Sickle Cell Anemia Most common genetic disease in US high incidence in African-Americans affects red blood cells potentially lethal

10 µm 10 µm Normal red blood cells are full of individual hemoglobin Fig. 5-22c 10 µm 10 µm Normal red blood cells are full of individual hemoglobin molecules, each carrying oxygen. Fibers of abnormal hemoglobin deform red blood cell into sickle shape.

Symptoms Anemia Hypoxia (low oxygen) & capillary damage Delayed growth Link to HHMI sickle cell link Anemia jaundice, fatigue, paleness, shortness of breath Hypoxia (low oxygen) & capillary damage severe pain in organs & joints retinal damage (blindness) Delayed growth delayed puberty, stunted growth Infections more susceptible depressed immune death from bacterial infections Stroke blocked small blood vessels in brain primarily in children

Genetics Sickle cell mutation Recessive allele Hb A Hb S HbAA HbAS changes 6th amino acid of  hemoglobin chain normal glutamic acid  valine Recessive allele heterozygote Hb AS, normal, but carrier homozygote recessive Hb SS, sickle cell disease 2 sickle cell carriers mate… each child has 1/4 chance of having the disease Hb A Hb S HbAA HbAS Hb A Hb S HbAS HbSS

The Malaria Connection Sickle cell disease is surprisingly common for a potentially lethal genetic disease Heterozygote advantage heterozygotes are tolerant of malaria infection & symptoms of sickle cell disease are not as severe

Malaria

Prevalence of Malaria Prevalence of Sickle Cell Anemia

Conformational change of hemoglobin when O2 binds

Sickle Cell is the result of a single point mutation in DNA

Compare the properties (size, shape, charge) of Valine vs Compare the properties (size, shape, charge) of Valine vs. Glutamic Acid. Glutamic Acid Valine

mutant hemoglobin (Hb S) Sickle cell hemoglobin mutant hemoglobin (Hb S)

HYDROPHOBIC “STICKY PATCHES” CAUSE MUTATED BETA SUBUNITS FROM DIFFERENT HEMOGLOBINS TO STICK TOGETHER

Fig. 5-22 Normal hemoglobin Sickle-cell hemoglobin Primary structure Val His Leu Thr Pro Glu Glu Val His Leu Thr Pro Val Glu 1 2 3 4 5 6 7 1 2 3 4 5 6 7 Exposed hydrophobic region Secondary and tertiary structures Secondary and tertiary structures  subunit  subunit     Quaternary structure Normal hemoglobin (top view) Quaternary structure Sickle-cell hemoglobin     Function Molecules do not associate with one another; each carries oxygen. Function Molecules interact with one another and crystallize into a fiber; capacity to carry oxygen is greatly reduced. 10 µm 10 µm Red blood cell shape Normal red blood cells are full of individual hemoglobin moledules, each carrying oxygen. Red blood cell shape Fibers of abnormal hemoglobin deform red blood cell into sickle shape.

Link to Sickle Cell Animation