scholarly journals Computational Analysis Revealed Five Novel Mutations in Human IL2RG gene Related to X-SCID

2019 ◽  
Author(s):  
Tamadur Babiker Abbas Mohammed ◽  
Asma Ali Hassan Ali ◽  
Areeg ElsirAbdelgadir Elemam ◽  
Wala Omer Mohammed Altayb ◽  
Tebyan Ameer Abdelhameed Abbas ◽  
...  
Keyword(s):  
Binding Sites ◽  
Computational Analysis ◽  
Severe Combined Immunodeficiency ◽  
Gene Interaction ◽  
Sequence Structure ◽  
Gamma Chain ◽  
Project Hope ◽  
Life Threatening ◽  
Il2rg Gene ◽  
And Function

ABSTRACTBackgroundX linked severe combined immunodeficiency (X-SCID) is a life-threatening disorder. It is due to mutation of the interleukin two receptor gamma-chain (IL2RG) gene. Nonsynonymous SNPs (nsSNPs) are the most common polymorphism, known to be deleterious or disease-causing variations because they alter protein sequence, structure, and function. Objective: is to reveal the effect of harmful SNPs in the function and structure of IL2RG protein.MethodData on IL2RG was investigated from dbSNP/NCBI database. Prediction of damaging effect was done using sift, polyphen, provean and SNAP2.more software were used for more analysis: phd-snp, and and go, Pmut, Imutant.modeling was done using chimera and project hope. Gene interaction was done by gene mania.3UTR prediction was done using polymiRTS software.ResultThe in-silico prediction identified 1479 SNPs within IL2RG gene out of which 253 were coding SNPs, 50 took place in the miRNA 3 UTR, 21 occurred in 5 UTR region and 921 occurred in intronic regions. a total of 12 missense nsSNPs were found to be damaging by both a sequence homology-based tool (SIFT) and a structural homology-based method (PolyPhen), Five of them were novel; rs1322436793(G305R), rs1064794027(C182Y), rs111033620(G114D), rs193922347 (Y105C) and rs1293196743(Y91C), Two SNPs(Rs144075871 and rs191726889) out of 50 in the 3UTR region were predicted to disrupt miRNAs binding sites and affect the gene expression.ConclusionsComputational analysis of SNPs has become a very valuable tool in order to discriminate neutral SNPs from damaging SNPs. This study revealed 5 novel nsSNPs in the IL2RG gene by using different software and 21 SNPs in 3UTR. These SNPs could be considered as important candidates in causing diseases related to IL2RG mutation and could be used as diagnostic markers.

scholarly journals Gene therapy improves immune function in preadolescents with X-linked severe combined immunodeficiency

Blood ◽  
2007 ◽  
Vol 110 (1) ◽  
pp. 67-73 ◽  
Author(s):  
Javier Chinen ◽  
Joie Davis ◽  
Suk See De Ravin ◽  
Beverly N. Hay ◽  
Amy P. Hsu ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Cell Function ◽  
Severe Combined Immunodeficiency ◽  
Marrow Transplant ◽  
Salvage Treatment ◽  
Combined Immunodeficiency ◽  
Gamma Chain ◽  
Gene Encoding ◽  
Il2rg Gene ◽  
The Common

Retroviral gene therapy can restore immunity to infants with X-linked severe combined immunodeficiency (XSCID) caused by mutations in the IL2RG gene encoding the common gamma chain (γc) of receptors for interleukins 2 (IL-2), −4, −7, −9, −15, and −21. We investigated the safety and efficacy of gene therapy as salvage treatment for older XSCID children with inadequate immune reconstitution despite prior bone marrow transplant from a parent. Subjects received retrovirus-transduced autologous peripherally mobilized CD34+ hematopoietic cells. T-cell function significantly improved in the youngest subject (age 10 years), and multilineage retroviral marking occurred in all 3 children.

