Mutations and hemoglobinopathies flashcards
Mutagens
Induce mutations in the genome
Oxidative deamination
Converts C to U. During next replication U is matched with A and in the second replication A is matched with T.
Apurination/Apyrimidation
Loss of purine/pyrimidine base
O6-methyl guanosine
Highly mutagenic, causes different mutations
Cyclobutane dimer
Forms between adjacent T-T dimers and blocks DNA polymerase
Invariant amino acids
In the functionally active site of the molecule, may result in loss of function even if a conservative change
Sickle cell disease mutation
6th amino acid of beta chain for Hb from Glu to Val
HbC mutation
6th amino acid of beta chain for Hb from Glu to Lys
Read-through mutation
Termination codon mutation which causes a larger than normal protein to be made
Transition mutation
One purine-pyrimidine based substituted for another
Transversion mutation
Purine-pyrimidine pair substituted for pyrimidine-purine pair and vice versa
Nitrous acid
Can deaminate A to hypoxanthine and G to xanthine
Peptide mapping (fingerprinting)
Sequences the protein and compares its primary structure to the normal protein. Enzymatic cleavage of protein and 2-D gel electrophoresis in 2 directions (one way for charge and one for size)
What are the most common type of mutatons in hemoglobinopathies?
95% of the time in globin genes. Could be in alpha or beta gene but most often in beta.
5 things Hb mutations can cause
- Unstable structure 2. Increased or decreased oxygen affinity 3. Increase in oxidation from ferrous to ferric iron 4. Imbalance in synthesis of globin chains 5. Changes in properties of globin chains
Unstable structure Hb mutations
Easily denature or precipitate and damage cell membrane seen as Heinz bodies. Substitution of Pro in alpha-helical region of globin fold will cause unstable Hb. Anemia, reticulocytosis (increase in reticulocytes), splenomegaly, urobilinuria (increased breakdown of Hb products in urine)
Increased or decreased oxygen affinity Hb mutations
Hb cowton is example where His that dissociates 50% of Bohr protons is lost and destabilizes T conformation. Hemolytic anemia, Heinz body formation.
Increase in oxidation from ferrous to ferric iron Hb mutations
HbM is an example. Cyanosis, weakness, possibly fatal.
Imbalance in synthesis of globin chains Hb mutations
Thalassemias result. Most frequent single gene disorders. RBCs are microcytic and hypochromic.
Beta thalassemia
Synthesis of beta-globin gene decreased or absent. Fetal hemoglobin synthesized but cannot be replaced by adult Hb. Alpha-globin chains form tetramers which precipitate and result in cell death. HbF and HbBart’s (4 gamma chains) accumulation typical.
Beta thalassemia minor
Make some adult Hb and do not need treatment
Cooley’s disease
Beta thalassemia major are homozygous. Severely anemic and require frequent blood transfusions resulting in iron overload (hemosiderosis). Bone marrow transplant helps.
Alpha thalassemia
Synthesis of alpha-globin gene decreased or absent. Since 2 copies on each chromosome 16 many levels deficiency. Can make HbA, HbH, HbBart’s, beta-chain precipitate.
Alpha thalassemia with 1 defective copy
Silent carrier with no symptoms
Alpha thalassemia with 2 defective copies
Alpha-thalassemia trait with mild anemia
Alpha thalassemia with 3 defective copies
Hemoglobin H with mild to severe hemolytic anemia (makes beta and gamma chains which form tetramers but are useless in carrying oxygen (no cooperativity and high oxygen affinity)
Alpha thalassemia with 4 defective copies
Hydrops fetalis resulting in fetal death (can’t make HbF)
