scholarly journals The genetic basis and evolution of red blood cell sickling in deer

2017 ◽  
Author(s):  
Alexander Esin ◽  
L. Therese Bergendahl ◽  
Vincent Savolainen ◽  
Joseph A. Marsh ◽  
Tobias Warnecke
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Genetic Basis ◽  
Balancing Selection ◽  
Incomplete Lineage Sorting ◽  
Alpha Helix ◽  
Cell Disease ◽  
Lineage Sorting ◽  
Deer Species ◽  
Erythrocyte Sickling

Crescent-shaped red blood cells, the hallmark of sickle cell disease, present a striking departure from the biconcave disc shape normally found in mammals. Characterized by increased mechanical fragility, sickled cells promote haemolytic anaemia and vaso-occlusions and contribute directly to disease in humans. Remarkably, a similar sickle-shaped morphology has been observed in erythrocytes from several deer species, without pathological consequences. The genetic basis of erythrocyte sickling in deer, however, remains unknown, limiting the utility of deer as comparative models for sickling. Here, we determine the sequences of human β-globin orthologs in 15 deer species and identify a set of co-evolving, structurally related residues that distinguish sickling from non-sickling deer. Protein structural modelling indicates a sickling mechanism distinct from human sickle cell disease, coordinated by a derived valine (E22V) in the second alpha helix of the β-globin protein. The evolutionary history of deer β-globins is characterized by incomplete lineage sorting, episodes of gene conversion between adult and foetal β-globin paralogs, and the presence of a trans-species polymorphism that is best explained by long-term balancing selection, suggesting that sickling in deer is adaptive. Our results reveal structural and evolutionary parallels and differences in erythrocyte sickling between human and deer, with implications for understanding the ecological regimes and molecular architectures that favour the evolution of this dramatic change in erythrocyte shape.

scholarly journals Renal complications of sickle cell disease

2021 ◽  
Vol 7 (1) ◽  
pp. e20-e20
Author(s):  
Sara Bahadoram ◽  
Bijan Keikhaei ◽  
Mohammad Bahadoram ◽  
Mohammad-Reza Mahmoudian-Sani ◽  
Shakiba Hassanzadeh
Keyword(s):  
Sickle Cell Disease ◽  
Reperfusion Injury ◽  
Sickle Cell ◽  
Cell Disease ◽  
Renal Complications ◽  
Erythrocyte Sickling

The nephropathy and renal complications of sickle cell disease are associated with various events such as hypoxic or ischemic conditions and reperfusion injury. Erythrocyte sickling occurs following these events and renal medullary acidosis.

scholarly journals Is There a Genetic Basis to Stroke in Children with Sickle Cell Disease?† 773

1998 ◽  
Vol 43 ◽  
pp. 134-134
Author(s):  
Allison A King ◽  
Linda Resar ◽  
Eliot Vichinsky ◽  
Charles Pegelow ◽  
J Paul Scott ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Genetic Basis ◽  
Cell Disease

scholarly journals Non-hematopoietic deficiency of proprotein convertase subtilisin/kexin type 9 deficiency leads to more severe anemia in a murine model of sickle cell disease

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
J. Venugopal ◽  
J. Wang ◽  
C. Guo ◽  
H. Lu ◽  
Y. E. Chen ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Ex Vivo ◽  
Vascular Complications ◽  
Lipid Lowering ◽  
Cell Disease ◽  
Proprotein Convertase ◽  
Beneficial Effects ◽  
Cholesterol Levels ◽  
Erythrocyte Sickling

Abstract Proprotein convertase subtilisin/kexin type 9 (PCSK9) deficiency leads to lower cholesterol and is associated with reduced vascular complications in the general population. Cholesterol lowering may also have beneficial effects in sickle cell disease (SCD). The objective of this study was to determine effects of PCSK9 deficiency in a mouse model of SCD. Bone marrow transplantation (BMT) was performed from donor SCD mice to wild-type, PCSK9-deficient, and LDLR-deficient recipients to generate SCD controls (Pcsk9+/+, SCDbmt) with preserved PCSK9 status, SCD mice with deficiency of PCSK9 (Pcsk9−/−, SCDbmt), and SCD mice with deficiency of LDLR (Ldlr−/−, SCDbmt). Although cholesterol levels were lower in Pcsk9−/−, SCDbmt mice compared to Pcsk9+/+, SCDbmt mice, anemia was more severe in Pcsk9−/−, SCDbmt mice. Increased reticulocytosis, enhanced ex vivo erythrocyte sickling, and increased erythrocyte phosphatidylserine exposure was also observed. Livers, spleens, and kidneys contained increased iron in Pcsk9−/−, SCDbmt mice compared to Pcsk9+/+, SCDbmt mice consistent with greater hemolysis. SCD mice with deficiency of LDLR (Ldlr−/−, SCDbmt mice) had similar anemia as Ldlr+/+, SCDbmt mice despite higher serum cholesterol. In conclusion, deficiency of PCSK9 is associated with worsened anemia in SCD mice due to increased hemolysis. These findings may have implications for lipid-lowering strategies in patients with SCD, as well as for potential novel modifiers of anemia severity.

