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

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.

Biallelic PI4KA variants cause neurological, intestinal and immunological disease

Phosphatidylinositol 4-kinase IIIα (PI4KIIIα/PI4KA/OMIM:600286) is a lipid kinase generating phosphatidylinositol 4-phosphate (PI4P), a membrane phospholipid with critical roles in the physiology of multiple cell types. PI4KIIIα’s role in PI4P generation requires its assembly into a heterotetrameric complex with EFR3, TTC7 and FAM126. Sequence alterations in two of these molecular partners, TTC7 (encoded by TTC7A or TCC7B) and FAM126, have been associated with a heterogeneous group of either neurological (FAM126A) or intestinal and immunological (TTC7A) conditions. Here we show that biallelic PI4KA sequence alterations in humans are associated with neurological disease, in particular hypomyelinating leukodystrophy. In addition, affected individuals may present with inflammatory bowel disease, multiple intestinal atresia and combined immunodeficiency. Our cellular, biochemical and structural modelling studies indicate that PI4KA-associated phenotypical outcomes likely stem from impairment of molecular roles requiring organ specific PI4KIIIα-TTC7-FAM126 complex functional interactions. Together these data define PI4KA gene alteration as a cause of a variable phenotypical spectrum and provide fundamental new insight into the combinatorial biology of the PI4KIIIα-FAM126-TTC7-EFR3 molecular complex.

A Novel Homozygous TTC7A Missense Mutation Results In Familial Multiple Intestinal Atresia And Combined Immunodeficiency

Multiple intestinal atresia with combined immune deficiency (MIA-CID) are autosomal recessive disorders characterized by intestinal obstructions and profound immune defects. The study of patients with MIA and related disorders has established that tetratricopeptide repeat domain 7A (TTC7A) plays a critical role in intestinal and immune homeostasis and it is now shown that biallelic missense mutations have better survival outcomes. However, clues to related underlying molecular dysfunction remains elusive. In this study, we reported a patient with the diagnosis of severe CID and MIA that involved the pyloric diaphragm, ileum atresia, and colon stenosis, and the clinical course was complicated by multiple episodes of sepsis. In spite of multiple surgeries and supportive treatment, the patient died of severe sepsis and multiple organ failure at 3 months of age. The whole exome sequencing (WES) identified a novel homozygous TTC7A missense mutation (c.206T>C, p. L69P). The structural analysis showed that a hydrogen bond present between Gly65 and Leu69 in the wild-type TTC7A was broken by the Leu69Pro mutation. Moreover, this homozygous missense mutation led to a severely reduced TTC7A expression in lymphocytes and intestinal tissues, accompanied by prohibited lymphocyte development. Further studies demonstrated that the PI4K-FAM126A-EFR3A pathway was impaired in intestinal tissues. Our results strongly suggest that the missense mutation in TTC7A gene causes severe MIA-CID. More knowledge of the TTC7A protein functions will have important therapeutic implications for patients with MIA-CID.

Management and Outcomes of Malformations Associated with Intestinal Malrotations in Newborns: About 5 Cases

Bowel malrotation is an abnormality in the rotation of the primary intestinal loop during embryonic life. It is a severe abnormality exposing the patient to fatal complications. We report here a series of five patients presenting digestive malrotation with various malformative associations. The first three cases are multiple intestinal atresia on incomplete common mesentery. They underwent an intestinal anastomosis: end-lateral duodeno-ileal for one and end-to-end jejuno-jejunal for the other two with Ladd procedure. In the latter two cases, the omphalocele was the associated malformation; complications such as rupture of the omphalocele with intestinal perforation for one and occlusion by strangulation at the level of the neck for the other were recorded. Ileal resection removing the perforation with end-to-end ileo-ileal anastomosis was performed for the first, while reduction of strangulation at the origin of the occlusion was sufficient for the second. The LADD procedure was the complementary gesture in all cases. The outcome was favorable in 3 cases; two of the newborns who had jejunal atresia died, one on day 5 in a picture of acute respiratory distress, the other on day 6 in a picture of disseminated intravascular coagulation.