scholarly journals A Mathematical Graph-Theoretic Model of Single Point Mutations Associated with Sickle Cell Anemia Disease

2021 ◽  
Vol 9 ◽  
pp. 1-14
Author(s):  
Edem K. Netsey ◽  
Dr. samuel Kakraba ◽  
Samuel M. Naandam ◽  
Aayire C. Yadem
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Single Point ◽  
Point Mutations ◽  
Sub Saharan Africa ◽  
Single Point Mutation ◽  
Theoretic Model ◽  
Related Disorder ◽  
Graph Theoretic ◽  
Single Point Mutations

Many diseases like cystic fibrosis and sickle cell anemia disease (SCD), among others, arise from single point mutations in the respective proteins. How a single point mutation might lead to a global devastating consequence on a protein remains an intellectual mystery. SCD is a genetic blood-related disorder resulting from mutations in the beta chain of the human hemoglobin protein (simply, β-globin), subsequently affecting the entire human body. Higher mortality and morbidity rates have been reported for patients with SCD, especially in sub-Saharan Africa. Clinical management of SCD often requires specialized interdisciplinary clinicians. SCD presents a major global burden, hence an improved understanding of how single point mutations in β-globin results in different phenotypes of SCD might offer insight into protein engineering, with potential therapeutic intervention in view. By use of mathematical modeling, we built a hierarchical (nested) graph-theoretic model for the β-globin. Subsequently, we quantified the network of interacting amino acid residues, representing them as molecular system of three distinct stages (levels) of interactions. Using our nested graph model, we studied the effect of virtual single point mutations in β-globin that results in varying phenotypes of SCD, visualized by unsupervised machine learning algorithm, the dendrogram.

scholarly journals A graph-theoretic model of single point mutations in the cystic fibrosis transmembrane conductance regulator

2016 ◽  
Vol 6 (1) ◽  
pp. 780-786
Author(s):  
Samuel Kakraba ◽  
Debra Knisley
Keyword(s):  
Cystic Fibrosis ◽  
Single Point ◽  
Point Mutations ◽  
Nucleotide Binding ◽  
Theoretic Model ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Graph Theoretic ◽  
Single Point Mutations ◽  
Cystic Fibrosis Transmembrane

Cystic fibrosis is one of the most prevalent inherited diseases. This disease is caused by a mutation in a membrane protein, the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is known to function as a chloride channel that regulates the viscosity of mucus that lines the ducts of a number of organs. The most prevalent mutation of CFTR is located in one of two nucleotide binding domains, namely, the nucleotide binding domain one (NBD1). However, some mutations in nucleotide binding domain two (NBD2) can equally cause cystic fibrosis. In this work, a graph-theoretic model is built for NBD2. Using this model for NBD2, we examine the consequences of single point mutations on NBD2. We collate the wildtype structure with eight of the most prevalent mutations and observe how the NBD2 is affected by each of these mutations.  

scholarly journals Sickling Cells, Cyclic Nucleotides, and Protein Kinases: The Pathophysiology of Urogenital Disorders in Sickle Cell Anemia

Anemia ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Mário Angelo Claudino ◽  
Kleber Yotsumoto Fertrin
Keyword(s):  
Protein Kinases ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Cyclic Nucleotides ◽  
Single Point ◽  
Clinical Manifestations ◽  
Single Point Mutation ◽  
Tract Infections

Sickle cell anemia is one of the best studied inherited diseases, and despite being caused by a single point mutation in theHBBgene, multiple pleiotropic effects of the abnormal hemoglobin S production range from vaso-occlusive crisis, stroke, and pulmonary hypertension to osteonecrosis and leg ulcers. Urogenital function is not spared, and although priapism is most frequently remembered, other related clinical manifestations have been described, such as nocturia, enuresis, increased frequence of lower urinary tract infections, urinary incontinence, hypogonadism, and testicular infarction. Studies on sickle cell vaso-occlusion and priapism using bothin vitroandin vivomodels have shed light on the pathogenesis of some of these events. The authors review what is known about the deleterious effects of sickling on the genitourinary tract and how the role of cyclic nucleotides signaling and protein kinases may help understand the pathophysiology underlying these manifestations and develop novel therapies in the setting of urogenital disorders in sickle cell disease.

