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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 probably stem from impairment of PI4KIIIα-TTC7-FAM126's organ-specific functions, due to defective catalytic activity or altered intra-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.

[Display omitted] The actin cytoskeleton has a crucial role in the maintenance of the immune homeostasis by controlling various cellular processes, including cell migration. Mutations in TTC7A have been described as the cause of a primary immunodeficiency associated to different degrees of gut involvement and alterations in the actin cytoskeleton dynamics. This study investigates the impact of TTC7A deficiency in immune homeostasis. In particular, the role of the TTC7A/phosphatidylinositol 4 kinase type III α pathway in the control of leukocyte migration and actin dynamics. Microfabricated devices were leveraged to study cell migration and actin dynamics of murine and patient-derived leukocytes under confinement at the single-cell level. We show that TTC7A-deficient lymphocytes exhibit an altered cell migration and reduced capacity to deform through narrow gaps. Mechanistically, TTC7A-deficient phenotype resulted from impaired phosphoinositide signaling, leading to the downregulation of the phosphoinositide 3-kinase/AKT/RHOA regulatory axis and imbalanced actin cytoskeleton dynamics. TTC7A-associated phenotype resulted in impaired cell motility, accumulation of DNA damage, and increased cell death in dense 3-dimensional gels in the presence of chemokines. These results highlight a novel role of TTC7A as a critical regulator of lymphocyte migration. Impairment of this cellular function is likely to contribute to the pathophysiology underlying progressive immunodeficiency in patients. [ABSTRACT FROM AUTHOR]

Hereditary multiple intestinal atresia (HMIA) with TTC7A mutation is caused by homozygous or compound heterozygous TTC7A gene mutation. It is characterized by multiple small and large intestinal atresias and/or stenoses. TTC7A mutation is described in some patients with inflammatory bowel disease and mild-severe forms of severe combined immunodeficiency without intestinal atresia or stenosis. We present 2 cases of intestinal atresia and documented TTC7A mutation with a novel variant. Both cases had different clinical and pathological manifestations. The first case is a male infant born at 35 weeks of gestation with failure to pass meconium. Intestinal biopsy reveals apoptotic enteropathy with villous atrophy and increased mucosal eosinophils. The second case is referred at birth for antenatally detected umbilical hernia, polyhydramnios and possible upper intestinal obstruction. The resected specimen reveals ileal atresia with partial villous atrophy, decreased number of lamina propria inflammatory cells and absence of plasma cells. In conclusion, these cases reflect an emerging TTC7A pathogenic variant with different histological manifestations and leads to characterization as immune dysregulation disorder. There is a need to differentiate TTC7A mutation associated ones from cases labeled as very early onset IBD and rule out other hereditary immunodeficiencies., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

We aimed to explore the genotypic and phenotypic characteristics of neonatal-onset inflammatory bowel disease (IBD) with combined immunodeficiency due to TTC7A mutation. We examined the clinical manifestations, imaging results, endoscopic and histological findings, interventions, and prognosis of a proband with neonatal-onset IBD and performed biochemical analyses, whole-exome sequencing (WES), and in silico analysis. Our proband developed severe early-onset diarrhea, malnutrition, electrolyte imbalance, dehydration, and recurrent infections after birth. Radiographic and ultrasonic images showed no specific manifestations. Endoscopic and histological examination revealed chronic inflammation. Immune function examination indicated immunodeficiency. WES identified compound heterozygous TTC7A mutations (c.2355+4A>G, c.643G>T) in the proband. In the expression analysis, no abnormal splicing in the TTC7A sequence was observed due to the c.2355+4A>G mutation; however, the mRNA expression was reduced. The proband's condition did not improve after treatment with methylprednisolone or leflunomide. The proband died when treatment was stopped at the age of 5 months and 19 days. Compound heterozygous mutations (c.2355+4A>G, c.643G>T) in the TTC7A gene are described and verified for the first time. Our report expands the phenotypic spectrum of TTC7A mutations and the genotypic spectrum of very early-onset IBD with combined immunodeficiency. [ABSTRACT FROM AUTHOR]

