scholarly journals LIG4 Syndrome: Clinical and Molecular Characterization in a Chinese Cohort

2020 ◽  
Author(s):  
Bijun Sun ◽  
Qiuyu Chen ◽  
Ying Wang ◽  
Danru Liu ◽  
Jia Hou ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Molecular Characteristics ◽  
Compound Heterozygous ◽  
Combined Immunodeficiency ◽  
Cord Blood Stem Cell ◽  
Potential Association ◽  
Ligase Iv ◽  
The Status ◽  
Chinese Cohort ◽  
Igm Deficiency

Abstract Background: DNA Ligase IV (LIG4) syndrome is a rare disease with few reports to date. Patients suffer from a broad spectrum of clinical features, including microcephaly, growth retardation, developmental delay, dysmorphic facial features, combined immunodeficiency, and malignancy predisposition. There is thought to be a potential association between genotypes and phenotypes. Here, we investigated the characteristics of LIG4 syndrome in a Chinese cohort.Results: All seven patients had growth restriction. Most patients (6/7) had microcephaly (< -3 SD). Recurrent bacterial infections of the lungs and intestines were the most common symptoms. One patient had myelodysplastic syndromes. One patient presented with an inflammatory bowel disease (IBD)-like phenotype. Patients presented with combined immunodeficiency. The proportions of naive CD4+ and naive CD8+ T cells decreased notably in five patients. All patients harbored compound heterozygous mutations in the LIG4 gene, consisting of a missense mutation (c.833G>T, p.R278L) and a deletion shift mutation, primarily c.1271-1275delAAAGA (p.K424Rfs). Two other deletion mutations, c.1144-1145delCT and c.1277-1278delAA, were novel. Patients with p.K424RfsX20/p.R278 might lead to milder dysmorphism, but more significant IgA/ IgM deficiency, compared with the frequent genotype p.R814X/p.K424RfsX20 reported. One patient underwent umbilical cord blood stem cell transplantation (UCBSCT) but died.Conclusions: This study reported the clinical and molecular characteristics of a Chinese cohort, further expanding the phenotypic and genotypic spectrum, and the understanding of genotype-to-phenotype correlations in LIG4 syndrome. The results may help to characterize the status of the disease in China.

Novel compound heterozygous DNA ligase IV mutations in an adolescent with a slowly-progressing radiosensitive-severe combined immunodeficiency

2015 ◽  
Vol 160 (2) ◽  
pp. 255-260 ◽  
Author(s):  
Shinobu Tamura ◽  
Kohei Higuchi ◽  
Masaharu Tamaki ◽  
Chizuko Inoue ◽  
Ryoko Awazawa ◽  
...  
Keyword(s):  
Severe Combined Immunodeficiency ◽  
Dna Ligase ◽  
Compound Heterozygous ◽  
Combined Immunodeficiency ◽  
Dna Ligase Iv ◽  
Ligase Iv

scholarly journals Study of The Collagen Type VI Alpha 3 (COL6A3) Gene in Parkinson’s Disease

2021 ◽  
Author(s):  
Chong-Yao Jin ◽  
Ran Zheng ◽  
Zhi-Hao Lin ◽  
Nai-Jia Xue ◽  
Ying Chen ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Collagen Type ◽  
Gene Mutations ◽  
Compound Heterozygous ◽  
Genetic Characteristics ◽  
Increased Risk ◽  
Collagen Type Vi ◽  
Chinese Cohort ◽  
Aggregate Burden

Abstract Background To date, the genetic contribution to Parkinson’s disease (PD) remains unclear. Mutations in the collagen type VI alpha 3 (COL6A3) gene were recently identified as a cause of isolated dystonia. Since PD and dystonia are closely related disorders with shared clinical and genetic characteristics, we explored the association between COL6A3 and PD in a Chinese cohort. Methods We performed genetic screening of COL6A3 in a Chinese cohort of 173 patients with sporadic PD and 200 healthy controls. We identified variants that are likely to have pathogenic effects based on: 1) a minor allele frequency of < 0.01; and 2) the variant being recognized as deleterious by at least 15 different in silico predicting tools. Finally, we tested the aggregate burden of COL6A3 on PD via SKAT-O analysis. Results First, we found compound heterozygous COL6A3 gene mutations in one early-onset PD patients. Then, we explored whether COL6A3 variants contributed to increased risk of developing PD in a Chinese population. We detected 21 rare non-synonymous variants. Pathogenicity predictions identified seven novel non-synonymous variants as likely to be pathogenic. SKAT-O analysis further revealed that an aggregate burden of variants in COL6A3 contributes to PD (p = 0.03). Conclusion An increased aggregate burden of the COL6A3 gene was detected in patients with PD.

