(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