Sickle Cell Anemia

1
Sickle Cell Anemia

• From DNA to Disorder
• A production

2

• /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)

3
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.

4
Gene(s) Involved DNA Code

• There are various globin genes
• Chromosome 16
• Alpha (3-9mos)
• Zeta (lt8wks)
• Chromosome 11
• Beta (after birth)
• Epsilon (lt8wks)
• Gamma (3-9mos)
• Delta (after birth)

5
Gene(s) Involved DNA Code

• Official Gene Symbol HBB
• Name of Gene Product hemoglobin, beta
• Alternate Name of Gene Product beta globin

6
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.

7
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.

8
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
9
Gene(s) Involved DNA Code

• A variety (376) of hemoglobin mutations exist
  including missense and nonsense substitutions,
  deletions, insertions, duplications and
  rearrangements (including inversions)

10
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.

11
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 alpha-alpha or beta-beta
  interactions, but many alpha-beta hydrophobic
  interactions

12
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.

13
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.   

14
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.
15
Cellular, Tissue Organ effects
A sickled red blood cell filled with sickle
hemoglobin fibers. Several fibers (see arrows)
are outside the cell.
16
Cellular, Tissue Organ effects

• Cycling between polymerization and
  depolymerization causes red blood cell membranes
  to become rigid    

17
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.
18
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.

19
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.

20
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
•      

21
Organism effects
22
Organism effects
23
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.

24
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.

25
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.
26
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

27
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.

28
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.

29
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
  cellswhich give rise to red blood cellsand
  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.co
  m/news/2001/12/1213_TVsickle.html

30
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.
31
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)

32
Resourcesthis is not appropriate APA format

• DOE Genomes http//www.ornl.gov/sci/techresources
  /Human_Genome/posters/chromosome/hbb.shtml
• Carnegie Institution Tutorial http//carnegieinst
  itution.org/first_light_case/horn/lessons/sickle.h
  tml
• Gene Card http//bioinfo.weizmann.ac.il/cards-bin
  /carddisp?HBBsearchHBBsufftxt
• Hemoglobin Architecture (CHIME)
  http//info.bio.cmu.edu/Courses/BiochemMols/BuildB
  locks/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/Sic
  kle_Cell_Anemia/SC2001/
• Gene Atlas http//www.dsi.univ-paris5.fr/genatlas
  /
• SSA Virtual Lab http//k12education.uams.edu/scvl
  ab/montage.htm
• Sickle Cell Disease PPT http//www.scinfo.org/tut
  orial/Sickle20Cell/sld001.htm

33
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?

34

• 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?