Glanzmann Mutations : New Allelic Variants and Role of the β3 Lys253 in the αIIb/β3 Interaction Highlighted by the Lys253Met Substitution.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1312-1312
Author(s):  
Vincent Jallu ◽  
Alexandre De Brevern ◽  
Simon Panzer ◽  
Marie-Francoise Torchet ◽  
Cecile Kaplan-Gouet
Keyword(s):  
Rna Processing ◽  
Conflicts Of Interest ◽  
Single Point ◽  
Point Mutations ◽  
Single Point Mutation ◽  
Platelet Surface ◽  
Cos Cells ◽  
Single Point Mutations ◽  
Complex Expression

Abstract Abstract 1312 Poster Board I-336 Introduction Glanzmann thrombasthenia (GT) is an autosomal recessive inherited bleeding disorder characterized by an impaired platelet aggregation. GT results from defects of the platelet fibrinogen receptor αIIbβ3. GT mutations provide useful tools for structure-function relationship studies of αIIbβ3. Patient and methods Genomic DNA from 6 patients has been amplified for αIIb and β3 promoters and exons sequences. PCR products were directly sequenced. Potential RNA processing alterations have been studied in silico by using Genscan, NNSPLICE and ESEFinder online tools. When no RNA splicing anomaly was predicted, the effect of single point mutation on αIIbβ3 expression has been studied by using transiently transfected Cos cells. Finally, structural consequences of amino acid substitutions has been studied using the published model of αIIbβ3 (code PDB 2VDL) and structural modelling. Results 7 new mutations have been characterized. 1 deletion / insertion, 2 single point mutations inducing stop codon and 1 resulting in splicing site disruption were identified. The 3 last identified single point mutations were not predicted to affect normal RNA processing but has been shown to prevent normal expression of mutant αIIbβ3 at the surface of Cos cells. The p.Meth118Arg and p.Gly221Asp substitutions that induce both important steric hindrance and charge modifications, are located inside the β-I domain of β3. So they should deeply alter the proper folding of the β-I domain, preventing the complex expression at the platelet surface. On the other hand, the p.Lys253Met protrudes from the β-I domain toward the αIIb β-propeller. A structural model of the Met253 β-I mutant has been done. An estimation of the direct electrostatic and desolvation free energies of interaction between the β-I domain surface and the αIIb β-propeller indicated that rather than the presence of a methionine, it is the lost of the Lys253 which is responsible for the complex expression defect. Conclusion Seven new GT mutations have been identified and the p.Lys253Met substitution helped to define a key role of the Lys253 in the αIIb β-propeller / β3 β-I domains interaction. Disclosures No relevant conflicts of interest to declare.

Competitive assay to improve the specificity of detection of single-point mutations in alpha 1-antitrypsin deficiency

1993 ◽  
Vol 39 (10) ◽  
pp. 2157-2162 ◽  
Author(s):  
A Gunneberg ◽  
G Scobie ◽  
K Hayes ◽  
N Kalsheker
Keyword(s):  
Signal To Noise Ratio ◽  
Single Point ◽  
Point Mutations ◽  
Base Substitution ◽  
Single Point Mutation ◽  
Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Single Point Mutations ◽  
Alpha 1 Antitrypsin ◽  
Lower Temperature

