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 PO 2 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 O 2 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, O 2 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