From the Guidelines
The amino acid substitution in sickle cell disease is a glutamic acid to valine substitution at codon 6 of the beta globin gene. This substitution is a result of a C to A substitution at codon 6 of the beta globin gene, leading to the formation of abnormal haemoglobin, HbS 1. The abnormal beta globin gene (ßs) is characterized by the replacement of glutamic acid by valine, resulting in the formation of HbS (a2 ßs2) 1.
Key Points
- The genetic mutation in HbS is a point mutation, where a single nucleotide substitution leads to the replacement of glutamic acid by valine 1.
- The severity of sickle cell disease varies according to genotype, with HbSS, HbSß0-thalassaemia, and HbSD disease being associated with severe disease 1.
- Fetal haemoglobin (HbF) reduces the polymerisation of the HbS molecules and offers some protection in sickle cell disease, with patients having high HbF levels (> 8%) tend to have mild phenotype with fewer symptoms 1.
Clinical Implications
The amino acid substitution in sickle cell disease has significant clinical implications, including the formation of abnormal haemoglobin, HbS, which can lead to vascular occlusion and other complications 1. Understanding the genetic mutation underlying sickle cell disease is essential for the development of effective management strategies, including the use of hydroxycarbamide to raise HbF levels and reduce the severity of the disease 1.
From the Research
Amino Acid Substitution in Sickle Cell Disease
- The amino acid substitution in sickle cell disease is a result of a point mutation in the β globin gene, where glutamic acid is replaced by valine at the sixth position of the β globin chain 2, 3, 4, 5, 6.
- This substitution leads to the formation of sickle hemoglobin (HbS), which is characterized by abnormal blood rheology and periods of painful vascular occlusive crises 2.
- The substitution of glutamic acid with valine results in a hydrophobic site on the outside of the HbS β chain, which interacts with other amino acid residues to form a HbS polymer that deforms the red blood cell and causes vaso-occlusive crisis 6.
- The specific substitution is due to a mutation where the codon for glutamic acid (GAA) is replaced by the codon for valine (GTA) 3, 6.
Molecular Mechanism
- The molecular mechanism of sickle cell disease involves the polymerization of deoxy-HbS, which is triggered by the substitution of glutamic acid with valine 4.
- The polymerization of HbS leads to the formation of sickle-shaped red blood cells, which can cause vaso-occlusive crises and other complications of the disease 5.
- The interaction between valine and glucose on the HbS molecule may also contribute to the destabilization of the red blood cell cytoskeleton and the development of sickle cell crises 4.