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Arya Bagherpour

Book Summary over Easoms Lecture on Thalassemia


(A summary transcribed by Arya Navid Bagherpour the 1
st
(ANB1))jk guys
The Hemoglobin genes are present in two gene clusters
Hemoglobin:
1 !onsist o" t#o pairs o" nonidentical polypeptides$ thus di""erent hemoglobins can
be "ormed by di""erent combinations o" these polypeptides
% &he alpha'like genes are on chromosome 1( and the Beta'like genes are on
chromosome 11 &hese gene clusters have some interesting "eatures:
a) )tructurally related genes are placed close together on the
chromosome
b) &he gene clusters contain pseudogenes (they are related structurally to the
real genes but they cannot be transcribed and*or translated
c) &he cluster on chromosome 1( contains t#o alpha genes o" identical
structure
Note$ not all o" the alpha and beta like globin genes are e+pressed at the same time ,ook
at the diagram
-rom looking at this$ the epsilon and b'looking symbol are limited to the early embryonic
stage$ and the alpha and gamma chains prevail during "etal development
Hb-: is the "etal hemoglobin
HbA: is adult hemoglobin
HbA completely replaces Hb- . months a"ter the birth o" the "etus
More than 4 di!!erent point mutations have been described in the globin genes
"/ost o" these mutations are single amino acid substitutions that can be traced to a single
base substitution in a gene At least hal" o" these mutations do not a""ect the "unction o"
the molecule su""iciently to cause disease &he changes that do a""ect o+ygen transport
varies according to the site and the kind o" the amino acid substitution:
1 Mutations in the heme-binding pocket can cause methemoglobinemia# #hich
replaces the pro+imal histidine #ith tyrosine0 this makes heme inaccessible
methemoglobin reducatase
% Some mutations that affect the interface between the subunits lead to
hemoglobins with abnormal oxygen-binding affinity: Hemoglobins can have
increased o+ygen binding a""inity or lo#er o+ygen binding a""inity
1 Some point mutations lead to abnormal processing of mRNA, premature
degradation of mRNA, or increased proteolytic degradation of the alpha or beta
chain: These mutations can cause thallasemia"like diseases
. Some abnormal hemoglobins cause hemolytic anemia because they hae
abnormal physical properties!
The thalassemias are caused by reduced alpha or beta chain production
1 &his results in anemia
% Also$ the polypeptide (alpha or beta) that is present in e+cess amounts "orms
insoluble aggregates that are damaging to the cell and reduce its li"espan
1 &he di""erent types o" thallasemia
a) alpha thalassemia# 2elative or absolute de"iciency o" alpha chains
b) beta thalassemia# 2elative or absolute de"iciency o" beta chains
c) Thalassemia minor# Hetero3ygous alpha or Beta thalassemia Anemia
may be present but is very mild
d) Thalassemia ma$or# Homo3ygous alpha or beta thalassemia )ever
anemia
%lpha Thalassemia is caused most o!ten by large deletions#
1 &here are "our rather than t#o alpha chain genes in diploid somatic cells /ost
patients #ith this disease have large deletions that remove one or both o" the alpha
genes &he diagram sho#s the e""ect o" di""erent gene deltions:
4+planation o" diagram:
A: one gene is deleted: asymptomatic
B: &#o genes deleted on di""erent chromosomes: alpha thalassemia minor$ very mild
anemia
!: &#o genes deleted on the same chromosome: alpha thalassemia minor$ very mild
anemia
5: &hree genes deleted: Hemoglobin H disease$ moderately severe anemia
' A beta 4 tetramer (hemoglobin H& is the predominant hemoglobin in patients #ith deltions o"
the three alpha genes 6t is unstable causing it to denature gradually and "orm inclusion bodies in the
cells
4 All "our genes deleted: hemoglobin Barth7s disease$ hydrops "etalis 8 "atal
' Because alpha chains are re9uired both be"ore and a"ter birth$ the "etus is a""ected as #ell$ and
a complete lack o" alpha chains is "atal be"ore or at birth :nder these conditions$ an abnormal
hemoglobin o" subunit gamma 4 (hemoglobin Barths) is "ormed that has a ten"old'higher o+ygen
a""inity than hemoglobin A0 thus it can7t "unction as an e""ected o+ygen carrier
Many di!!erent mutations can cause Beta thalassemia
1 !an be caused by large deletions$ but most patients have single'base substitutions
% ;romoter mutations$ splice site mutations$ nonsense and "rameshi"t mutations$ and
a mutation in the polyadenylation signal all have been observed in di""erent
patients )plice site mutations are very common
1 Beta not"thalassemia# mutations that result in a complete absence o" Beta chains
in the homo3ygous state 6" le"t untreated$ patients are likely to die o" severe
anemia and intercurrent in"ections during childhoold 6" treated$ patients are given
regular trans"usions o" blood or packed erythrocytes$ but are likely to die a"ter the
age o" %< due to iron overload 'es!errio(amine )a drug&* an iron chelator "orms
soluble iron comple+ that can be e+creted by the kidneys
. Beta plus"thalassemia# mutations that cause a decrease in Beta chain synthesis$
and homo3ygotes have a small number o" Beta chains /ilder "orms o" this
disaese$ #ith classical e+pression intermediate bet#een the classical minor and
major "orms$ are called thalassemia intermedia
= hetero3ygous state (betha thalassemia minor& is a benign condition that re9uires
no treatment
( &he homo3ygous state is kno#n as +ooleys anemia# this is a severe disease 6t is
the most common type o" severe thalassemia in the /editerranean region and in
many other countries )evere anemia develops during the "irst year o" li"e (this
occurs bc "etal hemoglobin diminishes during this "irst year) &his disease usually
leads to a condition kno#n as abortive erythropoiesis# 2B! precursors contain
aggregates o" alpha chains$ #hich appear abnormal to phagocytic cells #hich
destroy them be"ore they mature &hus$ the bone marro# responds to the anemia
by #orking e+tra hard (the conse9uent e+pansion o" red bone marro# leads to
"acial de"ormities)
High levels o! !etal hemoglobin protect the patient !rom the e!!ects o! Beta
thalassemia and sickle cell disease
"A high level o" Hb- in adults is protective in all Beta chain abnormalities$ including
sickle cell disease

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