 10.3389/fimmu.2017.01066


Related references

Identifying Mutations of the Tetratricopeptide Repeat Domain 37 (TTC37) Gene in Infants With Intractable Diarrhea and a Comparison of Asian and Non-Asian Phenotype and Genotype: A Global Case-report Study of a Well-Defined Syndrome With Immunodeficiency. Medicine 95(9): E2918, 2016

Bialellic Mutations in Tetratricopeptide Repeat Domain 7A (TTC7A) Cause Common Variable Immunodeficiency-Like Phenotype with Enteropathy. Journal of Clinical Immunology 37(7): 617-622, 2017

The novel tetratricopeptide repeat domain 7 mutation, Ttc7fsn-Jic, with deletion of the TPR-2B repeat causes severe flaky skin phenotype. Experimental Biology and Medicine 232(5): 695-699, 2007

Mutations in tetratricopeptide repeat domain 7A result in a severe form of very early onset inflammatory bowel disease. Gastroenterology 146(4): 1028-1039, 2014

Whole-exome sequencing identifies tetratricopeptide repeat domain 7A (TTC7A) mutations for combined immunodeficiency with intestinal atresias. Journal of Allergy and Clinical Immunology 132(3): 656-664.E17, 2013

Genotype-phenotype correlation for five new missense mutations in the DNA-binding domain of the p63 gene in EEC syndrome. British Journal of Dermatology 158(4): 906-907, 2008

Human TTC5, a novel tetratricopeptide repeat domain containing gene, activates p53 and inhibits AP-1 pathway. Molecular Biology Reports 40(11): 6183-6188, 2014

Regulation of rat tetratricopeptide repeat domain 29 gene expression by follicle-stimulating hormone. Bioscience, Biotechnology, and Biochemistry 76(8): 1540-1543, 2013

Identification of a novel human gene containing the tetratricopeptide repeat domain from the Down syndrome region of chromosome 21. Dna Research 3(1): 9-16, 1996

The Tetratricopeptide repeat domain 7 gene is mutated in flaky skin mice: a model for psoriasis, autoimmunity, and anemia. Experimental Biology and Medicine 230(9): 659-667, 2005

Molecular basis of EEC (ectrodactyly, ectodermal dysplasia, clefting) syndrome: five new mutations in the DNA-binding domain of the TP63 gene and genotype-phenotype correlation. British Journal of Dermatology 162(1): 201-207, 2010

A candidate gene for developmental dyslexia encodes a nuclear tetratricopeptide repeat domain protein dynamically regulated in brain. Proceedings of the National Academy of Sciences of the United States of America 100(20): 11553-8, 2003

The peptide-substrate-binding domain of collagen prolyl 4-hydroxylases is a tetratricopeptide repeat domain with functional aromatic residues. Journal of Biological Chemistry 279(50): 52255-52261, 2004

Interaction of FUN14 domain containing 1, a mitochondrial outer membrane protein, with kinesin light chain 1 via the tetratricopeptide repeat domain. Biomedical Reports 6(1): 46-50, 2017

Genotype-phenotype relationship in 2 SMA III patients with novel mutations in the Tudor domain. Neurology 78(8): 551-556, 2012