TY  - CHAP
M1  - Book, Section
TI  - The Sex Chromosomes and X Chromosome Inactivation
A1  - Willard, Huntington F.
A2  - Valle, David L.
A2  - Antonarakis, Stylianos
A2  - Ballabio, Andrea
A2  - Beaudet, Arthur L.
A2  - Mitchell, Grant A.
PY  - 2019
T2  - The Online Metabolic and Molecular Bases of Inherited Disease
AB  - The  sex  chromosome  constitution  differs  between  males  and  females.  The  Y  chromosome  is  normally  found  only  in  males  and  is  responsible  for  primary  sex  determination,  but  has  relatively  few  other  functions.  The  X  chromosome  is  present  in  normal  males  in  one  copy  and  in  normal  females  in  two  copies.  X  chromosome  inactivation  acts  as  a  means  of  dosage  compensation  by  inactivating  one  of  the  two  X  chromosomes  in  female  somatic  cells  early  in  development.The  active  and  inactive  X  chromosomes  are  distinguished  by  a  number  of  features.  In  addition  to  being  largely  transcriptionally  repressed,  the  inactive  X  becomes  late  replicating,  heterochromatic  (forming  the  Barr  body  in  interphase  nuclei),  and  extensively  methylated  at  gene  control  regions.  All  these  features  can  be  used  in  clinical  cytogenetic  settings  to  determine  whether  an  X  chromosome  is  active  or  inactive.  X  chromosome  inactivation  is  believed  to  be  random  at  the  blastocyst  stage  of  development.  Accordingly,  females  heterozygous  for  X-linked  traits  are  mosaic  for  two  cell  types  that  express  one  or  the  other  X  chromosome.  Considerable  variation  occurs  in  the  proportion  of  the  two  expected  cell  types  in  different  individuals.  At  least  5  to  10  percent  of  normal  females  demonstrate  extreme  skewing  of  X  inactivation,  in  which  a  cell  type  expressing  one  X  predominates  over  the  other  cell  type.  In  heterozygotes  for  an  X-linked  disorder,  this  skewing  of  X  inactivation  correlates  with  the  degree  to  which  females  demonstrate  symptoms  of  the  X-linked  disease.  X  inactivation  is,  therefore,  a  key  determinant  of  the  clinical  phenotype  in  female  carriers  of  X-linked  diseases.  In  several  disorders,  such  as  X-linked  immunodeficiencies,  postinactivation  cell  selection  is  typically  observed  in  affected  tissues,  and  nonrandom  X  inactivation  of  the  X  carrying  the  mutant  allele  is  observed.Not  all  X-linked  genes  are  subject  to  X  chromosome  inactivation.  Of  the  few  hundred  X-linked  genes  examined  for  X  inactivation  status,  several  dozen  genes  have  been  described  that  “escape”  X  inactivation  and  continue  to  be  expressed  from  both  active  and  otherwise  inactive  X  chromosomes.  These  genes  are  located  in  several  regions  of  the  X  chromosome  and  can  be  clustered  together  or  interspersed  with  genes  known  to  be  subject  to  X  inactivation.  Extrapolating  from  current  studies,  it  is  possible  that  many  hundreds  of  the  expected  total  of  several  thousand  X-linked  genes  will  escape  X  inactivation.  These  genes  are  candidates  to  explain  the  clinical  symptoms  found  in  patients  with  X  chromosome  aneuploidy  in  whom  additional  X  chromosomes  are  invariably  inactive.X  inactivation  requires  a  locus—the  X  inactivation  center—on  the  long  arm  of  the  chromosome  in  band  Xq13.2.  In  most  instances,  structurally  abnormal  X  chromosomes  found  in  patients  contain  the  X  inactivation  center  and  are  nonrandomly  inactivated.  The  gene  for  inactive  X  [Xi]-specific  transcripts  (XIST)  gene  maps  within  the  X  inactivation  center  region  and  plays  a  critical  role  in  X  inactivation.  XIST  is  only  expressed  from  inactive  X  chromosomes  and  produces  an  RNA  molecule  that  remains  associated  with  the  inactive  X.  Although  its  mechanism(s)  of  action  is  not  understood  completely,  XIST  is  useful  as  a  marker  for  X  inactivation,  as  its  expression  in  patients  is,  ...
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
Y2  - 2024/04/23
UR  - ommbid.mhmedical.com/content.aspx?aid=1181418428
ER  -