scholarly journals Toxin-Antitoxin Genes of the Gram-Positive Pathogen Streptococcus pneumoniae: So Few and Yet So Many

2012 ◽  
Vol 76 (4) ◽  
pp. 773-791 ◽  
Author(s):  
Wai Ting Chan ◽  
Inma Moreno-Córdoba ◽  
Chew Chieng Yeo ◽  
Manuel Espinosa
Keyword(s):  
Streptococcus Pneumoniae ◽  
Biofilm Formation ◽  
Bacterial Infections ◽  
Host Cells ◽  
Molecular Characteristics ◽  
Type Ii ◽  
Pneumococcal Infections ◽  
Interesting Phenomenon ◽  
Content Type ◽  
Toxin Protein

SUMMARYPneumococcal infections cause up to 2 million deaths annually and raise a large economic burden and thus constitute an important threat to mankind. Because of the increase in the antibiotic resistance ofStreptococcus pneumoniaeclinical isolates, there is an urgent need to find new antimicrobial approaches to triumph over pneumococcal infections. Toxin-antitoxin (TA) systems (TAS), which are present in most living bacteria but not in eukaryotes, have been proposed as an effective strategy to combat bacterial infections. Type II TAS comprise a stable toxin and a labile antitoxin that form an innocuous TA complex under normal conditions. Under stress conditions, TA synthesis will be triggered, resulting in the degradation of the labile antitoxin and the release of the toxin protein, which would poison the host cells. The three functional chromosomal TAS fromS. pneumoniaethat have been studied as well as their molecular characteristics are discussed in detail in this review. Furthermore, a meticulous bioinformatics search has been performed for 48 pneumococcal genomes that are found in public databases, and more putative TAS, homologous to well-characterized ones, have been revealed. Strikingly, several unusual putative TAS, in terms of components and genetic organizations previously not envisaged, have been discovered and are further discussed. Previously, we reported a novel finding in which a unique pneumococcal DNA signature, the BOX element, affected the regulation of the pneumococcalyefM-yoeBTAS. This BOX element has also been found in some of the other pneumococcal TAS. In this review, we also discuss possible relationships between some of the pneumococcal TAS with pathogenicity, competence, biofilm formation, persistence, and an interesting phenomenon called bistability.

Novel compound heterozygous variants in the LHCGR gene identified in a subject with Leydig cell hypoplasia type 1

2018 ◽  
Vol 31 (2) ◽  
pp. 239-245 ◽  
Author(s):  
Yufei Xu ◽  
Yulin Chen ◽  
Niu Li ◽  
Xuyun Hu ◽  
Guoqiang Li ◽  
...  
Keyword(s):  
Leydig Cell ◽  
Splice Site Mutation ◽  
Molecular Characteristics ◽  
Compound Heterozygous ◽  
Site Mutation ◽  
Family Pedigree ◽  
Correlation Spectrum ◽  
Compound Heterozygous Variants ◽  
Leydig Cell Hypoplasia

Abstract Background: Leydig cell hypoplasia (LCH) is a rare disease and one of the causes of male disorder of sexual differentiation (DSD). Inactivating mutations in the luteinizing hormone/chorionic gonadotropin receptor (LHCGR) gene account for the underlying LCH pathogenicity. This study aimed to analyze the clinical presentation and diagnosis as well as highlight the molecular characteristics of a subject with LCH type 1. Case presentation: Clinical data were collected from the subject and analyzed. Next generation sequencing of the immediate family pedigree using peripheral blood genomic DNA was performed, and the relevant mutations were verified with Sanger sequencing. We describe the case of a 5-year-old patient with DSD, presenting with a lateral inguinal hernia accompanied by abnormal hormone tests. The genetic analysis revealed novel compound heterozygous variants in the LHCGR gene, including a splice site mutation (c.681-1 G>A) and a frameshift variant (c.1582_1585del ATAT, p.Ile528*). Conclusions: We identified novel compound heterozygous variants in the LHCGR gene, and expanded the genotype-phenotype correlation spectrum of LHCGR variants.

scholarly journals Metabolic abnormalities in G6PC3-deficient human neutrophils result in severe functional defects

2020 ◽  
Vol 4 (23) ◽  
pp. 5888-5901
Author(s):  
Christopher McKinney ◽  
Michael Ellison ◽  
Natalie J. Briones ◽  
Angelina Baroffio ◽  
John Murphy ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Bacterial Infections ◽  
Neutrophil Function ◽  
Functional Improvement ◽  
Human Neutrophils ◽  
Compound Heterozygous ◽  
Cd11b Expression ◽  
Exon 2 ◽  
Metabolic Defects ◽  
Functional Defects