Limiting γc expression differentially affects signaling via the interleukin (IL)-7 and IL-15 receptors

Blood ◽  
2007 ◽  
Vol 110 (1) ◽  
pp. 91-98 ◽  
Author(s):  
Christine M Smyth ◽  
Samantha L Ginn ◽  
Claire T Deakin ◽  
Grant J Logan ◽  
Ian E Alexander
Keyword(s):  
Signal Transduction ◽  
B Cells ◽  
Nk Cells ◽  
Nk Cell ◽  
Severe Combined Immunodeficiency ◽  
Gamma Chain ◽  
Experimental Conditions ◽  
Il2rg Gene ◽  
The Common ◽  
Cell Ontogeny

X-linked severe combined immunodeficiency (SCID-X1) results from mutations in the IL2RG gene, which encodes the common gamma chain (γc) of the receptors for interleukin (IL)-2, 4, 7, 9, 15, and 21. Affected infants typically lack T and natural killer (NK) cells as a consequence of loss of signaling via the IL-7 receptor (IL-7R) and the IL-15R, respectively. In some infants, however, autologous NK cells are observed despite failure of T-cell ontogeny. The mechanisms by which mutations in γc differentially impact T- and NK-cell ontogeny remain incompletely understood. We used SCID-X1 patient–derived EBV-transformed B cells to test the hypothesis that the IL-15R–mediated signaling is preferentially retained as γc expression becomes limiting. Signal transduction via the IL-15R was readily detected in control EBV-transformed B cells, and via the IL-7R when modified to express IL-7Rα. Under the same experimental conditions, patient-derived EBV-transformed B cells expressing trace amounts of γc proved incapable of signal transduction via the IL-7R while retaining the capacity for signal transduction via the IL-15R. An equivalent result was obtained in ED-7R cells modified to express varying levels of γc. Collectively, these results confirm that signal transduction via the IL-15R, and hence NK ontogeny, is preferentially retained relative to the IL-7R as γc expression becomes limiting.

scholarly journals Identification and Computational Analysis of 3D-Structure Of MOCS1

2021 ◽  
Author(s):  
Maham Hamid ◽  
uzma habib ◽  
Javeria Batool ◽  
Arshemah Qaisar ◽  
Rehan Zafar Paracha
Keyword(s):  
Binding Sites ◽  
Biosynthetic Pathway ◽  
Computational Analysis ◽  
Tertiary Structure ◽  
3D Structure ◽  
Structure And Function ◽  
Molybdenum Cofactor ◽  
Recognition Method ◽  
And Function ◽  
Ramachandran Plots

Abstract Cyclic pyranopterin monophosphate (cPMP) is one of the most stable intermediates in Molybdenum cofactor (MoCo) biosynthetic pathway. In humans, synthesis of cPMP from Guanosine triphosphate (GTP) requires functional genes i.e. Molybdenum Cofactor Synthesis-1 (MOCS1) genes that contains for two catalytic proteins MOCS1A and MOCS1B. Importance of MOCS1A and MOCS1B for biosynthesis of MoCo reveals from the fact that its deficiency leads to MoCo type A deficiency. As there is no structure available for MOCS1 genes in the literature, tertiary structure of MOCS1 genes were investigated in this research via threading or folds recognition method by i-TASSER and validation was done using ERRAT, Verify3D and Ramachandran plots. Binding sites were predicted and validated. Docking of MOCS1A with GTP and MOCS1B with 3, 8 dihydroguanosine was done using Autodock via PyRx. Apart from this, highly confident mutations were also predicted using SIFT and polyphen2 that can alter the structure and function of MOCS1 gene.

scholarly journals Somatic Reversion of a Novel IL2RG Mutation Resulting in Atypical X-Linked Combined Immunodeficiency

Genes ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 35
Author(s):  
Yujuan Hou ◽  
Hans Peter Gratz ◽  
Guillermo Ureña-Bailén ◽  
Paul G. Gratz ◽  
Karin Schilbach-Stückle ◽  
...  
Keyword(s):  
Respiratory Infections ◽  
Functional Characterization ◽  
Severe Combined Immunodeficiency ◽  
Interleukin 2 ◽  
Combined Immunodeficiency ◽  
Gamma Chain ◽  
Normal Expression ◽  
Somatic Reversion ◽  
Atypical Scid ◽  
Il2rg Gene

