Sickle Cell Anemia
From DNA to Disorder
A
production
• /1pt Gene(s) Involved & DNA Code (length, arm, +/- strand and loci on
chromosome, name of gene, discovery info, actual base sequence, introns/exons,
cDNA, mRNA)
• /1pt Protein Affected (How are primary through quaternary structure affected?
How is enzyme activity affected? normal vs abnormal expression)
• /1pt Cellular, Tissue & Organ effects (What signal transduction pathways are
interrupted? What morphological changes in cells, tissues and organs result?)
• /1pt Organ system effects
(What body system(s) is(are) affected?
How is it affected? How is disordered function different than normal function?)
• /1pt Organism effects
(What symptoms exist? How is it diagnosed?)
• /1pt Treatment/Prevention (What preventative measure can be taken? What
treatments are available? What treatments are presently being researched or are in
clinical trials?)
• /1pt Genetics
(What is the mode of inheritance? Possibly include a Punnett
Square and pedigree)
• /1pt Ecological/Evolutionary effects/significance
(In what
geographic/ethnic population(s) is this disorder prevalent? Why those?)
• /1pt Your Choice/Miscellaneous (choose an area not mentioned above to delve
further into)
• /1pt References (complete APA format bibliography with at least 3 references)
Introduction
Sickle Cell Anemia is a blood disorder caused due to
mutation in the beta chain of the protein Hemoglobin.
Hemoglobin primarily binds with oxygen allowing its
transport throughout the blood for cellular processes.
Gene(s) Involved & DNA Code
There are various globin genes
Chromosome 16
• Alpha
(3-9mos)
• Zeta
(<8wks)
Chromosome 11
• Beta
(after birth)
• Epsilon (<8wks)
• Gamma (3-9mos)
• Delta
(after birth)
Gene(s) Involved & DNA Code
Official Gene Symbol: HBB
Name of Gene Product: hemoglobin, beta
Alternate Name of Gene Product: beta globin
Gene(s) Involved & DNA Code
Locus: 11p15.5 - The HBB gene is found
in region 15.5 on the short (p) arm of
human chromosome 11
Gene Structure: The normal allelic variant
for this gene is 1600 base pairs (bp) long
and contains three exons
mRNA: The intron-free mRNA transcript
for the HBB gene is 626 base pairs long.
Coding Sequence (CDS): 444 base pairs
within the mRNA code for the amino
acid sequence of the gene's protein
product
Protein Size: The HBB protein is 146
amino acids long and has a molecular
weight of 15,867 Da.
Gene(s) Involved & DNA Code
Sickle Cell is due to a point mutation. A substitution of
the 2nd base in the 6th amino acid of the protein.
Gene(s) Involved & DNA Code
Gene Structure: The normal allelic variant for this gene is
1600 base pairs (bp) long and contains three exons
mRNA: The intron-free mRNA transcript for the HBB
gene is 626 base pairs long.
Coding Sequence (CDS): 444 base pairs within the
mRNA code for the amino acid sequence of the gene's
protein product
Gene(s) Involved & DNA Code
A variety (376) of hemoglobin mutations exist including
missense and nonsense substitutions, deletions, insertions,
duplications and rearrangements (including inversions)
Protein Affected
Although several hundred HBB gene variants are known,
sickle cell anemia is most commonly caused by the
hemoglobin variant Hb S.
In this variant, the hydrophobic amino acid valine takes the
place of hydrophilic glutamic acid at the sixth amino acid
position of the HBB polypeptide chain.
Protein Affected
Hemoglobin is a protein
with 4 subunits
Alpha chains consist of
141 amino acids
Beta chains consist of
146 amino acids
There are few alphaalpha or beta-beta
interactions, but many
alpha-beta
hydrophobic
interactions
Protein Affected
The SCA substitution creates a hydrophobic spot on the
outside of the protein structure that sticks to the
hydrophobic region of an adjacent hemoglobin molecule's
beta chain. This clumping together (polymerization) of Hb S
molecules into rigid fibers causes the "sickling" of red blood
cells.
Protein Affected
Polymerization occurs only after red blood cells have
released the oxygen molecules that they carry to various
tissues throughout the body. Once red blood cells return to
the lungs where hemoglobin can bind oxygen, the long
fibers of Hb S molecules depolymerize or break apart into
single molecules.
Protein Affected
Polymerized sickle hemoglobin does not form single
strands. Instead, the molecules group in long bundles of 14
strands each that twist in a regular fashion, much like a
braid
These bundles self-associate into even larger structures
that stretch and distort the cell. An analogy would be a
water balloon which was stretched and deformed by
icicles.
Polymers of deoxygenated sickle
hemoglobin molecules. Each
hemoglobin molecule is represented
as a sphere. The spheres twist in an
alpha helical bundle made of 14
sickle hemoglobin chains.
Cellular, Tissue & Organ effects
A sickled red blood cell
filled with sickle
hemoglobin fibers.
Several fibers (see
arrows) are outside the
cell.
Cellular, Tissue & Organ effects
Cycling between polymerization and depolymerization
causes red blood cell membranes to become rigid
Cellular, Tissue & Organ effects
Another problem with sickle cells is that they do not last as
long as normal red blood cells. Normal round red cells live
about 120 days. Sickled red cells are more fragile than
normal red cells and live for less than 60 days. The body
cannot make red cells as fast as the sickle cells are being
broken down. As a result the body has fewer red cells and
less hemoglobin than normal, and this we call anemia.
To determine the
hematocrit, whole blood in a
tube is centrifuged to pellet
the red cells (packed red
cells). Plasma remains on
top of the packed red cells.
The fraction of the blood
that is packed red cells is the
hematocrit. In this example,
the hematocrit is about 40%.
