Sickle Cell Disease Case Study

hemoglobin (Hb)

proteins in red blood cells that carry oxygen throughout the body; a tetramer (4 polypeptide units) with 2 alpha and 2 beta subunits

recessive genetic disorders of beta globin

beta thalassemia

sickle cell disease

beta thalassemia

low concentration of beta globin → problems with Hb, RBC, and oxygen delivery

sickle cell disease (SCD)

SNP in beta globin coding → Hb aggregation and RBC sickling

vaso-occlusive crisis (VOC)

sickled cells cause this by blocking blood vessels, very painful and potentially lethal

carriers for SCD are more resistant to ___

malaria

fetal hemoglobin vs. adult hemoglobin

fetal hemoglobin has a higher affinity for O₂

why do fetuses need a different type of hemoglobin?

since O₂ must travel from mother to fetus, fetal hemoglobin (HbF) must have a higher affinity for oxygen so the fetus can be properly oxygenated

what is the difference in polypeptide structure between HbF and HbA (adult hemoglobin)?

HbF uses gamma globin while HbA uses beta globin

how does expression of HbF as an adult affect sickle cell disease outcome?

higher % of HbF in adults → higher probability of survival and better outcome

what kind of study can be used to determine what alleles lead to high levels of HbF?

GWAS

a GWAS showed that BCL11A was associated with ___

persistent HbF (high levels of HbF as an adult)

BCL11A

transcription factor that silences gamma globin (HbF) production in RBCs

erythroid enhancer

cis regulatory sequence;

GATA1 (transcription factor) binds to it in order to turn on BCL11A in RBCs

relationship between BCL11A expression and HbF

higher expression of BCL11A = lower HbF

less expression of BCL11A = higher HbF

using gene therapy to treat SCD and/or beta thalassemia, what should you target - erythroid enhancer or GATA1?

the erythroid enhancer; CRISPR on the cis regulatory sequence won’t allow GATA1 to bind, which means BCL11A won’t be turned on

if you target GATA1, it might be lethal since GATA1 might have other functions that are important for the cell