Mutations of the IL2RG gene, which encodes for the interleukin-2 receptor common gamma chain (γC, CD132), can lead to X-linked severe combined immunodeficiency (X-SCID) associated with a T−B+NK− phenotype as a result of dysfunctional γC-JAK3-STAT5 signaling. Lately, hypomorphic mutations of the IL2RG gene have been described causing atypical SCID with a milder phenotype. Here, we report three brothers with low-normal lymphocyte counts and susceptibility to recurrent respiratory infections and cutaneous warts. The clinical presentation combined with dysgammaglobulinemia suspected an inherited immunity disorder, which has been proven by Next Generation Sequencing as a novel c.458T > C; p.Ile153Thr IL2RG missense-mutation. Subsequent functional characterization revealed impaired T-cell proliferation, low TREC levels and a skewed TCR Vβ repertoire in all three patients. Interestingly, investigation of various subpopulations showed normal expression of CD132 but with partially impaired STAT5 phosphorylation compared to healthy controls. Additionally, we performed precise genetic analysis of subpopulations revealing spontaneous somatic reversion, predominately in lymphoid derived CD3+, CD4+ and CD8+ T cells. Our data demonstrate that the atypical SCID phenotype noticed in these three brothers is due to the combination of hypomorphic IL-2RG function and somatic reversion.

scholarly journals The first patient reported with X-linked severe combined immunodeficiency in Peru

2020 ◽  
Author(s):  
Juan Carlos Aldave ◽  
Enrique Cachay ◽  
Guisela Alva ◽  
Mariela Milla ◽  
Joel Calero
Keyword(s):  
Family Background ◽  
Severe Combined Immunodeficiency ◽  
Pathogenic Mutation ◽  
Combined Immunodeficiency ◽  
Immune Disorder ◽  
Case Presentation ◽  
Novel Treatment ◽  
Patient Reported ◽  
Life Threatening ◽  
Il2rg Gene

Abstract Background X-linked severe combined immunodeficiency (X-SCID) is a life-threatening immune disorder caused by pathogenic mutations in the IL2RG gene. We report the first patient with genetically confirmed X-SCID in Peru. Case presentation Diagnosis was suspected before patient’s birth because of family history. At birth, blood immunophenotype was compatible with X-SCID and genetic analysis revealed a pathogenic mutation in IL2RG . Intravenous immunoglobulin and antibiotic prophylaxis were initiated until patient’s referral for an available novel treatment: gene therapy. Conclusions Family background is a key point to suspect X-SCID, allowing a timely diagnosis and treatment. X-SCID requires prompt immune reconstitution. However, HSCT is frequently not available to treat newborns in developing countries.

Conformation of Ribosomes from Escherichia Coli

1974 ◽  
Vol 32 ◽  
pp. 210-211
Author(s):  
M. Boublik ◽  
W. Hellmann ◽  
F. Jenkins
Keyword(s):  
Binding Sites ◽  
Ribosomal Proteins ◽  
Fluorescent Dyes ◽  
Protein Biosynthesis ◽  
Three Dimensional ◽  
Spatial Arrangement ◽  
Dimensional Structure ◽  
Complete Understanding ◽  
And Function

The present knowledge of the three-dimensional structure of ribosomes is far too limited to enable a complete understanding of the various roles which ribosomes play in protein biosynthesis. The spatial arrangement of proteins and ribonuclec acids in ribosomes can be analysed in many ways. Determination of binding sites for individual proteins on ribonuclec acid and locations of the mutual positions of proteins on the ribosome using labeling with fluorescent dyes, cross-linking reagents, neutron-diffraction or antibodies against ribosomal proteins seem to be most successful approaches. Structure and function of ribosomes can be correlated be depleting the complete ribosomes of some proteins to the functionally inactive core and by subsequent partial reconstitution in order to regain active ribosomal particles.

scholarly journals riboCIRC: a comprehensive database of translatable circRNAs

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Huihui Li ◽  
Mingzhe Xie ◽  
Yan Wang ◽  
Ludong Yang ◽  
Zhi Xie ◽  
...  
Keyword(s):  
De Novo ◽  
Species Conservation ◽  
Structure And Function ◽  
Research Community ◽  
Genome Browser ◽  
Valuable Resource ◽  
Sequence Structure ◽  
A Genome ◽  
Context Specific ◽  
And Function

AbstractriboCIRC is a translatome data-oriented circRNA database specifically designed for hosting, exploring, analyzing, and visualizing translatable circRNAs from multi-species. The database provides a comprehensive repository of computationally predicted ribosome-associated circRNAs; a manually curated collection of experimentally verified translated circRNAs; an evaluation of cross-species conservation of translatable circRNAs; a systematic de novo annotation of putative circRNA-encoded peptides, including sequence, structure, and function; and a genome browser to visualize the context-specific occupant footprints of circRNAs. It represents a valuable resource for the circRNA research community and is publicly available at http://www.ribocirc.com.