Abstract Allele-specific oligonucleotides are used widely for the detection of single point mutations in genes. A modification of this assay based on competition has been developed for detection of the Z mutation of alpha 1-antitrypsin (alpha 1-AT). The normal alpha 1-AT allele is referred to as M, and the Z mutation arises from a single base substitution. Amplified DNA products corresponding to homozygous M, heterozygous MZ, and homozygous Z obtained by the polymerase chain reaction were incubated with a twofold molar excess of unlabeled oligonucleotide prior to hybridization with a radiolabeled oligonucleotide. Thus, initial incubation with unlabeled M-specific oligonucleotide was followed by hybridization with radiolabeled Z-specific oligonucleotide, and vice versa. This assay increased the specificity of single-point mutation detection three- to four-fold. Furthermore, specific hybridization was obtained at a lower temperature as a consequence of improving the signal-to-noise ratio.

scholarly journals Concurrent Sickle Cell Anemia and Diabetes Mellitus with Ketosis in a Libyan Toddler: First National Report and Youngest Case Study

2020 ◽  
pp. 15-19
Author(s):  
Moftah Alhagamhmad ◽  
Alia Alhassony ◽  
Abdulhamid . ◽  
Aisha Elarwah ◽  
Shirin Alougly ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Glucose Tolerance ◽  
Impaired Glucose Tolerance ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Chronic Condition ◽  
Single Point ◽  
Growth Delay ◽  
Single Point Mutation

Sickle cell Anemia (SCA) is a common inherited haemoglobinopathy resulting from a single-point mutation on the β-globin subunit of hemoglobin. It is a chronic condition with multi-system involvement. Growth delay, osteopenia and hypogonadism are common endocrine dysfunctions with a lower frequency of impaired glucose tolerance. However, there is an association between SCA and diabetes mellitus (DM), though it is very rare. Certainly, there are only a few published reports worldwide outlined this uncommon combination. In this report, we will present the first Libyan case study of co-existence of the two diseases in a-16-month-old male toddler recording the youngest patient diagnosed with such a rare combination. The child, who was diagnosed earlier with SCA, brought with concerns of frequent changing nappies (polyuria) and excessive thirst (polydipsia) for 2 weeks that worsened recently. On admission, the toddler was distressed, lethargic and his lab parameters showed hyperglycemia, ketonuria, glycosuria and acidosis, a diagnosis of diabetic ketoacidosis (DKA) on the background of SCA therefore was made. Further observations are warranted to properly guide about the diagnosis and management of such rare cases.

scholarly journals Sickle Cell Anemia: A review on the most severe form of Sickle Cell Disease

Bionatura ◽  
2019 ◽  
Vol 02 (Bionatura Conference Serie) ◽  
Author(s):  
María Belén Paredes ◽  
María Eugenia Sulen
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Globin Gene ◽  
Single Point ◽  
Clinical Manifestations ◽  
Severe Form ◽  
Single Point Mutation ◽  
Cell Disease ◽  
Hemoglobin S

Sickle cell disease (SCD) is a group of hereditary disorders caused by a single point mutation in the β-globin gene. This mutation results in the formation of a mutated hemoglobin S (HbS) and the consequent sickle phenotype of erythrocytes. SCD is common in regions of malaria endemicity. However, changes in population dynamics enabled the movement of the mutated gene to other areas such as North America and Europe. Sickle cell anemia (SCA) is the most severe form of SCD and affects millions of people around the globe. The clinical manifestations of SCA arise primarily from the polymerization of deoxygenated hemoglobin S (deoxyHbS) leading to vascular occlusion and hemolytic anemia. Clinical complications of the disease are derived from deoxyHbS polymerization, but there are several therapeutic strategies to reduce the severity of the symptoms. Gene therapy has arisen as a new therapeutic approach aimed to cure rather than to treat the symptomatology of SCA by targeting the altered β-globin gene for gene correction.

scholarly journals Single-point mutation detection in RNA extracts using gold nanoparticles modified with hydrophobic molecular beacon-like structures

