Genetics of Hemoglobinopathies Flashcards Table View
Novel property mutations
1. Change in ____ ____ sequence causes disease by conferring a novel property on the ______, without altering it's normmal functions.
3. How is this example a novel mutation?
1. amino acid sequence cause....protein
2. Sickle Cell Disease
3. SCD is due to an amino acid substitution that has NO effect on the ability of sickle hemoglobin to transport oxygen.
Mutations Associated with Heterochronic or Ectopic Gene Expression:
1. Muations that alter regulatory regions of a gene to cause inappropriate expression, at abnormal time or place...EXAMPLE?
2. What is a comparable example in hemoglobin?
1. Cancer ..due to abnormal expression of ONCOGENE that promotes cell proliferation.
2. Some mutations in hemoglobin regulatory elements can lead to continued expression in adult of the y-globin gene, whch is only expressed in fetal life.
3. LEADS TO persistance of fetal hemoglobin.
For development of a biologically active protein:
Information must be __________ from the _______ sequence of the gene onto the ______ and then translated into a _________, which then undergoes progressive stages of ___________.
Structure and function of HEMOGLOBIN
1. Hemoglobin carries what in red blood cells?
2. What are the 4 subunits ?
3. What is each subunit composed of?
2. two alpha chains, 2 beta chains
3. SUBUNIT: a polypeptide chain, globin, prosthetic group HEME (iron pigment that combines with oxygen to give molecule oxygen-transporting ability).
Above all, what is the quality of the globin structure that has been conserved during evolution?
It's TERTIARY STRUCTURE: all globins have 7 or 7 helical regions.
STRUCTURE OF HEMOGLOBIN:
what areas are mutations most likely to cause hemoglobinopathies? 3
- one that alters globin confirmation
- substitutes a highly conserved amino acid
- replaces a nonpolar residue that forms the hydrophobic shell excluding water from interior of molecule
DEVELOPMENTAL EXPRESSION OF GLOBIN GENES AND GLOBIN SWITCHING
1 What is globin switching?
2. What is this an example of ?
3. Embryonic globin synthesis occurs in the ____ ____ from 3rd to 8th weeks of gestation
4. At 5th week of gestation, synthesis moves from ____ ____ to ____ _____
1. the change in expression during development of the various globin genes
2. classic example of regulation of developmental gene expression
3. yolk sac
4. yolk sac to fetal liver
1. What hemoglobin is there during fetal life ?
2. How much of it is present at birth?
3. How much is present in adult life?
1. less than 1%
1. When do BETA chain synthesis become significant?
2. At what age is almost all the adult hemoglobin present?
1. BETA chain synthesis becomes significant right before birth
2. THREE MONTHS
Developmental Regulation of BETA Globin Gene Expression: L:Locus Control Region
1. What is the Locus control region?
2. LCR is required for expression of all genes in B-globin cluster on what chromosome?
1. A 20-kb domain that is the B-GLOBIN COMPLEX
2. chromosome 11
1. alter globin peptide without affecting synthesis
2. decreased synthesis of one or more globin chains--imbalance in alpha and beta chains
3. clinically benign conditions that don't allow switch from Y-globin to BETA globin
Hemoglobin structural variants:
make hemoglobin _____ unstable
sickle cell globin and what?
What causese SCD?
Single nucleotide substitution that changes codon of 6th amino acid of BETA globin from glutamic acid to valine.
Why is HbC milder than sickle cell disease, even though it involves same gene and codon?
Because the nucleotide change that changes the codon of the 6th amino acid of the beta globin is from glutamic to lysine. HbC is less soluble and tends to crystallize in red blood cells, reducing their deformity in capillaries and causing mild hemolytic disorder.
How do mutations that make a-globin or b-globin unstable lead to thalassemias?
B/c the a:B chain is in excess, the absensce of a complementary chain to form a tetramer leads to excess cells and cell destruction.