scholarly journals Development of Autologous, Oligoclonal, Poorly Functioning T Lymphocytes in a Patient With Autosomal Recessive Severe Combined Immunodeficiency Caused by Defects of the Jak3 Tyrosine Kinase

Blood ◽  
1998 ◽  
Vol 91 (3) ◽  
pp. 949-955 ◽  
Author(s):  
Duilio Brugnoni ◽  
Luigi D. Notarangelo ◽  
Alessandra Sottini ◽  
Paolo Airò ◽  
Marta Pennacchio ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Tyrosine Kinase ◽  
Cd4 T Cells ◽  
Severe Combined Immunodeficiency ◽  
Combined Immunodeficiency ◽  
T Helper ◽  
T Helper 1 ◽  
In Vitro Susceptibility ◽  
And Function

Abstract Defects of the common gamma chain subunit of the cytokine receptors (γc) or of Jak3, a tyrosine kinase required for γc signal transduction, result in T−B+ severe combined immunodeficiency (SCID). However, atypical cases, characterized by progressive development of T lymphocytes, have been also reported. We describe a child with SCID caused by Jak3 gene defects, which strongly but not completely affect Jak3 protein expression and function, who developed a substantial number (>3,000/μL) of autologous CD3+CD4+ T cells. These cells showed a primed/activated phenotype (CD45R0+ Fas+HLA-DR+ CD62Llo), defective secretion of T-helper 1 and T-helper 2 cytokines, reduced proliferation to mitogens, and a high in vitro susceptibility to spontaneous (caused by downregulation of bcl-2 expression) as well as activation-induced cell death. A restricted T-cell receptor repertoire was observed, with oligoclonal expansion within each of the dominant segments. These features resemble those observed in γc-/y and in Jak3−/−mice, in which a population of activated, anergic T cells (predominantly CD4+) also develops with age. These results suggest that residual Jak3 expression and function or other Jak3-independent signals may also permit the generation of CD4+ T cells that undergo in vivo clonal expansion in humans; however, these mechanisms do not allow development of CD8+ T cells, nor do they fully restore the functional properties of CD4+ T lymphocytes.

A naturally occurring Tyr143HisαIIb mutation abolishes αIIbβ3 function for soluble ligands but retains its ability for mediating cell adhesion and clot retraction: comparison with other mutations causing ligand-binding defects

Blood ◽  
2003 ◽  
Vol 101 (9) ◽  
pp. 3485-3491 ◽  
Author(s):  
Teruo Kiyoi ◽  
Yoshiaki Tomiyama ◽  
Shigenori Honda ◽  
Seiji Tadokoro ◽  
Morio Arai ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Ligand Binding ◽  
Binding Sites ◽  
Clot Retraction ◽  
Naturally Occurring ◽  
Binding Function ◽  
293 Cells ◽  
Ligand Binding Sites ◽  
Functional Defect ◽  
And Function

The molecular basis for the interaction between a prototypic non–I-domain integrin, αIIbβ3, and its ligands remains to be determined. In this study, we have characterized a novel missense mutation (Tyr143His) in αIIb associated with a variant of Glanzmann thrombasthenia. Osaka-12 platelets expressed a substantial amount of αIIbβ3(36%-41% of control) but failed to bind soluble ligands, including a high-affinity αIIbβ3-specific peptidomimetic antagonist. Sequence analysis revealed that Osaka-12 is a compound heterozygote for a single 521T>C substitution leading to a Tyr143His substitution in αIIb and for the null expression of αIIb mRNA from the maternal allele. Given that Tyr143 is located in the W3 4-1 loop of the β-propeller domain of αIIb, we examined the effects of Tyr143His or Tyr143Ala substitution on the expression and function of αIIbβ3 and compared them with KO (Arg-Thr insertion between 160 and 161 residues of αIIb) and with the Asp163Ala mutation located in the same loop by using 293 cells. Each of them abolished the binding function of αIIbβ3 for soluble ligands without disturbing αIIbβ3 expression. Because immobilized fibrinogen and fibrin are higher affinity/avidity ligands for αIIbβ3, we performed cell adhesion and clot retraction assays. In sharp contrast to KO mutation and Asp163AlaαIIbβ3, Tyr143HisαIIbβ3-expressing cells still had some ability for cell adhesion and clot retraction. Thus, the functional defect induced by Tyr143HisαIIb is likely caused by its allosteric effect rather than by a defect in the ligand-binding site itself. These detailed structure–function analyses provide better understanding of the ligand-binding sites in integrins.

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