Thalassemia syndromes are characterized by varying degrees of ineffective hematopoiesis and increased hemolysis. Clinical syndromes are divided into a- and P-thalassemias, each with varying numbers of their respective globin genes mutated. There is a wide array of genetic defects and a corresponding diversity of clinical syndromes. Most P-thalassemias are due to point mutations in one or both of the two P-globin genes (chromosome 11), which can affect every step in the pathway of P-globin expression from initiation of transcription to messenger RNA synthesis to translation and post translation modification. Figure 7-7 shows the organization of the genes (i.e., e and y, which are active in embryonic and fetal life, respectively) and activation of the genes in the locus control region (LCR), which promote transcription of the P-globin gene.
There are four genes for a-globin synthesis (two on each chromosome 16). Most a-thalassemia syndromes are due to deletion of one or more of the a-globin genes rather than to point mutations. Mutations of P-globin genes occur predominantly in children of Mediterranean, Southern, and Southeast Asian ancestry. Those of a-globin are most common in those of Southeast Asian and African ancestry. The main genetic variants are listed as follows.
1. b0-Thalassemia: No detectable P-chain synthesis due to absent P-chain messenger RNA (mRNA)
2. b+-Thalassemia: Reduced P-chain synthesis due to reduced or nonfunctional P-chain mRNA
3. Sb-Thalassemia: 5- and P-chain genes deleted
Dnase I hypersensitive sites
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