Genetic basis of Hemoglobinopathies, Thalassemia and Hemophilia Flashcards
Globin genes:
How many α and β-globin gene?
adult and fetal Hb proteins?
- there are 2 α-globin genes on chrom 16 = 4α genes in a nl individual.
- 1 β-globin gene on chrom 11 and 2 β in a nl indiv.
Adult Hb: (98%HbA “2α & 2β” + 3.5%HbA2 “2α & 2s”
Fetal Hb: (HbF “α2γ2”)
Globin genes in early fetal dvlp. and site of EPO
Post-conceptual age “wks”:
Postnatal age “wks”:
α globin remains relatively constant throughout.
- γ globin high and decreases at birth. B globin low and increases at birth. EPO in the liver and spleen.
- γ globin low and B globin high postnatal. EPO in the BM.
Hemoglobinopathies
Qualitatitive change: Mutation in nucleotide sequence of globin chain
Thalassemia
Quantitative change: Decreased or absent globin chain synthesis
HbS
- single pt mutation in B-globin gene
- Glutamic acid (-ve) substituted by Val (hydrophobic). GAG>GTG “transversion mutation”
- HbS moves slower to anode than HbA.
- homozygous HbSS causes SCA; no production of HbA.
- No manifestation of SCA during fetal life b/c B-globin production is low in early infancy. Age of presentation 6mo-1yr.
Sickle cell crisis caused by?
anemia, hemolysis and vaso-occlusive ischemia round the abd and long bones.
Treatment w/ fetal Hb inducers.
Drugs that increase expression of fetal globins (y) are
5-azacytidine (Decitabine; demethylating agent), Hydroxyurea, Butyrate compounds (inhibit histone deactylation)
- all these agents derepression of gamma globin gene.
- they alter epigenetic gene regulatory mechanism and may change the acetylation of chromatin proteins => more HbF formation.
- HbF has altered O2 affinity which means HbS is less likely to polymerize.
Heterozygous carrier HbAS
- 1 nl B-globin gene and 1 Bs globin gene.
- benign condition but may develop sickle crisis in low O2 saturation (deep sea diving and unpressurised aircraft or extreme exercises)
Heterozygote advantage
- parasite failed to propagate in peiople w/ the sickle cell trait (RBCs w/ HbA and HbS).
- explains high incidence of carriers in the area (Africa, Mediterranean basin, Middle East, India)
HbC
- missense point mutation (Glu-> Lys)+ve
- HbC moves the slowest (HbA>HbS>HbC)
- homozygote for HbC have mild hemolysis
- HbC has lower solubility and crystallize in RBCs.
- pts w/ HbSC: episodes of sickling similar to sickle cell disease.
Thalassemias:
alpha:
beta:
- rate of synthesis of globin chain is reduced.
- reduced alpha chain synthesis
- reduced B chain synth “more common b/c only 2 B globin gene present as opposed to 4 alpha”
α-Thalassemia
loss of one gene (αα/α_)
loss of two genes (α_/α_) or (αα/__)
loss of three genes (α_/__)
loss of all genes (__/__)
- defic. in α globin chain synth.
- α globin deletion caused by unequal crossing over/misalignment during homologous recombination.
- frontal bossing, malar prominence - indicative of extramedullary HPO, “hair on end” skull radiograph.
- no clinical problems
- trans/cis => mild anemia
- cause B4 tetramers referred to as HbH, = moderate hemolytic anemia
- lethal, known as hydrops fetalis
Hemoglobin Bart hydrops fetalis (Hb Bart) syndrome
- most severe form of a-thal.
- Hb Bart: aggregation of Y4 tetramers
- edema, ascites, pleural and pericardial effusions and severe hypochromic anemia.
- death in neonatal period.
- all for a-globin alleles deleted or dysfunctional.
- both parents are cis carrers and have donated chrom w/o a-globin
HbH disease
- mild-to-moderate microcytic hypochromic hemolytic anemia and hepatosplenomegaly.
- 1/3rd of affected indiv have mild thalassemia like bone changes.
- compatible w/ survival into adulthood.
- aggregation of B4 tetramers
- deletion or dysfunction of 3/4 a-globin alleles.
- parent 1 is a cis carrier and parent 2 is a trans carrier.
B-thalassemia
- AR w/ high carrier frequencies
- many mutations cause B-thal “allelic heterogeneity”
- absent or reduced synth of B globin gene
- B+ thal: reduced gene exp
- B0 thal: complete suppresion of gene exp “more severe”
- excess a-globin chains precipitate and results in severe hemolytic anemia
- BM compensate and expands to perform EPO = bone deformity and fractures.
- frontal bossing, malar prominence = extramedullary HPO, hair on end skull
B-thal major (Cooley’s Anemia and Mediterranean Anemia)
- homozy or compound hetero for B0 or B+ genes - two severe mutations
- mutations in both B-globin
- low/absent HbA levels; High HbA2 and HbF levels
- present at ~6mo as y-globin genes are switched off.
B-thal intermedia
- mostly homozy or compound hetero (diff B+ mutations on B-globin genes) one severe mu, second mut is less severe.
- Low HbA levels
B-thal minor (B-thal carrier or B-thal trait or heterozygous B-thal)
- mostly heterozygous (one nl and one mutant B-globin gene)
- almost nl HbA levels; phenotypically nl
Molecular basis/defect of B-thal
- excess of a-chain that don’t form tetramers. They bind to the RBC membranes, producing memb damage, and at high conc they form toxic aggregates.
- rarely results from gross gene deletion
- cure is via BM transplantation from an HLA identical sibling.
Hemophilia A
- XL recessive bleeding disorder caused by defic. in activity of caogulation factor VIII
- affected indiv = hemorrhage into joints and muscles, easy bruising and prolonged bleeding from wounds.
Hemophilia A and B
- both express allelic hetrogeneity
- genes for both Factor VIII and IX are located on long arm of X-chrom.
- gene of F8 is large; 40% of cases of severe FVIII from large inversion of intron “most frequent mutation”
- deletions, insertions and pt mut account for the remaining 50-60% of hemophilia A (allelic hetero).
- F9 gene is small; pt mutations and deletions most common causes of Hemophilia B.
- inheritance pattern: affected male > carrier female > affected male
- no male to male
Hemophilia A - inversion
-if there’s a mis-alignment during hom. recombination where the repeats align w/ each other then part of the F8 gene is lost.
Phenotypes of carrier females
- generally asymptmatic due to random X inactivation/Lyonization “skewed X” results in equal proportions of somatic cells.
- Manifesting heterozygotes: some carrier females showing a lower level of clotting factors and manifestations resemble affected males
