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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)
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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+3 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(+)
• 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 crossingover 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
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Thalasemia major:
Severe anemia
Hypochromic microcytic RBC
Signs of accelerated hemolysis and
regeneration (hyperbilirubiemia)
• Hepato-splenomegali
• Growth retardation
• Bony abnormalities
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Thalassemia minor:
Common γ mild condition
Hypochromia
Mild microcytosis of RBC
Mild elevation of RBC
Slight/no anemia
• Thalassemia trait:
• Heterozygout state