RT Book, Section
A1 Sapienza, Carmen
A1 Hall, Judith G.
A2 Valle, David L.
A2 Antonarakis, Stylianos
A2 Ballabio, Andrea
A2 Beaudet, Arthur L.
A2 Mitchell, Grant A.
SR Print(0)
ID 1181402996
T1 Genome Imprinting in Human Disease
T2 The Online Metabolic and Molecular Bases of Inherited Disease
YR 2019
FD 2019
PB McGraw-Hill Education
PP New York, NY
SN 9780071459969
LK ommbid.mhmedical.com/content.aspx?aid=1181402996
RD 2024/04/18
AB An  important  challenge  for  contemporary  genetics  is  to  understand  the  mechanisms  underlying  those  traits  and  conditions  that  do  not  follow  traditional  patterns  of  inheritance.  Many  recent  observations  demonstrate  that  the  expression  of  a  number  of  traits  in  humans,  mice,  and  other  organisms  depends  on  which  parent  transmitted  the  gene  responsible  for  the  trait.In  both  the  mouse  and  the  human,  inheritance  of  the  entire  chromosome  complement  from  only  one  parent  results  in  developmental  failure.  The  gross  morphologic  complementarity  of  the  phenotypes  yielded  by  inheriting  both  sets  of  chromosomes  from  the  father  versus  inheriting  both  sets  from  the  mother  suggests  that  the  paternal  genetic  contribution  is  important  to  placental  development,  while  the  maternal  contribution  is  essential  for  development  of  the  embryo  proper.Inheritance  of  all  or  part  of  individual  chromosomes  from  only  one  parent  may  also  result  in  an  abnormal  phenotype,  even  if  the  genes  responsible  for  that  phenotype  are  demonstrably  wild-type  by  both  genetic  and  biochemical  criteria.  An  important  mechanism  by  which  such  uniparental  disomy  may  be  achieved  in  the  human  is  by  the  in  utero  reduction  of  trisomies.  Evidence  derived  from  chorionic  villus  sampling  indicates  that  as  many  as  1  percent  of  all  pregnancies  may  carry  uniparental  disomy  for  particular  chromosomes.  Uniparental  disomy  has  been  demonstrated  in  several  cases  of  a  number  of  human  diseases,  including  Beckwith-Wiedemann,  Prader-Willi,  and  Angelman  syndromes.The  mechanism  by  which  differential  expression  of  maternal  and  paternal  genomes  is  achieved  is  unknown  but  there  is  a  strong  correlation  between  parental  origin-specific  gene  expression  and  differential  DNA  methylation  and  chromatin  structure.  The  tendency  to  find  more  than  one  gene  to  be  imprinted  in  a  region  tends  to  argue  for  some  imprinting  controls  to  operate  over  domains  that  are  larger  than  a  single  gene.  Recent  data  also  indicate  that  important  biochemical  differences  between  alleles  at  imprinted  loci  are  manifested  as  asynchronous  replication  of  the  alleles  during  S  phase  of  the  cell  cycle.  In  addition,  “antisense”  transcripts  have  been  shown  to  be  associated  with  silenced  alleles  at  several  imprinted  loci.Regardless  of  the  biochemical  mechanism  by  which  alleles  at  imprinted  loci  are  marked  as  “imprinted,”  cases  of  most  human  disease  phenotypes  that  exhibit  a  strong  parental  origin  effect  may  be  viewed  as  having  failed  to  complete  one  or  more  steps  in  the  imprinting  process.  These  steps  include:  (a)  erasure  of  the  imprint  from  the  previous  generation;  (b)  establishment  of  a  new  imprint  that  is  appropriate  to  the  gender  of  the  individual  in  which  the  gametes  are  being  created;  (c)  transmission  of  a  complete  and  appropriately  imprinted  genome  to  the  zygote;  (d)  stable  inheritance  of  the  maternal  and  paternal  imprint  through  somatic  cell  division;  and  (e)  proper  maintenance  and  translation  of  the  imprint  in  those  somatic  cells  in  which  a  parental  origin-dependent  effect  on  phenotype  is  required  or  observed.*Genetics,  Biochemistry,  and  Molecular  Bases  of  Variant  Human  Phenotypes,  Appendix  1  names  all  the  genes  referred  to  by  their  symbols  (italicized  uppercase)  in  the  present  chapter.