GENOMIC IMPRINTING

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GENOMIC IMPRINTING
What is an imprinted gene? Using Prader-Willi
and Angelman syndrome as an example describe the
imprinting control centre and explain how the
imprint is maintained or erased within the germ
line. What are the clinical and diagnostic
implications of errors in this process?
ELAINE WHITFIELD
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What Is an Imprinted Gene?

• A gene which is expressed from only one allele in
  a parent-specific manner due to epigenetic
  modification
• Mouse embryo manipulation in vitro provided first
  clear evidence for the phenomenom of gametic
  imprinting
• Paternal genome more important for proliferation
  of the extraembryonic tissues
• Maternal genome more important for
  post-implantation embryonic development

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• Selective breeding studies in mice and naturally
  occurring cases of UPD in humans have shown
  that only a minor proportion of the genome is
  imprinted
• 80 human genes have been determined to be
  imprinted to date
• Imprinted genes are clustered within the genome
• Imprinting centres - specific DNA sequences
  identify some of these clusters as targets of the
  imprinting machinery of the gamete

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How Does Imprinting Occur?

• Genes are stamped so that the expression of the
  inherited information is modified according to
  whether it is passed on via the egg or sperm
• Differential allele-specific DNA methylation is
  present in imprinted regions localised to
  differentially methylated regions (DMRs)
• The Prader-Willi / Angelman region on chromosome
  15 is a well-characterised imprinted region

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Prader-Willi Syndrome

• PWS - 1 in 20 000 births failure to thrive
  during infancy, hyperphagia and obesity
  during early childhood, mental retardation
  behavioural problems
• Due to the loss of paternally expressed genes in
  2Mb imprinted domain at 15q11-q13
• No single gene has been shown to cause PWS when
  its expression is lost
• PWS Imprinting Control Region (ICR) mapped to a
  segment of 4kb that spans 1st exon and promoter
  of SNRPN/SNURF locus
• 70 cases of PWS due to paternal deletions in
  15q11-13 region
• 20-30 cases due to maternal UPD
• 5-10 cases due to paternally derived
  microdeletions of the ICR, loss of imprinting at
  the ICR (de novo methylation of the paternal
  allele) or balanced translocations that disrupt
  SNURF/SNRPN gene

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Angelman Syndrome

• AS - 1 in 15 000 births mental retardation,
  speech impairment behavioural abnormalities
• AS arises from the loss of a single gene
  maternally expressed UBE3A which is imprinted
  only in the brain
• 65-70 cases maternally derived deletions of
  15q11-q13
• 5 cases caused by paternal UPD
• 10 cases maternal UBE3A mutations
• 5 cases imprinting defects
• 10 caused by an unknown defect

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The PWAS region of chr. 15q11-q13
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(No Transcript)
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Erasure re-establishment of the imprint in the
germ line
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Diagnosis of Prader-Willi / Angelman Syndrome

• DNA methylation testing to detect abnormal
  parent specific imprinting will detect gt99 of
  PWS and 75 of AS affected individuals
• If paternal expression is shown to be absent
  PWS
• If maternal expression is shown to be absent AS
• If normal methylation in ? AS direct mutation
  analysis of UBE3A may be considered

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174bp 100bp
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• If PWS or AS are detected it is important to
  determine the mechanism responsible
• De novo deletions and UPD have a very low
  recurrence risk
• Imprinting mutations have a recurrence risk of up
  to 50
• UBE3A mutations have recurrence risk as high as
  50
• AS cases with no cause identified-recurrence risk
  is high and no testing available

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In Conclusion

• Imprinting is a complex process which is critical
  for normal development
• Few genes are imprinted these are clustered
• Defects in imprinting are implicated in abnormal
  fetal growth and disease.
• Mechanism is important to discover as recurrence
  risk may be very high