Organ system effects
The rigidity of
these red blood
cells and their
distorted shape
when they are not
carrying oxygen
can result in
blockage of small
blood vessels.
This blockage can
cause episodes of
pain and can
damage organs.
Organism effects
Anemia results in less oxygen being carried to various
organs and tissues, including the heart, brain, lungs, and
muscles. Without enough oxygen, these organs do not
function effectively.
Weariness and general fatigue
may be signs of Anemia.
Organism effects
Due to poor circulation of blood (oxygen
and nutrients) SCA sufferers are subject
to several complications in addition to
anemia: Sickle Dactylitis, bone pain,
priapism, leg ulcers, strokes, bone pain,
splenic sequestion, kidney damage, chest
syndrome, pain episodes
Organism effects
Organism effects
Genetics
Sickle cell anemia is an autosomal recessive genetic
disorder. For the disease to be expressed, a person must
inherit either two copies of Hb S variant or one copy of
Hb S and one copy of another variant.
Genetics
Individuals
who have one
copy of the
normal HBB
gene (Hb A)
and one copy of
Hb S, are
described as
having sickle
cell trait and do
not express
disease
symptoms.
Ecological/Evolutionary effects/significance
Malaria
Sickle Cell
Sickle cell anemia is particularly common among people
whose ancestors come from sub-Saharan Africa; Spanish
speaking regions (South America, Cuba, Central America);
Saudi Arabia; India; and Mediterranean countries, such as
Turkey, Greece, and Italy.
Ecological/Evolutionary
effects/significance
In areas where the sickle cell gene is
common, the immunity conferred has
become a selective advantage.
Individuals heterozygous for SCA
have a higher resistance to infection
from malaria
Treatment/Prevention
Many treatments are being used and researched to
prolong the lives and quality of life in SCA
sufferers. These include: Hydroxyurea, bone
marrow transplant, gene therapy, stroke
prevention (STOP) study and adhesion blockers.
Treatment/Prevention
Hydroxyurea All people have fetal
hemoglobin in their circulation before birth.
Fetal hemoglobin protects the unborn child and
newborns from the effects of sickle cell
hemoglobin. Unfortunately, this hemoglobin
disappears within the first year after birth. One
approach to treating sickle cell disease is to
rekindle production of fetal hemoglobin.
The drug, hydroxyurea induces fetal
hemoglobin production in some patients with
sickle cell disease and improves the clinical
condition of some people.
Hydroxyurea also helps to fight against HIV.
Treatment/Prevention
Gene therapy This is a technique whereby the absent or
faulty gene is replaced by a working gene, so that the body
can make the correct enzyme or protein and consequently
eliminate the root cause of the disease.
Leboulch's team removed the bone marrow from mice with a sickle cell disease, isolated the stem
cells—which give rise to red blood cells—and inserted the new anti-sickling gene. When the
genetically modified stem cells were transplanted back into the mice, they produced healthy
round red blood cells.
http://news.nationalgeographic.com/news/2001/12/1213_TVsickle.html
Your Choice/Miscellaneous
The precise mechanism by which sickle cell trait imparts
resistance to malaria is unknown. A number of factors likely
are involved and contribute in varying degrees to the
defense against malaria. People with normal hemoglobin (left of
the diagram) are susceptible to death from
malaria. People with sickle cell disease
(right of the diagram) are susceptible to
death from the complications of sickle
cell disease. People with sickle cell trait,
who have one gene for hemoglobin A and
one gene for hemoglobin S, have a
greater chance of surviving malaria and
do not suffer adverse consequences from
the hemoglobin S gene.
Your Choice/Miscellaneous
Homologues for the HBB gene have been found in a variety
of organisms such as the: rat, mouse (Hbb-b2), African
clawed frog (LOC397871), C. elegans nematode
(C24A3.4), rainbow trout and tropical clawed frog
(Str.8573)
Resources
this is not appropriate APA format
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DOE Genomes:
http://www.ornl.gov/sci/techresources/Human_Genome/posters/chromosome/hbb.shtml
Carnegie Institution Tutorial:
http://carnegieinstitution.org/first_light_case/horn/lessons/sickle.html
Gene Card: http://bioinfo.weizmann.ac.il/cards-bin/carddisp?HBB&search=HBB&suff=txt
Hemoglobin Architecture (CHIME):
http://info.bio.cmu.edu/Courses/BiochemMols/BuildBlocks/Hb.html
SSA & Genetics, Background Info:
http://chroma.gs.washington.edu/outreach/genetics/sickle/sickle-back.html
Your Genes, Your Health, SSA: http://www.ygyh.org/sickle/whatisit.htm
SSA & the use of Bioinformatics:
http://peptide.ncsa.uiuc.edu/tutorials_current/Sickle_Cell_Anemia/SC2001/
Gene Atlas: http://www.dsi.univ-paris5.fr/genatlas/
SSA Virtual Lab: http://k12education.uams.edu/scvlab/montage.htm
Sickle Cell Disease PPT: http://www.scinfo.org/tutorial/Sickle%20Cell/sld001.htm
Questions I WILL ask you…
• What is the name of the gene that causes this
disorder?
• What protein does this gene code for?
• On what chromosomes (and where) is it found?
• How is the mutated protein function different than
the original/normal/intended protein function?
• How does the difference in protein cause a
difference in the cell?
• How are cells with mutated proteins different (in
structure, in function etc.) that normal cells?
• How does the mutated tissue behave differently than
normal tissue?
• How does the organ system function differently than
normal?
• What are the symptoms of this disorder?
• How can this disorder be prevented?
• How can this disorder be treated?
• How is this disorder inherited/continued in future
generations?
• What is the occurrence of this disorder
(quantitatively) in the general population? In special
(gender, ethnic, geographic) populations? Why?