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

2021 ◽  
Author(s):  
Wenjun Mou ◽  
Shen Yang ◽  
Ruolan Guo ◽  
Libing Fu ◽  
Li Zhang ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Critical Role ◽  
Intestinal Atresia ◽  
Multiple Organ ◽  
Missense Mutations ◽  
Therapeutic Implications ◽  
Protein Functions ◽  
In The Wild ◽  
Tetratricopeptide Repeat Domain ◽  
Multiple Intestinal Atresia

Abstract 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.

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

2021 ◽  
Vol 12 ◽  
Author(s):  
Wenjun Mou ◽  
Shen Yang ◽  
Ruolan Guo ◽  
Libing Fu ◽  
Li Zhang ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Intestinal Atresia ◽  
Multiple Organ ◽  
Missense Mutations ◽  
Combined Immunodeficiency ◽  
Therapeutic Implications ◽  
Protein Functions ◽  
In The Wild ◽  
Tetratricopeptide Repeat Domain ◽  
Multiple Intestinal Atresia

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.

scholarly journals Mutation of the Transcriptional Regulator YtoI Rescues Listeria monocytogenes Mutants Deficient in the Essential Shared Metabolite 1,4-Dihydroxy-2-Naphthoate (DHNA)

2019 ◽  
Vol 88 (1) ◽  
Author(s):  
Grischa Y. Chen ◽  
Cheng-Yen Kao ◽  
Hans B. Smith ◽  
Drew P. Rust ◽  
Zachary M. Powers ◽  
...  
Keyword(s):  
Listeria Monocytogenes ◽  
Metabolic Regulation ◽  
Critical Role ◽  
Transcriptional Regulator ◽  
Host Cells ◽  
Missense Mutations ◽  
Content Type ◽  
Independent Functions ◽  
In The Wild ◽  
Suppressor Mutants

ABSTRACT Listeria monocytogenes, a Gram-positive, facultative intracellular pathogen, survives and replicates in the cytosol of host cells. Synthesis of 1,4-dihydroxy-2-naphthoate (DHNA), an intermediate of menaquinone biosynthesis, is essential for cytosolic survival of L. monocytogenes independent from its role in respiration. Here, we demonstrate that DHNA is essential for virulence in a murine model of listeriosis due to both respiration-dependent and -independent functions. In addition, DHNA can be both secreted and utilized as an extracellular shared metabolite to promote cytosolic survival inside host macrophages. To understand the role(s) of DHNA in L. monocytogenes intracellular survival and virulence, we isolated DHNA-deficient (ΔmenD strain) suppressor mutants that formed plaques in monolayers of fibroblasts. Five ΔmenD suppressor (mds) mutants additionally rescued at least 50% of the cytosolic survival defect of the parent ΔmenD mutant. Whole-genome sequencing revealed that four of the five suppressor mutants had independent missense mutations in a putative transcriptional regulator, ytoI (lmo1576). Clean deletion and complementation in trans confirmed that loss of ytoI could restore plaquing and cytosolic survival of DHNA-deficient L. monocytogenes. RNA-seq transcriptome analysis revealed five genes (lmo0944, lmo1575, lmo1577, lmo2005, and lmo2006) expressed at a higher level in the ΔytoI strain than in the wild-type strain, whereas two genes (lmo1917 and lmo2103) demonstrated lower expression in the ΔytoI mutant. Intriguingly, the majority of these genes are involved in controlling pyruvate flux. Metabolic analysis confirmed that acetoin, acetate, and lactate flux were altered in a ΔytoI mutant, suggesting a critical role for regulating these metabolic programs. In conclusion, we have demonstrated that, similar to findings in select other bacteria, DHNA can act as a shared resource, and it is essential for cytosolic survival and virulence of L. monocytogenes. Furthermore, we have identified a novel transcriptional regulator in L. monocytogenes and determined that its metabolic regulation is implicated in cytosolic survival of L. monocytogenes.

