The erythrocyte or red blood cell (RBC) is a critical structure in the life of animals. Red blood cells serve primarily as oxygen-carriers and this role is made possible by hemoglobin – a protein combined with a porphyrin (special ring structure) molecule that binds and carries iron atoms. Hemoglobins are able to bind and hold oxygen and release this oxygen under appropriate conditions.
Sometimes gene changes or mutations occur that alter the amino acids in the protein chains of hemoglobin. These amino acid changes distort the hemoglobin molecule and this alteration of structure often affects the oxygen-transport function. Read how some of these changes occur and the consequences that may follow.
Hemoglobin and Gene Mutations, DNA Mutations, Protein Changes and Red Blood Cell Effects
Genes on chromosomes mutate from time to time throughout the human genome (46 chromosomes with about 30,000 genes total). Gene mutations are permanent changes in the DNA of a cell. All genes are subject to gene mutations. The cellular enzyme called DNA polymerase may or may not be able to repair gene mutations. The DNA is the information molecule of the cell. When gene mutations occur, amino acid changes may also occur. Some gene mutations are simple base-pair changes of the DNA. Other mutations are more complicated.
Gene mutation may be spontaneous and have no known cause. Some mutations are related to the effects of certain physical or chemical influences such as X- or gamma- radiations or certain known chemical mutagens. Some gene mutations are repaired by cells soon after their formation. Other gene mutations are not repaired and these mutations are permanent and can be passed on to the children of those bearing the gene mutations.
The occurrence of gene mutations that control peptide formation is well-documented. The globulin proteins of the hemoglobin molecule may be changed by base pair mutations that result in small or major changes in the globulin (proteins). Hemoglobin is composed of four polypeptide chains – two identical alpha-chains and two identical beta chains, and a central heme (porphyrin) that binds iron. There are two kinds of hemoglobin alpha genes found on chromosome 16 – HBA1 and HBA2 – and only one kind of hemoglobin beta gene – HBB – found on chromosome 11.
Deletion mutations (lost pieces of DNA from genes HBA1 and/or HBA2) are responsible for the majority of alpha-thalassemias. Other types of mutations are usually involved with the HBB gene and beta-thalassemias.
Thalassemia Major and Thalassemia Minor of Alpha and Beta Thalassemias
Thalassemia major indicates that there are two mutant genes (homozygous recessive) inherited by the child, one gene on the homologous chromosome from each parent. This is a more dangerous and serious disease situation. Thalassemia minor is a heterozygous genotype (heterozygous): there is a normal gene and a mutant gene inherited on the corresponding chromosome from each parent. A simple understanding of this type of inheritance, gene terminology and chromosome definitions may be seen by reviewing Mendel's studies with pea plants.
Thalassemias, Hemoglobinopathies and Gene Mutations
Thalassemias are inheritable diseases associated with abnormal hemoglobin synthesis. Anemia, shortness of breath, abnormal-looking RBCs (see photos 2 and 4 below – click to enlarge), jaundice, as well as lung, liver, spleen, kidney and brain damage are among the various and common signs of severe thalassemias. Thalassemias indicate a relationship to the Mediterranean Sea (Greek "thalassa" = sea). Please note that beta thalassemia is common also to Africa, Asia and the Middle East. Alpha thalassemias are more indigenous to Southeast Asia, the Middle East, China, and to persons of African descent.
Alpha-thalassemias have these features:
- they are caused most often by deletion mutations of DNA
- they show decreased production of α-chains
- oxygen binds poorly to the alpha hemoglobin chains
- oxygen saturation (amount bound) decreases
- anemia is a common disease sign
Over 100 types of mutations of HBB are known:
- gene deletion HBB mutations are rare (whereas they are common in the alpha thalassemias)
- there are HBB gene splice mutations of the promoter gene region that reduce the number of β-globin chains and cause mild disease.
- nonsense mutations and frame-shift mutations occur, which lead to no β-globin chains and severe disease
- excess of alpha-hemoglobin chains over beta-chains causes alpha chains to become insoluble and precipitate inside the erythrocytes
- red cells die and are removed by the spleen which enlarges (splenomegaly)
- anemia - decreased red cells - is a common disease sign
In thalassemias, the number and kinds of genes that are lost determines the gravity of the disease. Loss of one or two genes is often asymptomatic, whereas deletion occurring in all four genes is fatal to the unborn child.
Treatments for Thalassemias
Currently, severe thalassemias are treated by blood transfusions and folate supplementation to stimulate red blood cell formation. Some patients are cured by bone marrow transplantation. Mouse studies indicate the future potential value of gene therapy.
Sickle Cell Trait and Sickle Cell Disease
Sickle-cell disease (genotype = homozygous recessive) and sickle-cell trait (genotype is heterozygous and each person is a carrier of one mutant gene) are the most common of all the hemoglobin anomalies. About 1 in every 12 Africans carries the gene for this disease. The mutant gene causes the substitution of a single valine for glutamic acid in both of the hemoglobin beta chains (see photo 1 below – click to enlarge). When oxygen is lowered during exercise or excessive metabolism then the RBCs change to a sickle shape which causes internal clots and tissue and organ damage related to oxygen deprivation (also shown in photo 1, part B).
Sources
MedlinePlus. 2010. "Thalassemia." Accessed 27, February, 2011 @ nlm.nih.gov/medlineplus/ency/article/000587.htm
New Jersey, Department of Health and Senior Services. 2011. "Common Questions About Sickle-Cell Disease." Accessed 27 February, 2011 @ nj.gov/health/fhs/sicklecell/familyguide/questions.shtml
NIH. 2011. "Thalassemia." Accessed 8 February, 2011 @ ncbi.nlm.nih.gov/books/NBK22200/
Donald Reinhardt - Think, read, write & live well always. DJR has a PhD in Biology/Microbiology & is a Fellow & Diplomate, ASM Amer Acad Micro.
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