Hemoglobinopathies

Question 1

Globin contains

Answer 1

One heme group with covalently linked iron that binds O2, so one HbA can simultaneously bind 4 O2 mlcs

Question 2

Alpha and beta gene locations on chromosomes

Answer 2

Alpha on chromo 16. TWO COPIES.
beta on chromo 11. ONE COPY.
Spatial coincides with temporal order.

Question 3

Alpha cluster

Answer 3

zeta-alpha-alpha

Question 4

Beta-cluster

Answer 4

epsilon-gamma-gamma-delta-beta

Question 5

Locus Control Region

Answer 5

LCR. Makes physical contact with promoter and/or negative regulatory regions via specific transcriptional factors to influence gene expression.

Question 6

Deletion of LCR

Answer 6

Can lead to beta-thalassemia (NO BETA SYNTHESIS) so you get alpha clusters.

Question 7

HbA2

Answer 7

alpha2 delta 2 (2%)

Delta has weaker promoter that’s why less

Question 8

Embryonic hemoglobins

Answer 8

Hb gower I and II and hb portland (zeta2 gamma2)

Question 9

The fetal hemoglobin

Answer 9

Alpha2 gamma2

Question 10

Globin switching

Answer 10

Turn of zeta/epsilon and turn ON alpha and gamma

Turn off gamma, turn on BETA AND DELTA

Question 11

HbF vs. HbA

Answer 11

HbF has higher O2 affinity at low pO2 than Hba. So HbF is better for the placenta (has lower pO2 vs. lungs).

Question 12

Structural Variants

Answer 12

QUALITATIVE hemoglobinopathies.
Most alter the beta-globin chain. Hb Kempsey or kansas (alter O2 binding)
or make Hb less soluble (HbS and HbC).

Question 13

Thalassemias

Answer 13

QUANTITATIVE hemoglobinopathies.

Get markedly reduced or no synthesis of one globin type. So you get precipitation of globin that is in excess. Can be caused by all kinds of mutations including deletions, missense and nonsense. Defective transcriptional.

Question 14

HPFH

Answer 14

A group of clinically benign conditions that impair the perinatal switch from gamma to beta-globin synthesis.

Question 15

Sickle Cell Anemia

Answer 15

Most common in people of african origin.
Single base mutation at codon 6 (glut to valine) on beta chain.
HbS is 80% less soluble than HbA when not bound to O2 so it polymerizes into long fibers.

AR inheritance. Heterozygotes are okay.

Question 16

Hemoglobin C disease

Answer 16

Milder form of hemolytic anemia than sickle cell.
Caused by single base mutation at same spot as HbS (glut to LYSINE) on beta chain, HbC is also less soluble than HbA.
Tends to form crystals (RBC deformability reduced).

AR inheritance.

Question 17

Compound SC disease

Answer 17

They have betaS and betaC.

Milder anemia than sickle cell disease.

Question 18

Restriction fragment length polymorphism

Answer 18

Recognition site of MstII… get two fragments in normal beta chain, but only ONE FRAGMENT WITH SICKLE CELL.

Question 19

Silent alpha thalassemia

Answer 19

alphaalpha/–alpha

Question 20

Alpha thalassemia 1

Answer 20

alphaalpha/–
Heterozygotes have mild anemia
Common in Southeast Asia.
If reproducing with another they can produce a child with hydrops fetalis (homozygous for alpha thal 1). Most fetal Hb is HbBarts (gamma 4) there is enough zeta2gamma2 (HbPortland) to get fetal development.

Question 21

Hb Barts

Answer 21

Gamma 4

Question 22

Alpha thalassemia 2

Answer 22

Alpha–/alpha–
Mild anemia.
Common in Africa, Mediterranean, and Asia.
Heterozygotes have no diesase, mild anemia in homozygotes. (alpha–/alpha–)

Question 23

Thalassemia major and minor

Answer 23

Severity of phenotype.

Major is severe anemia (treat with blood transfusions, get iron accumulation, iron chelation therapy).
Minor: clinically normal, carrying one thalassemia allele.

Question 24

Simple vs. complex thalassemias

Answer 24

Complex: beta globin genes and others
Simple: only beta-globin genes.

Question 25

Beta+ thalassemia

Answer 25

Based on biochemical nature of the disease.
Most common form of beta.
Some beta-globin is made so that some HbA is present.
Decrease in beta globin synthesis can be caused by mutations affecting trx., RNA processing, or protein stability.

Question 26

Beta0 thalassemia

Answer 26

ZERO beta globin synthesis. Which means you have no HbA.
Caused by deletion of Beta-globin gene, nonsense or frameshift mutations at the 5’ end of coding region that led to an early stop codon, or mutations that lead to NO RNA synthesis.

Only 5% of normal Hb. 95% of this is alpha2gamma2, 5% alpha2gamma2.

Question 27

Delta-beta0 thalassemia

Answer 27

No delta or beta synthesis due to deletion of coding sequences for both delta and beta-globin

Question 28

Alpha thal 1/ alpha thal 2

Answer 28

Compound heterozygotes.
Only 25% of normal alpha (alpha–/—-)
SEVERE ANEMIA. HBH disease. 5-30% of their hb is beta-4 (HbH) which precipiates

Question 29

HbH

Answer 29

Beta-4

Question 30

HPFH

Answer 30

No delta or beta synthesis b/c deletions both genes. Increased gamma-globin expression caused by:

1. ) Extended deletion of add’l downstream seq which brings a cis-acting enhancer closer to gamma-globin gene
2. ) Mutations in promoter region of one of two gamma-globin genes that destroy the binding site of a repressor

They are disease free because they have enough. 100% of normal HbF.

They have HIGHER HBF THAN DELTA-BETA0 THAL

Question 31

Who has higher HbF levels?

Answer 31

HPFH do. (versus delta-beta0 thal).

Mechanisms make it possible to express it postnatally to treat pts of b-thal and sickle cell.