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A Novel Homozygous TTC7A Missense Mutation Results in Familial Multiple Intestinal Atresia and Combined Immunodeficiency.

ABSTRACT: Rare autosomal-recessive variants in tetratricopeptide repeat domain 7A (TTC7A) gene have been shown to cause intestinal and immune disorders of variable severity. Missense mutations in TTC7A gene, usually retaining most of the functional motifs, is associated with relative milder clinical presentations. In this study, we reported a patient who was suffering from severe multiple intestinal atresia (MIA) with combined immunodeficiency (CID) that led to the pyloric diaphragm, ileum atresia, colon stenosis, and multiple episodes of sepsis. In spite of several surgeries and supportive treatment, the patient died of severe sepsis and multiple organ failure at age of 3 months. The whole exome sequencing (WES) of peripheral blood samples identified a novel homozygous TTC7A missense mutation (c. 206T>C, p. L69P), inherited from his parents with consanguineous marriage. In silico analysis revealed that a hydrogen bond present between Gly65 and Leu69 in the wild-type TTC7A was disrupted by the Leu69Pro mutation. Moreover, this homozygous missense mutation led to a reduced TTC7A expression in lymphocytes and intestinal tissues, accompanied by impeded lymphocyte development. Further studies demonstrated that the PI4K-FAM126A-EFR3A pathway was impaired in colon tissues. Our data strongly support the linkage of severe MIA-CID with the missense mutation in TTC7A gene. More knowledge of the TTC7A protein functions will have important therapeutic implications for patients with MIA-CID.

SUBMITTER: Mou W

PROVIDER: S-EPMC8714664 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Meconium peritonitis in multiple intestinal atresia with combined immune deficiency caused by a TTC7A mutation: A case report.

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TTC7A Mutations for Combined Immunodeficiency with Intestinal Atresia

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Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2015-11-25 | E-GEOD-75358 | biostudies-arrayexpress

Whole-exome sequencing identifies tetratricopeptide repeat domain 7A (TTC7A) mutations for combined immunodeficiency with intestinal atresias.

Project description:BackgroundCombined immunodeficiency with multiple intestinal atresias (CID-MIA) is a rare hereditary disease characterized by intestinal obstructions and profound immune defects.ObjectiveWe sought to determine the underlying genetic causes of CID-MIA by analyzing the exomic sequences of 5 patients and their healthy direct relatives from 5 unrelated families.MethodsWe performed whole-exome sequencing on 5 patients with CID-MIA and 10 healthy direct family members belonging to 5 unrelated families with CID-MIA. We also performed targeted Sanger sequencing for the candidate gene tetratricopeptide repeat domain 7A (TTC7A) on 3 additional patients with CID-MIA.ResultsThrough analysis and comparison of the exomic sequence of the subjects from these 5 families, we identified biallelic damaging mutations in the TTC7A gene, for a total of 7 distinct mutations. Targeted TTC7A gene sequencing in 3 additional unrelated patients with CID-MIA revealed biallelic deleterious mutations in 2 of them, as well as an aberrant splice product in the third patient. Staining of normal thymus showed that the TTC7A protein is expressed in thymic epithelial cells, as well as in thymocytes. Moreover, severe lymphoid depletion was observed in the thymus and peripheral lymphoid tissues from 2 patients with CID-MIA.ConclusionsWe identified deleterious mutations of the TTC7A gene in 8 unrelated patients with CID-MIA and demonstrated that the TTC7A protein is expressed in the thymus. Our results strongly suggest that TTC7A gene defects cause CID-MIA.

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