We aimed to explore the genotypic and phenotypic characteristics of neonatal-onset inflammatory bowel disease (IBD) with combined immunodeficiency due to TTC7A mutation. We examined the clinical manifestations, imaging results, endoscopic and histological findings, interventions, and prognosis of a proband with neonatal-onset IBD and performed biochemical analyses, whole-exome sequencing (WES), and in silico analysis. Our proband developed severe early-onset diarrhea, malnutrition, electrolyte imbalance, dehydration, and recurrent infections after birth. Radiographic and ultrasonic images showed no specific manifestations. Endoscopic and histological examination revealed chronic inflammation. Immune function examination indicated immunodeficiency. WES identified compound heterozygous TTC7A mutations (c.2355+4A>G, c.643G>T) in the proband. In the expression analysis, no abnormal splicing in the TTC7A sequence was observed due to the c.2355+4A>G mutation; however, the mRNA expression was reduced. The proband’s condition did not improve after treatment with methylprednisolone or leflunomide. The proband died when treatment was stopped at the age of 5 months and 19 days. Compound heterozygous mutations (c.2355+4A>G, c.643G>T) in the TTC7A gene are described and verified for the first time. Our report expands the phenotypic spectrum of TTC7A mutations and the genotypic spectrum of very early-onset IBD with combined immunodeficiency.

Abstract Background Congenital tufting enteropathy (CTE) is a rare disease that manifests as intractable diarrhea during the neonatal period which is associated with mutations of the epithelial cell adhesion molecule (EpCAM) gene. Case presentation A male infant who presented with vomiting, diarrhea, abdominal distention, malnutrition and growth failure was admitted to our department when he was 2 months old. His parents were healthy and nonconsanguineous. Etiologic examinations of stool, inflammatory markers, blood gas and electrolytes levels, serum albumin level, serum immunoglobin levels were all normal. And there was no indication for metabolic diseases. Additionally, gastrointestinal contrast did not reveal abnormality of gastrointestinal. The patient was diagnosed with intestinal malabsorptive syndrome and severe malnutrition without definite cause. He was on supportive treatment and nutritional therapy for 13 months. However, he did not gain weight obviously. He was discharged at the age of 15 months and was fed with partial hydrolyzed formula and rice paste at home. Three months later he developed hypoglycemia and severe respiratory infection. Finally, he died due to sepsis and multiple organs failure. The next generation sequencing revealed one homozygous mutation of EpCAM gene and one complex heterozygous mutation of TTC7A gene. He was diagnosed CTE according to the genetic results and clinical manifestations. Conclusions CTE is rarely reported in Asia. Patients present with congenital diarrhea, poor weight gain and growth failure are recommended to perform endoscopy examination with proper immunohistochemistry study as early as possible, and genetic testing is necessary when suspecting congenital diarrhea and enteropathy.

The objective was to conduct a comprehensive review of the morbidity and mortality observed in published patients with gastrointestinal defects and immunodeficiency syndrome-1 (GIDID1) related to TTC7A abnormalities. This included phenotypic, genotypic, and therapeutic aspects. Twenty-seven articles were included, which represented a total of 83 patients. Mortality was of 65.8% of the cases with a mean death at 11.8 months. The mortality rate was 197.1 per 1,000 patients-years, which is significantly higher than other enteropathy types caused by defects in epithelial trafficking and polarity (such as MOY5B, STX3, EPCAM, SPINT2, TTC37 and SKIV2L ). Prematurity was also significant, with an average gestational age of 34.8 weeks. Antenatal signs were observed in 30 patients, including 14 cases of hydramnios. Three distinct phenotypic associations were identified: immune deficiency and multiple intestinal atresia without enteropathy (ID/MI), immune deficiency and enteropathy without atresia (ID/E), and immune deficiency with multiple intestinal atresia and enteropathy (ID/ MIA/E). The mortality rates for these groups were 91.6%, 47.3% and 55.5%, respectively ( p = 0.03), at earlier age of mortality for the ID/MIA phenotype and a later one for the ID/E phenotype. ELA syndrome (Enteropathy, Lymphopenia and Alopecia) was only observed in the ID/E group. Among the three genotypes (double variant Nonsense NS/NS, variant Missense/Nonsense MS/NS, double variant Missense MS/MS), NS/NS was significantly associated with the ID/MIA phenotype (77.8%), while MS/MS was associated with the ID/E phenotype (73.7%). Few therapies have been shown to be effective in treating enteropathy, particularly immunosuppressive therapies and hematopoietic stem cell transplants. The use of Leflunomide in one patient did not yield successful treatment outcomes. In conclusion, we confirm association between mortality and phenotype, which is itself linked to genotype., Competing Interests: None.The authors have no conflicts of interest to disclose., (2024, International Research and Cooperation Association for Bio & Socio - Sciences Advancement.)

