hemoglobinopathy prof.dr.arzu seven. hemoglobinopathy mutations in the genes that encode the α or...
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HEMOGLOBINOPATHY
Prof.Dr.Arzu SEVEN
HEMOGLOBINOPATHY
• Mutations in the genes that encode the α or β subunits of Hb potentially can affect its biological function
• More than 800 known mutant human Hbs are both extremely rare and benign, with no clinical abnormalities
• When a mutation compromises bilogic function hemoglobinopathy
• Diagnosis of hemoglobinopathies
• The mobility of a protein during elecrophoresis or chromatography is determined by its charge and interaction with matrix
• 3 commonly used techniques
• Electrophoresis in agar gel at pH:6.2
• IEF (using polyacrylamide gel)
• Ion exchange chromatography
Sickling disorders=sickle cell disease HbS
• Inherited, single point mutation in the gene encoding β_globulin
• Glu Val
• A surface-localized charged AA is replaced by a hydrophobic (nonpolar) residue
• At low PO2 deoxy HbS can polymerize to form long, insoluble fibers
• Sickle shape erythrocytes
vulnerable to lysis• HbS, when deoxygenated, is less soluble
it forms long, filamentous polymers that readily precipitate
characteristic sickle shape
• In homozygous individual (HbS/HbS)
the complex process of nucletion γ polymerization occurs readily
• In heterozygous individual (HbA/HbS) sickle cell trait
asymptomatic
• Sickled erythrocytes block blood flow especially in the spleeen γ joints
cells lose water, become fragile, have shorter life span
hemolysis γ anemia
• Intermittent episodes of hemolytic anemia • Acute vasoocclusive crises, impaired
growth ,increased susceptibility to infections, multiple organ damage
• Heterozygosity is associated with an increased resistance to malaria, specifically growth of the infectious agent plasmodium falciparum in erythrocytes
(selective advantage)
HbC (glu lys)
• Copolymerize (interact) with HbS
• when both are present, causing a sickling disorder resembling homozygous HbS disease
• HbA ,F and most Hb variants do not copolymerize with HbS they prevent severe sickling disorders when they are present with HbS
• When HbS trait is inherited together with β°_thalasemia trait severe sickling disorders
• α_thalassemia are protective against severe sickling
Met Hbemia (Hb M)
• Heme iron is ferric
can neither bind nor transport O2
• Inherited due to metHb reductase deficiency (autosomal recessive)
• Acquired by ingestion of certain drugs (sulfonamides) γ chemicals
HbM: Histidin F8 tyr (congenital)
Fe makes a tight ionic complex with phenolate anion of tyrosine
• If α chain is affected: T state, O2 affinity Bohr effect (-)
• If β chain is affected:R_T switching Bohr effect(+)
+3
• Infants are particulary vulnerable to metHbemi because HbF is more sensitive to oxidants compared to Hb A
>%10 of Hb is in metHb cyanosis
• Diagnosis:electrophoresis ,characteristic absorption spectrum of metHb
• Therapy:ingestion of methylene blue or ascorbic acid
Unstable Hb Hemolytic Anemia
• More than 100 Hb variants show instability of either α or β globulin chain
• Due to a substituon of a polar (or hydrophilic) AA for a nonpolar (or hydrophobic) AA that lines the pocket where heme is located
• Köln Hbpati compensated hemolytic anemia
• Zürich Hbpati sulfonamide_induced hemolysis
Thalassemias
• Hereditory disorders characterized by a reduction in the synthesis of one type of globulin chain
• α thalassemia: mutations in α-globulin genes(unequal crossing- over γ large deletions)
reduction in α chain synthesis
• β thalassemia: a very wide variety of mutations in β_globulin
gene including deletions, nonsense γ frameshift mutations
reduction in β chain synthesis
• Thalasemia major:• Severe anemia• Hypochromic microcytic RBC• Signs of accelerated hemolysis and
regeneration (hyperbilirubiemia)• Hepato-splenomegali• Growth retardation• Bony abnormalities
• Thalassemia minor:
• Common γ mild condition
• Hypochromia
• Mild microcytosis of RBC
• Mild elevation of RBC
• Slight/no anemia
• Thalassemia trait:
• Heterozygout state