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