Background: Congenital tufting enteropathy (CTE) is a rare disease that manifests as intractable diarrhea during the neonatal period which is associated with mutations of the epithelial cell adhesion molecule (EpCAM) gene.Case Presentation: A male infant who presented with vomiting, diarrhea, abdominal distention, malnutrition and growth failure was admitted to our department when he was 2 months old. His parents were healthy and nonconsanguineous. Etiologic examinations of stool, inflammatory markers, blood gas and electrolytes levels, serum albumin level, serum immunoglobin levels were all normal. And there was no indication for metabolic diseases. Additionally, gastrointestinal contrast did not reveal abnormality of gastrointestinal. The patient was diagnosed with intestinal malabsorptive syndrome and severe malnutrition without definite cause. He was on supportive treatment and nutritional therapy for 13 months. However, he did not gain weight obviously. He was discharged at the age of 15 months and was fed with partial hydrolyzed formula and rice paste at home. Three months later he developed hypoglycemia and severe respiratory infection. Finally, he died due to sepsis and multiple organs failure. The next generation sequencing revealed one homozygous mutation of EpCAM gene and one complex heterozygous mutation of TTC7A gene. He was diagnosed CTE according to the genetic results and clinical manifestations.Conclusions: CTE is rarely reported in Asia. Patients present with congenital diarrhea, poor weight gain and growth failure are recommended to perform endoscopy examination with proper immunohistochemistry study as early as possible, and genetic testing is necessary when suspecting congenital diarrhea and enteropathy. [ABSTRACT FROM AUTHOR]

Highlights from the article: Keywords: Multiple intestinal atresia; combined immunodeficiency; TTC7A; VEOIBD In our patient, we demonstrate two novel deletions within I TTC7A i including a multi-exonic heterozygous deletion (exon 12-15) and a trans-allelic exon 15 deletion giving rise to MIA-CID complicated by very early onset inflammatory bowel disease and death in the first year of life. The patient's overlap panel (g) demonstrates complete absence of TTC7A (h) expression with retained beta-catenin expression (i), confirming TTC7A null expression status The patient was therefore compound heterozygous for two different deletions, which overlapped in exon 15, leading to homozygous deletion of exon 15 in the patient.

Tricho-hepato-enteric syndrome (SD/THE) and Multiple intestinal atresia with combined immune deficiency (MIA-CID) are autosomal recessive disorders that present immunological and gastrointestinal features. There are two different phenotypes of patients with TTC7A mutations: the severe form, caused by null mutations and leading to the classical MIA-CID; and the mild form, caused by missense mutations and leading to predominant features of VEO-IBD, less severe immunological involvement and hair abnormalities. We expand the knowledge about TTC7A deficiency, describing a patient with the mild phenotype of TTC7A deficiency but presenting overlapping features of SD/THE and MIA-CID: intestinal atresia and inflammatory bowel disease evocative of MIA-CID, but also dental abnormalities, huge forehead, liver abnormalities, autoimmune thyroiditis and hypogammaglobulinemia, evocative of SD/THE. [ABSTRACT FROM AUTHOR]

Familial multiple intestinal atresias is an autosomal recessive disease with or without combined immunodeficiency. In the last year, several reports have described mutations in the gene TTC7A as causal to the disease in different populations. However, exact correlation between different genotypes and various phenotypes are not clear. In this study, we report identification of novel compound heterozygous mutations in TTC7A gene in a Malay girl with familial multiple intestinal atresias and severe combined immunodeficiency ( MIA-SCID) by whole exome sequencing. We found two mutations in TTC7A: one that destroyed a putative splicing acceptor at the junction of intron 17/exon 18 and one that introduced a stop codon that would truncate the last two amino acids of the encoded protein. Reviewing the recent reports on TTC7A mutations reveals correlation between the position and nature of the mutations with patient survival and clinical manifestations. Examination of public databases also suggests carrier status for healthy individuals, making a case for population screening on this gene, especially in populations with suspected frequent founder mutations. [ABSTRACT FROM AUTHOR]

Background: Combined immunodeficiency with multiple intestinal atresias (CID-MIA) is a rare hereditary disease characterized by intestinal obstructions and profound immune defects., Objective: We 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., Methods: We 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., Results: Through 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., Conclusions: We 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., (Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)