THALASSEMIA -HISTORY AND GENETICS

1.  What is Thalassemia?
It is an AUTOSOMAL RECESSIVE disorder characterized by specific morphological features with ineffective erythropoiesis and extensive hemolysis due to defect in globin chain synthesis.
 
2.  What does word Thalassemia mean?
Thalassemia is derieved from Greek word which means great sea as it was first described around the area of Mediterranean sea.

Thus it is also known Mediterranean anemia.
 
3.   Cooley and Lee were first to describe the disease thus it is also known as Cooley’s anemia.
 
4.  What is Malaria hypothesis?
It is a hypothesis that suggests the thalassemia syndromes to be a protective evolution against malarial parasites.

There are no exact well understood mechanisms but there are various hypothesis.
·        Some believe that the growth impairment of malarial parasites in beta thalassemia is due to the protective effect of HbF.
·        Some believe that the defective Hbs in thalssemia are rapidly hemolysed in spleen which happen to be infected by parasite that ultimately leads to the death of parasites.
·        There are also hypothesis that the defective RBCs in thalassemia cannot stick to other RBCs for rosette formation which is an important pathophysiological event leading to cerebral malaria.
·        The malarial parasites may be incapable of obtaining nutrition from diseased Hemoglobin.
·        Also the RBCs in thalassemia patients promote enhanced binding of antibody against parasite.

        Kindly refer to blog of Hemoglobin structure (click here) for better                       understanding.

A    Alpha thalassemia is believed to have more protective role.

 
5.  GENETICS
 As discussed earlier the genes for beta like clusters at located at chromosome 11 and for alpha like clusters at chromosome 16.

 More than 200 different mutations are identified out of which 20 are common mutations and others are rare.

·       β like cluster of includes five genes, δ (HBD), β (HBB), ε (HBE), Gγ (HBG2), and Aγ (HBG1)
 
·       α like cluster of genes include α gene, zeta  genes.
 
As we know each Hb molecule contains 2α globin chains for which 4 genes are present i.e. 2 in each chromosomes.
 
But for 2β globin chains there only 2 genes.
 
 For β thalassemia the most common abnormality leading to disease is mutation of gene that leads to abnormality of protein synthesis.

A    Deletion of beta gene is rare.

 
For α thalassemia the most common abnormality is deletion of gene rather than mutation.
 
Inheritance of Genes Inherited by autosomal recessive pattern
 
·        If the child inherits one normal and one abnormal gene from each parent, child will have no disease (carrier/ minor)
·        If both parents are carriers, i.e. thalassemia minor (single gene affected), there is a 1 in 4 (25%) chance of having a thalassemia major child in each pregnancy.
 
 

In each chromosomal DNA are coding area and non-coding area.

 The coding region transcribes to form protein and the non coding region helps the protein synthesis.

 Similarly in thalassemia there are coding regions and the noncoding regions which include
·        Promoter elements
·        Enhancer and silencer elements
·        Locus control region which acts as a master switch.
 

Absence or mutation in any of the above components can lead to defective protein synthesis leading to thalassemia syndromes

6. What are the common genes associated with mutation in β thalassemia?

·        619 bp deletion
·        IVS 1-5(G-C)
·        IVS 1-1(G-T)
·        FS (8/9) (+G)
·        FS(41/42) (-CTTT)
 
 
7.  What is BCL11a?
BCL11a, a transcription factor that in erythroblasts binds near the gamma globin locus and has the net effect of shutting down gamma globin synthesis in postnatal life.
 
In animal models, blockade of BCL11a leads to high level of HbF production. Since partial persistence of HbF correlates with milder disease in beta chain hemoglobinopathies, therapeutic inhibition of BCL11a offers an appealing therapeutic target.

 GOOD TO KNOW
 
·        GATA-1 mutations and beta thalassemia — GATA-1 is a transcription factor on the X chromosome that is important for activating many genes during erythropoiesis, including globin genes. In rare cases defect in cofactor of GATA1 known as Fog-1  has been associated with beta thalassemia in conjunction with thrombocytopenia and dyserythropoietic anemia.
 
·        ATRX mutations and alpha thalassemia — Mutations affecting the ATRX gene on the X chromosome are associated with the alpha thalassemia/mental retardation syndrome.
 
·        The defect gene encoding the transcription factor TFIIH can lead to beta thalassemia trait along with xeroderma pigmentosum  and tricothiodystrophy.