2014 ◽  
Vol 50 (23) ◽  
pp. 3018-3020 ◽  
Author(s):  
Alfonso Latorre ◽  
Christian Posch ◽  
Yolanda Garcimartín ◽  
Susana Ortiz-Urda ◽  
Álvaro Somoza
Keyword(s):  
Gold Nanoparticles ◽  
Point Mutation ◽  
Mutation Detection ◽  
Molecular Beacon ◽  
Single Point ◽  
Point Mutations ◽  
Single Point Mutation ◽  
Target Sequence ◽  
Cholesterol Derivative ◽  
Single Point Mutations

The functionalization of gold nanoparticles with a cholesterol derivative affords a sensor that is able to detect single-point mutations. The solubility of the nanoparticles is modulated by the presence of the target sequence inducing its aggregation.

Cupin Variants as Macromolecular Ligand Library for Stereoselective Michael Addition of Nitroalkanes

2019 ◽  
Author(s):  
Nobutaka Fujieda ◽  
Miho Yuasa ◽  
Yosuke Nishikawa ◽  
Genji Kurisu ◽  
Shinobu Itoh ◽  
...  
Keyword(s):  
Michael Addition ◽  
In Silico ◽  
Addition Reaction ◽  
Single Point ◽  
Point Mutations ◽  
Unsaturated Ketone ◽  
Michael Addition Reaction ◽  
Beta Barrel ◽  
Cupin Superfamily ◽  
Single Point Mutations

Cupin superfamily proteins (TM1459) work as a macromolecular ligand framework with a double-stranded beta-barrel structure ligating to a Cu ion through histidine side chains. Variegating the first coordination sphere of TM1459 revealed that H52A and H54A/H58A mutants effectively catalyzed the diastereo- and enantio-selective Michael addition reaction of nitroalkanes to an α,β-unsaturated ketone. Moreover, in silico substrate docking signified C106N and F104W single-point mutations, which inverted the diastereoselectivity of H52A and further improved the stereoselectivity of H54A/H58A, respectively.

Single-Point Mutations in Qβ Virus-like Particles Change Binding to Cells

2021 ◽  
Author(s):  
Marisa L. Martino ◽  
Stephen N. Crooke ◽  
Marianne Manchester ◽  
M.G. Finn
Keyword(s):  
Single Point ◽  
Point Mutations ◽  
Virus Like Particles ◽  
Single Point Mutations

MinD directly interacting with FtsZ at the H10 helix suggests a model for robust activation of MinC to destabilize FtsZ polymers

2017 ◽  
Vol 474 (18) ◽  
pp. 3189-3205 ◽  
Author(s):  
Ashoka Chary Taviti ◽  
Tushar Kant Beuria
Keyword(s):  
Cell Division ◽  
Single Point ◽  
Point Mutations ◽  
Direct Interaction ◽  
Ring Formation ◽  
Z Ring ◽  
Single Point Mutations ◽  
Biochemical Analyses ◽  
Ftsz Assembly ◽  
The Mind

Cell division in bacteria is a highly controlled and regulated process. FtsZ, a bacterial cytoskeletal protein, forms a ring-like structure known as the Z-ring and recruits more than a dozen other cell division proteins. The Min system oscillates between the poles and inhibits the Z-ring formation at the poles by perturbing FtsZ assembly. This leads to an increase in the FtsZ concentration at the mid-cell and helps in Z-ring positioning. MinC, the effector protein, interferes with Z-ring formation through two different mechanisms mediated by its two domains with the help of MinD. However, the mechanism by which MinD triggers MinC activity is not yet known. We showed that MinD directly interacts with FtsZ with an affinity stronger than the reported MinC–FtsZ interaction. We determined the MinD-binding site of FtsZ using computational, mutational and biochemical analyses. Our study showed that MinD binds to the H10 helix of FtsZ. Single-point mutations at the charged residues in the H10 helix resulted in a decrease in the FtsZ affinity towards MinD. Based on our findings, we propose a novel model for MinCD–FtsZ interaction, where MinD through its direct interaction with FtsZ would trigger MinC activity to inhibit FtsZ functions.

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