The primary defect which leads to sickle cell anemia is –
Sickle cell anemia                                                             

Sickle cell anemia is a hereditary hemoglobinopathy, i.e. the type of disease characterized by the production of defective hemoglobin.

Normal hemoglobin

The hemoglobin molecule is an assembly of four globular protein.
Each subunit is composed of a protein part, i.e, globin and a nonprotein part, i.e. heme, i.e. Each hemoglobin molecule contain four heme units and two pairs of a similar protein, globin.
The heme part of the globular protein is same in all types of hemoglobin.
The protein part vary in different hemoglobin -


Adult hemoglobin (Hemoglobin A) consists of two identical α-chains and two identical δ-chains.
Fetal hemoglobin (HbF) consists of two identical a-chains and two identical γ chains.
Minor hemoglobin (HbA,) consists of two identical a-chains and two identical δ chains.


Normally adult blood contains about 96% of HbA (α2 β2) 3-3.5% HbA2(α2 δ2), and small amount of fetal hemoglobin HbF (α2 γ2).

Defect in sickle cell anemia 

Sickle cell anemia results from a mutation in β-globin gene.
It is caused by a point mutation at the sixth position of the β-globin chain leading to a substation of a valine residue for a glutamic acid residue. resulting in sickle hemoglobin (HbS).
Sickle cell anemia is an autosomal recessive disorder.
If an individual is homozygous for the sickle cell mutation, almost all the hemoglobin in the red cell is HbS.
In heterozygotes, only about 40% of the hemoglobin is HbS, the remainder being normal hemoglobins.
An abnormality in porphyrin part of hemoglobin
Replacement of glutamate by valine in β–chain of HbA
A nonsence mutation in the β chain of HbA
Substitution of valine by glutamate in the a–chain of HbA