Imprinting: Angelman, PraderWilli, and other syndromes

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ImprintingAngelman, Prader-Willi, and other
syndromes

• Advanced Human Genetics
• Jonathan Wolfe

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androgenetic embryos
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gynogentic and androgenetic embryos

• Experimental ...
• gynogenetic (two female pronuclei)
• androgenetic (two male pronuclei)
• and see also the naturally occurring ...
• ovarian teratoma- 46,XX karyotype, benign
  tumour, many differentiated tissues
• hydatidiform mole- 46, XX karyotype,-
  hyperplasia of trophoblast- choriocarcinoma (50
  0f cases)

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uniparental isodisomy
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Robertsonian translocations

• Fusion of two chromosomes with the loss of the
  short arms

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Mouse maps
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sites

• http//www.mgu.har.mrc.ac.uk/research/imprinting/
• http//www.geneimprint.com/

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references

• Tilghman, 1999 Cell, 96, 185193, The Sins of
  the Fathers and Mothers Genomic Imprinting in
  Mammalian Development
• Vu, and Hoffman, 2000 Genome Research, 10,
  1660-1663, Comparative Genomics Sheds Light on
  Mechanisms of Genomic Imprinting
• Freking et al., 2002 Genome Research 12,
  1496-1506, Identification of the Single Base
  Change Causing the Callipyge Muscle Hypertrophy
  Phenotype, the Only Known Example of Polar
  Overdominance in Mammals
• Ferguson-Smith and Surani, 2001, Science, 293,
  1086-1089Imprinting and the Epigenetic Asymmetry
  Between Parental Genomes
• Nicholls and Knepper, 2001, Ann. Rev. Genomics
  and Hum. Genet., 2, 153-175Genome organization,
  function and imprinting in Prader-Willi and
  Angelman syndromes.
• David A. F. Loebel and Patrick P. L. Tam, 2004,
  Mice without a father, Nature 428, 810-811

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Beckwith Wiedeman Syndrome

• frequency in the general population is about
  1/14,000
• characterized by somatic overgrowth, congenital
  malformations and a predisposition to embryonic
  neoplasia.
• The majority of cases occur sporadically. In up
  to 60 of sporadic cases, the epigenetic changes
  occur at differentially methylated regions within
  11p15.5 in a region of approximately 1 Mb.
• This region contains an imprinted cluster of at
  least 12 genes,
• including
• paternally expressed genes IGF2 and KCNQ1OT1
• maternally expressed genes H19, CDKN1C and KCNQ1

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Transcription regulation in the BWS region
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• Approximately 25 to 50 of BWS patients have
  biallelic expression of the IGF2 gene
• some of these cases exhibit loss of imprinting
  (LOI) of IGF2 which is dependent on
  hypermethylation changes of H19
• Approximately 50 of sporadic BWS have a loss of
  methylation associated to a LOI at KCNQ1OT1, an
  untranslated RNA within the KCNQ1 gene
• Some BWS cases exhibit LOI for KCNQ1OT1 as well
  as LOI for IGF2
• aberrant methylation of KCNQ1OT1 is specifically
  associated with overgrowth and congenital defects
• aberrant methylation of H19 is specifically
  associated with an increased risk of developing
  tumors.

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Angelman, Prader-Willi syndromes

• Usually caused by large (megabase) deletions of
  15q11-q13
• Delete maternal chromosome AS
• Delete paternal chromosome PWS

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• Paternally expressed genes are imprinted in all
  tissues
• UBE3A, is only differentially expressed in parts
  of the brain

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Callipyge

• Beautiful buttocks
• A mutation which arose in a Dorset Ram
• Polar Overdominance

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Polar overdominance

• Heterozygote expresses the phenotype but neither
  homozygote does
• Heterozygote only expresses the phenotype if the
  mutant gene is inherited from the father

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