Molecular pathology

The main classes of mutations that cause P-thalassaemia are summarized in Table 6.2 and in Figure 6.3. They may involve any step in globin chain production: transcription, translation or the post-translational stability of the globin gene product.

Transcription

The mutations that involve transcription include deletions and point mutations involving the globin gene promoter regions. With the exception of a deletion of about 600 bases at the 3' end of the P-globin gene, which is restricted to certain Indian populations, major deletions are uncommon. A large number of point mutations involve the promoters or adjacent regions, most of which downregulate the P-globin gene to a varying degree and hence cause relatively mild forms of P-thalassaemia.

Processing

A wide variety of mutations interfere with processing of the primary mRNA transcript. Those within introns or exons, or at

Figure 6.3 The classes of mutations that underlie P-thalassaemia. PR, promoter; C, CAP site; I, initiation codon; FS, frameshift; NS, nonsense mutation; SPL, splicing mutation; Poly-A, poly-A addition site mutation.

Figure 6.3 The classes of mutations that underlie P-thalassaemia. PR, promoter; C, CAP site; I, initiation codon; FS, frameshift; NS, nonsense mutation; SPL, splicing mutation; Poly-A, poly-A addition site mutation.

their junctions, interfere with the mechanism of splicing the exons together after the introns have been removed. Single-base substitutions at the invariant GT or AG sequences at intron-exon junctions prevent splicing altogether and cause P°-thalas-saemia. The sequences adjacent to the GT in the introns are also relatively conserved, so-called consensus sequences. Several P-thalassaemia mutations involve this region or other parts of the introns and are associated with variable degrees of defective P-globin production; alternative splicing sites are produced so that both normal and abnormal mRNA species are synthesized. An incorrectly spliced mRNA is not functional because it contains intron sequences; in some cases a nonsense mutation or frameshift is generated.

In exons, there are also sequences that resemble the consensus sequences at the intron-exon junctions. Mutations may activate these 'cryptic' sites, again leading to abnormal splicing.

Translation

Mutations that involve translation of P-globin mRNA fall into two groups. First, there are nonsense mutations, that is singlebase changes that produce stop codons in the middle of the coding part of the mRNA. Mutations of this type would cause premature termination of globin chain synthesis but, as part of the surveillance mechanism that is active in quality control of the processed mRNA, it appears that message that contains mutations of this type is not transferred to the cell cytoplasm, a phenomenon called nonsense-mediated decay. Other exon mutations result in frameshifts, that is one or more bases are lost or inserted and the reading frame for the genetic code is thrown out of phase.

Post-translational stability

Finally, some forms of thalassaemia result from instability of the P-globin gene product. For example, it appears that nonsense mutations in exon 3 are not subjected to nonsense-mediated decay and hence abnormal mRNA is transported to the cytoplasm and translated. The result may be long, unstable P-globin gene products that form inclusion bodies in the red cell precursor. This is the basis for dominant P-thalassaemia. In other cases, highly unstable P-chains may be produced, which, although they form a viable haemoglobin molecule, are rapidly destroyed in the circulation, leading to a chronic haemolytic anaemia (see later in chapter).

Was this article helpful?

0 0
How To Bolster Your Immune System

How To Bolster Your Immune System

All Natural Immune Boosters Proven To Fight Infection, Disease And More. Discover A Natural, Safe Effective Way To Boost Your Immune System Using Ingredients From Your Kitchen Cupboard. The only common sense, no holds barred guide to hit the market today no gimmicks, no pills, just old fashioned common sense remedies to cure colds, influenza, viral infections and more.

Get My Free Audio Book


Post a comment