Tetratricopeptide Repeat Domain 7A (TTC7A) Mutation in a Newborn with Multiple Intestinal Atresia and Combined Immunodeficiency

2014 ◽  
Vol 34 (6) ◽  
pp. 607-610 ◽  
Author(s):  
Niti Sardana Agarwal ◽  
Lesley Northrop ◽  
Kwame Anyane-Yeboa ◽  
Vimla S. Aggarwal ◽  
Peter L. Nagy ◽  
...  
Keyword(s):  
Intestinal Atresia ◽  
Tetratricopeptide Repeat ◽  
Combined Immunodeficiency ◽  
Repeat Domain ◽  
Tetratricopeptide Repeat Domain ◽  
Multiple Intestinal Atresia

A Novel Mutation Glyl672→Arg in Type 2A and a Homozygous Mutation in Type 2B von Willebrand Disease

1996 ◽  
Vol 76 (02) ◽  
pp. 253-257 ◽  
Author(s):  
Takeshi Hagiwara ◽  
Hiroshi Inaba ◽  
Shinichi Yoshida ◽  
Keiko Nagaizumi ◽  
Morio Arai ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Novel Mutation ◽  
Point Mutations ◽  
Japanese Patients ◽  
Von Willebrand Disease ◽  
Homozygous Mutation ◽  
Missense Mutations ◽  
Reaction Products ◽  
Type 3 ◽  
Von Willebrand

SummaryGenetic materials from 16 unrelated Japanese patients with von Willebrand disease (vWD) were analyzed for mutations. Exon 28 of the von Willebrand factor (vWF) gene, where point mutations have been found most frequent, was screened by various restriction-enzyme analyses. Six patients were observed to have abnormal restriction patterns. By sequence analyses of the polymerase chain-reaction products, we identified a homozygous R1308C missense mutation in a patient with type 2B vWD; R1597W, R1597Q, G1609R and G1672R missense mutations in five patients with type 2A; and a G1659ter nonsense mutation in a patient with type 3 vWD. The G1672R was a novel missense mutation of the carboxyl-terminal end of the A2 domain. In addition, we detected an A/C polymorphism at nucleotide 4915 with HaeIII. There was no particular linkage disequilibrium of the A/C polymorphism, either with the G/A polymorphism at nucleotide 4391 detected with Hphl or with the C/T at 4891 detected with BstEll.

scholarly journals Incidence of the CHEK2 Germline Mutation and Its Impact on Clinicopathological Features, Treatment Responses, and Disease Course in Patients with Papillary Thyroid Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 470
Author(s):  
Danuta Gąsior-Perczak ◽  
Artur Kowalik ◽  
Krzysztof Gruszczyński ◽  
Agnieszka Walczyk ◽  
Monika Siołek ◽  
...  
Keyword(s):  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Missense Mutation ◽  
Vascular Invasion ◽  
Germline Mutations ◽  
Primary Treatment ◽  
Clinicopathological Characteristics ◽  
Missense Mutations ◽  
Papillary Thyroid ◽  
Treatment Responses

The CHEK2 gene is involved in the repair of damaged DNA. CHEK2 germline mutations impair this repair mechanism, causing genomic instability and increasing the risk of various cancers, including papillary thyroid carcinoma (PTC). Here, we asked whether CHEK2 germline mutations predict a worse clinical course for PTC. The study included 1547 unselected PTC patients (1358 women and 189 men) treated at a single center. The relationship between mutation status and clinicopathological characteristics, treatment responses, and disease outcome was assessed. CHEK2 mutations were found in 240 (15.5%) of patients. A CHEK2 I157T missense mutation was found in 12.3%, and CHEK2 truncating mutations (IVS2 + 1G > A, del5395, 1100delC) were found in 2.8%. The truncating mutations were more common in women (p = 0.038), and were associated with vascular invasion (OR, 6.91; p < 0.0001) and intermediate or high initial risk (OR, 1.92; p = 0.0481) in multivariate analysis. No significant differences in these parameters were observed in patients with the I157T missense mutation. In conclusion, the CHEK2 truncating mutations were associated with vascular invasion and with intermediate and high initial risk of recurrence/persistence. Neither the truncating nor the missense mutations were associated with worse primary treatment response and outcome of the disease.