Sickle Cell Disease

2015 ◽  
Author(s):  
Caroline Freiermuth ◽  
Idan Cudykier
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Blood Cells ◽  
Genetic Basis ◽  
Globin Gene ◽  
The United States ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
The Past ◽  
Pain Medications

Sickle cell disease affects between 70,000 and 90,000 individuals in the United States, the majority of whom are of African-American descent. The genetic basis of the disease is an abnormality in the β-globin gene, which causes the red blood cells to change to a “sickle” shape due to low oxygenation. The life span of patients with this disease has improved over the past few decades, although morbidity remains high. This review covers the pathophysiology of sickle cell disease and the stabilization and assessment, diagnosis and treatment, maintenance and preventive therapies, and cure of patients with sickle cell disease. Figures show hemoglobin electrophoresis; age at death for individuals with sickle cell disease in the years 1979, 1989, 1999, and 2006; sickled cells blocking blood flow; acute chest syndrome; dactylitis; and avascular necrosis. Tables list important trials, topics in need of further research, common complications, most common intravenous pain medications, and indications for transfusion. This review contains 6 highly rendered figures, 5 tables, 97 references, and a list of educational resources.

scholarly journals P-selectin deficiency promotes liver senescence in sickle cell disease mice

Blood ◽  
2021 ◽  
Author(s):  
Ravi Vats ◽  
Tomasz W Kaminski ◽  
Eun-Mi Ju ◽  
Tomasz Brzoska ◽  
Egemen Tutuncuoglu ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Globin Gene ◽  
Homozygous Mutation ◽  
Epithelial Cell Proliferation ◽  
Cell Disease ◽  
Long Term Effects ◽  
Chronic Effect ◽  
Erythrocyte Sickling

Sickle cell disease (SCD) is caused by a homozygous mutation in the β-globin gene, which leads to erythrocyte sickling, vaso-occlusion, and intense hemolysis. P-selectin inhibition has been shown to prevent vaso-occlusive events in SCD patients, however, the chronic effect of P-selectin inhibition in SCD remains to be determined. Here, we used quantitative liver intravital microscopy in our recently generated P-selectin deficient SCD mice to show that chronic P-selectin deficiency attenuates liver ischemia, but fails to prevent hepatobiliary injury. Remarkably, we find that this failure in resolution of hepatobiliary injury in P-selectin deficient SCD mice is associated with the increase in cellular senescence and reduced epithelial cell proliferation in the liver. These findings highlight the importance to investigate the long-term effects of chronic P-selectin inhibition therapy on liver pathophysiology in SCD patients.

scholarly journals The Association ofCD81Polymorphisms with Alloimmunization in Sickle Cell Disease

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Zohreh Tatari-Calderone ◽  
Ryad Tamouza ◽  
Gama P. Le Bouder ◽  
Ramita Dewan ◽  
Naomi L. C. Luban ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Genetic Basis ◽  
Strong Association ◽  
Predictive Biomarkers ◽  
Nucleotide Polymorphisms ◽  
Cell Disease ◽  
Single Nucleotide ◽  
Patients At Risk ◽  
Shed Light

The goal of the present work was to identify the candidate genetic markers predictive of alloimmunization in sickle cell disease (SCD). Red blood cell (RBC) transfusion is indicated for acute treatment, prevention, and abrogation of some complications of SCD. A well-known consequence of multiple RBC transfusions is alloimmunization. Given that a subset of SCD patients develop multiple RBC allo-/autoantibodies, while others do not in a similar multiple transfusional setting, we investigated a possible genetic basis for alloimmunization. Biomarker(s) which predicts (predict) susceptibility to alloimmunization could identify patients at risk before the onset of a transfusion program and thus may have important implications for clinical management. In addition, such markers could shed light on the mechanism(s) underlying alloimmunization. We genotyped 27 single nucleotide polymorphisms (SNPs) in theCD81,CHRNA10,andARHGgenes in two groups of SCD patients. One group (35) of patients developed alloantibodies, and another (40) had no alloantibodies despite having received multiple transfusions. Two SNPs in theCD81gene, that encodes molecule involved in the signal modulation of B lymphocytes, show a strong association with alloimmunization. If confirmed in prospective studies with larger cohorts, the two SNPs identified in this retrospective study could serve as predictive biomarkers for alloimmunization.

scholarly journals Minireview: Genetic basis of heterogeneity and severity in sickle cell disease

2016 ◽  
Vol 241 (7) ◽  
pp. 689-696 ◽  
Author(s):  
Alawi Habara ◽  
Martin H Steinberg
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Genetic Basis ◽  
Cell Disease
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