Mutations thalassemias

The genetic defects known as thalassemias result from the partial or total absence of one or more a or P chains of hemoglobin. Over 750 different mutations have been identified, but only three are common. Either the a chain (alpha thalassemias) or P chain (beta thalassemias) can be affected. A superscript indicates whether a subunit is completely absent (a or p ) or whether its synthesis is reduced (a or P ). Apart from marrow transplantation, treatment is symptomatic. 

Point mutations Protein folding Transcriptional control Frameshiftand nonsense mutations RNA processing Sickle cell disease P-Thalassemia P-Thalassemia P-Thalassemia... 

Mutations in splice sites can lead to abnormal proteins. For example, mutations that interfere with proper splicing of p-globin mRNA are responsible for some cases of P-thalassemia. 

Mutations in splice sites have now been documented in many different diseases induding P-thalassemia. Gaudier disease, and Tay-Sachs,... 

ATRX ATRX Human Not known Mutations in the gene that code tiATRX cause severe syndromal mental retardation associated with u-thalassemia. ATRX is localized to heterochromatin including rDNA repeats where it plays a role in conferring patterns of DNA methylation [318]. 

Gibbons, R.J., Picketts, D.J., Villard, L., and Higgs, D.R. (1995) Mutations in a putative global transcriptional regulator cause X-linked mental retardation with alpha-thalassemia (ATR-X syndrome). Cell 80, 837-845. 

The thalassemias are the most common disorders caused by mutations of a single gene worldwide both a-thalassemia and -thalassemia occur, depending on which subunit is deficient. 

Several variants of -thalassemia are caused by nonsense mutations leading to production of truncated, unstable 3-globin chains. 

A one-year-old male with chronic anemia is found to have (B-thalassemia. Genetic analysis shows that one of his (B-globin genes has a G to A mutation that creates a new splice acceptor site nineteen nucleotides upstream from the normal splice acceptor site of the first intron. Which of the following best describes the new messen ger RNA molecule that can be produced from this mutant gene ... 

Another possible application of suppressor genes is in vivo suppression of undesirable termination codons. An example comes from a p° thalassemia caused by mutation of lysine codon CAG to UAG. By changing the anticodon of a human tRNALys gene to... 

P. Sutcharitchan, R. Saiki, T.H. Huisman, A. Kutlar, V. McKie, H. Erlich, S.H. Embury, Reverse Dot-Blot Detection of the African-American Beta-thalassemia Mutations , Blood, 86(4), 1580-1585 (1995). 

Abnormal mRNA splicing can be one cause of /3+-thalassemia in which the production of /3-hemoglobin chains is greatly reduced. The defect appears to be caused by mutations that interfere with the correct removal of introns from the globin pre-mRNAs. 

Abnormal hemoglobulins can be detected by electrophoresis, as shown in Figure 7.4, which includes a pattern observed in /3+-thalassemia and one in a newborn with a-thalassemia (possibly HbH disease). It should also be mentioned that, unless there is a coexisting hemoglobin abnormality resulting from a point mutation or crossover problem, the globin chains of classic a- and /3-thalassemia are perfectly normal. It is usually the quantities of either the a or the /3 chains that are decreased. Some frameshifts have been found near the terminus of the /3 chain that lead to frameshift mutations in certain areas. 

The mutation for sickle hemoglobin occurred at least three times in Africa and once on the Indian subcontinent. The disease has spread from Africa to the Mediterranean, areas of Turkey, North and South America, the Caribbean, and the United Kingdom. The sickle hemoglobin combined with common hemoglobin variants in those areas (3-thalassemia in the... 

Yes, a number of human diseases are caused by point mutations in the promoter regions of important genes. For example, /3-thalassemia is a genetic disease in which mutations in the promoter of the /3-globin gene result in reduced production of this protein and subsequent anemia. The mutation is usually associated with a reduction in the binding affinity of the promoter for a positive transcription factor. 

Aberrant splicing causes some forms of thalassemia, a group of hereditary anemias characterized by the defective synthesis of hemoglobin. In one patient, a mutation of G to A 19 nucleotides away from the normal 3 splice site... 

Figure 28.28. Splicing Defects. Mutation of a single base (G to A) in an intron of the P-globin gene leads to thalassemia. This mutation generates a new 3 splice site (blue) akin to the normal one (yellow) but farther upstream.

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