RT Book, Section
A1 Townes, Tim M.
A1 Cavazzana, Marina
A2 Gladwin, Mark T.
A2 Kato, Gregory J.
A2 Novelli, Enrico M.
SR Print(0)
ID 1179345611
T1 Gene Therapy for Sickle Cell Disease
T2 Sickle Cell Disease
YR 2021
FD 2021
PB McGraw-Hill Education
PP New York, NY
SN 9781260458596
LK hemonc.mhmedical.com/content.aspx?aid=1179345611
RD 2024/04/24
AB The  sickle  mutation  is  a  transversion  from  A  to  T  in  the  sixth  codon  of  the  β-globin  gene.  The  sixth  codon  is  normally  GAG,  which  encodes  glutamic  acid,  but  the  transversion  results  in  GTG,  which  encodes  valine.  Valine  forms  a  hydrophobic  projection  on  the  surface  of  the  hemoglobin  tetramer  (α2βS2;  HbS),  and  when  HbS  releases  oxygen,  the  valine  fits  into  a  natural  hydrophobic  pocket  on  a  second  tetramer  in  a  nucleation  event  that  stimulates  the  polymerization  of  thousands  of  HbS  tetramers.  The  elongated  polymers  interact  with  each  other  to  form  a  14-stranded  polymer,  which  is  one  of  the  most  interesting  and  destructive  polymers  in  nature.  The  HbS  polymers  convert  normally  pliable  red  blood  cells  (RBCs)  into  fragile,  rigid  rods  and  sickle-shaped  structures  that  occlude  small  vessels  and  that  lyse  and  release  a  host  of  products  causing  extensive  tissue  and  organ  damage.1Figure  29-1  is  a  magnetic  resonance  angiography  of  the  brain  of  a  young  sickle  cell  patient  who  has  suffered  a  massive  stroke.  Her  left  internal  carotid  artery  is  completely  occluded  and,  therefore,  invisible  in  the  image.  She  has  permanent  right  hemiplegia.  Occlusions  of  smaller  vessels  in  the  brain  in  53%  of  sickle  patients  result  in  “silent  infarcts,”  which  is  a  misnomer  because  they  result  in  cognitive  impairment.2  Pathology  caused  by  occlusions  and  by  extensive  oxidative  stress  in  many  other  tissues  and  organs  result  in  a  severe  disease  that  affects  100,000  patients  in  the  United  States  and  millions  worldwide.