Which of the following genetic defects characterizes β-thalassemia major?
A. Point mutations or deletions in the β-globin gene leading to absent or severely reduced β-globin chain synthesis
B. Mutation in the α-globin gene resulting in chain termination
C. Deficiency of the enzyme heme synthase
D. Deletion of the entire β-globin gene cluster
Explanation
Genetic Basis of β-Thalassemia Major
Key Point
β-thalassemia major results from homozygous or compound heterozygous mutations in the β-globin gene on chromosome 11, leading to absent or severe reduction in β-globin chain production.
Molecular Defects
The mutations in β-thalassemia major include:
Point mutations — most common; affect transcription, translation, or splicing
Deletions — variable size; remove part or all of the β-globin gene
Insertions — less common; disrupt the reading frame
High-YieldNEET PG
In β-thalassemia major, both alleles are mutated (homozygous or compound heterozygous), resulting in absent or <10% normal β-globin production.
Pathophysiology
1.
Severe reduction in β-globin chains
2.
Excess α-globin chains precipitate → hemolysis
3.
Ineffective erythropoiesis and hemolytic anemia
4.
Extramedullary hematopoiesis and iron overload
Clinical Pearl
β-thalassemia trait (heterozygous) shows mild anemia with target cells and normal or elevated RBC count; β-thalassemia major presents in infancy with severe hemolytic anemia requiring transfusion.
Differential Genetic Defects
Table
Feature
β-Thalassemia Major
α-Thalassemia
Hereditary Persistence of HbF
Gene affected
β-globin (Chr 11)
α-globin (Chr 16)
γ-globin regulation
Inheritance
Autosomal recessive
Autosomal recessive
Autosomal dominant
Severity
Severe (homozygous)
Varies with # deletions
Benign
Robbins 10e Ch 12
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