scholarly journals Cytosolic Phospholipase A2α–deficient Mice Are Resistant to Collagen-induced Arthritis

2003 ◽  
Vol 197 (10) ◽  
pp. 1297-1302 ◽  
Author(s):  
Martin Hegen ◽  
Linhong Sun ◽  
Naonori Uozumi ◽  
Kazuhiko Kume ◽  
Mary E. Goad ◽  
...  
Keyword(s):  
Critical Role ◽  
Wild Type ◽  
Collagen Induced Arthritis ◽  
Cytosolic Phospholipase ◽  
Severity Scores ◽  
In The Wild ◽  
Cytosolic Phospholipase A2α ◽  
Antibody Levels ◽  
Deficient Mice

Pathogenic mechanisms relevant to rheumatoid arthritis occur in the mouse model of collagen-induced arthritis (CIA). Cytosolic phospholipase A2α (cPLA2α) releases arachidonic acid from cell membranes to initiate the production of prostaglandins and leukotrienes. These inflammatory mediators have been implicated in the development of CIA. To test the hypothesis that cPLA2α plays a key role in the development of CIA, we backcrossed cPLA2α-deficient mice on the DBA/1LacJ background that is susceptible to CIA. The disease severity scores and the incidence of disease were markedly reduced in cPLA2α-deficient mice compared with wild-type littermates. At completion of the study, &gt;90% of the wild-type mice had developed disease whereas none of the cPLA2α-deficient mice had more than one digit inflamed. Furthermore, visual disease scores correlated with severity of disease determined histologically. Pannus formation, articular fibrillation, and ankylosis were all dramatically reduced in the cPLA2α-deficient mice. Although the disease scores differed significantly between cPLA2α mutant and wild-type mice, anti-collagen antibody levels were similar in the wild-type mice and mutant littermates. These data demonstrate the critical role of cPLA2α in the pathogenesis of CIA.

scholarly journals 122 Multiple intestinal atresia with combined immunodeficiency due to TTC7A gene mutation – case report

2021 ◽  
Author(s):  
Iva Vukšić ◽  
Katja Dumić Kubat ◽  
Tomislav Ćaleta ◽  
Toni Matić ◽  
Nevenka Cigrovski ◽  
...  
Keyword(s):  
Case Report ◽  
Gene Mutation ◽  
Intestinal Atresia ◽  
Combined Immunodeficiency ◽  
Multiple Intestinal Atresia

scholarly journals A systematic review of immune pathogenesis of SARS-COV-2 infection

2021 ◽  
Vol 8 (7) ◽  
pp. 978
Author(s):  
Shabarini Srikumar ◽  
Shridharan Perumal
Keyword(s):  
Immune Responses ◽  
Critical Role ◽  
Clinical Manifestations ◽  
Multiple Organ ◽  
World Health ◽  
Multiple Organ Dysfunction ◽  
Viral Immunity ◽  
Secondary Infections ◽  
Rational Management ◽  
Health Organization

The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was declared a pandemic by the world health organization on March 11, 2020. The host immune response to SARS-CoV-2 appears to play a critical role in disease pathogenesis and clinical manifestations. SARS-CoV-2 causes direct activation of anti-viral immune responses and leads to the release of uncontrolled inflammatory mediators. These SARS-CoV-2-induced immune responses may lead to various other abnormalities like lymphopenia, thrombocytopenia and granulocyte and monocyte dysfunction, making the patient more prone to secondary infections by microorganisms, which may result in further further serious complications like septic shock, severe multiple organ dysfunction and eventually death. Therefore, mechanisms underlying immune abnormalities in patients with COVID-19 disease must be elucidated to guide clinical management of the disease. Rational management in combating the disease includes enhancing anti-viral immunity and inhibiting systemic inflammation, which is key to successful treatment.

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