Abstract Severe congenital neutropenia type 4 (SCN-4) is an autosomal recessive condition in which mutations in the G6PC3 gene encoding for the catalytic 3 subunit of glucose-6-phosphatase-β result in neutropenia, neutrophil dysfunction, and other syndromic features. We report a child with SCN-4 caused by compound heterozygous mutations in G6PC3, a previously identified missense mutation in exon 6 (c.758G&gt;A[p.R235H]), and a novel missense mutation in exon 2 (c.325G&gt;A[p.G109S]). The patient had recurrent bacterial infections, inflammatory bowel disease, neutropenia, and intermittent thrombocytopenia. Administration of granulocyte colony–stimulating factor (G-CSF) resolved the neutropenia and allowed for detailed evaluation of human neutrophil function. Random and directed migration by the patient’s neutrophils was severely diminished. Associated with this were defects in CD11b expression and F-actin assembly. Bactericidal activity at bacteria/neutrophil ratios &gt;1:1 was also diminished and was associated with attenuated ingestion. Superoxide anion generation was &lt;25% of control values, but phox proteins appeared quantitatively normal. Extensive metabolomics analysis at steady state and upon incubation with stable isotope–labeled tracers (U-13C-glucose, 13C,15N-glutamine, and U-13C-fructose) demonstrated dramatic impairments in early glycolysis (hexose phosphate levels), hexosemonophosphate shunt (required for the generation of the NADPH), and the total adenylate pool, which could explain the dramatic cell dysfunction displayed by the patient’s neutrophils. Preliminary experiments with fructose supplementation to bypass the enzyme block demonstrated that the metabolic profile could be reversed, but was not sustained long enough for functional improvement. In human deficiency of G6PC3, metabolic defects resulting from the enzyme deficiency account for diverse neutrophil functional defects and present a major risk of infection.

scholarly journals Indole Derivatives Maintain the Status Quo Between Beneficial Biofilms and Their Plant Hosts

2019 ◽  
Vol 32 (8) ◽  
pp. 1013-1025 ◽  
Author(s):  
Hadas Ganin ◽  
Natalie Kemper ◽  
Sagit Meir ◽  
Ilana Rogachev ◽  
Shir Ely ◽  
...  
Keyword(s):  
Plant Growth ◽  
Bacterial Infections ◽  
Growth Promoter ◽  
Indole Derivatives ◽  
Plant Polysaccharides ◽  
Plant Polysaccharide ◽  
Symbiotic Interactions ◽  
Plant Hosts ◽  
The Status ◽  
Rhizosphere Environment

Biofilms formed by bacteria on plant roots play an important role in maintaining an optimal rhizosphere environment that supports plant growth and fitness. Bacillus subtilis is a potent plant growth promoter, forming biofilms that play a key role in protecting the host from fungal and bacterial infections. In this work, we demonstrate that the development of B. subtilis biofilms is antagonized by specific indole derivatives that accumulate during symbiotic interactions with plant hosts. Indole derivatives are more potent signals when the plant polysaccharide xylan serves as a carbon source, a mechanism to sustain beneficial biofilms at a biomass that can be supported by the plant. Moreover, B. subtilis biofilms formed by mutants resistant to indole derivatives become deleterious to the plants due to their capacity to consume and recycle plant polysaccharides. These results demonstrate how a dynamic metabolite-based dialogue can promote homeostasis between plant hosts and their beneficial biofilm communities.

scholarly journals A Severe Form of Human Combined Immunodeficiency Due to Mutations in DNA Ligase IV

2006 ◽  
Vol 176 (8) ◽  
pp. 5060-5068 ◽  
Author(s):  
Anselm Enders ◽  
Paul Fisch ◽  
Klaus Schwarz ◽  
Ulrich Duffner ◽  
Ulrich Pannicke ◽  
...  
Keyword(s):  
Severe Form ◽  
Dna Ligase ◽  
Combined Immunodeficiency ◽  
Dna Ligase Iv ◽  
Ligase Iv

Severe combined immunodeficiency and microcephaly in siblings with hypomorphic mutations in DNA ligase IV

2006 ◽  
Vol 36 (1) ◽  
pp. 224-235 ◽  
Author(s):  
Dietke Buck ◽  
Despina Moshous ◽  
Régina de Chasseval ◽  
Yunmei Ma ◽  
Françoise le Deist ◽  
...  
Keyword(s):  
Severe Combined Immunodeficiency ◽  
Dna Ligase ◽  
Combined Immunodeficiency ◽  
Dna Ligase Iv ◽  
Ligase Iv
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