Download Lecture 2 4285 2016

What we are going to review
today:
Imprinting
Beckwith-Weidman Syndrome
Angelman Syndrome
Prader-Willi Syndrome
DNA Methylation
• Beckwith-Wiedemann syndrome
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DNA Methylation
• Beckwith-Wiedemann syndrome
– Above average birth weight
– Increase growth after birth (>95% growth
curve)
– Enlarged organs
– Hypoglycemic following birth
– Increase risk of cancers
• Imprinting defect located at 11p15.5
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Beckwith-Wiedemann syndrome
• Genetic causes of BWS:
– Maternal DMR hypermethylation
– UPD
– Remainder unknown
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The Journal of Pathology
Volume 211, Issue 3, pages 261-268, 18 DEC 2006 DOI: 10.1002/path.2116
http://onlinelibrary.wiley.com/doi/10.1002/path.2116/full#fig1
The Journal of Pathology
Volume 211, Issue 3, pages 261-268, 18 DEC 2006 DOI: 10.1002/path.2116
http://onlinelibrary.wiley.com/doi/10.1002/path.2116/full#fig3
Genes Dev. Vol. 11, No. 23, pp. 3128-3142, December 1, 1997
Mouse mutant embryos overexpressing IGF-II exhibit phenotypic
features of the Beckwith-Wiedemann and Simpson-GolabiBehmel syndromes
Jonathan Eggenschwiler,1 Thomas Ludwig,2 Peter Fisher,3 Philip A.
Leighton,4,5 Shirley M. Tilghman,4 and Argiris Efstratiadis1,6
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Prader-Willi and Angelman
Syndrome
Prader-Willi
Angelman
Mild mental retardation
endocrine abnormalities
Severe impairment and
loss of speech
seizures and ataxia
temper tantrums
unprovoked laughter
Obesity
1 in 15,000
hyperactivity
1 in 15,000
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Prader-Willi and Angelman
Syndrome
• Angelman syndrome
• UBE3A
• Paternally imprinted
• Prader-Willi syndrome
15q11-13
• Maternally imprinted genes
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Prader-Willi and Angelman
Syndrome
• UBE3A is paternally silenced
• This primarily occurs in brain, other tissues
show biallelic expression
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Prader-Willi and Angelman
Syndrome
• What happens in each pathologies?
• If the maternal copy of chromosome 15 is
missing, then genes normally expressed
from this parental origin are not expressed
• Consequences…
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Prader-Willi and Angelman
Syndrome
• If paternal chromosome 15 is missing, then only
the maternally expressed proteins are made
• Consequence: UBE3A is ok, but other genes in
the region are not expressed…Prader-Willi
syndrome
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Prader-Willi and Angelman
Syndrome
• Thus, two different diseases based on the
cells “memory” of methylation – alter the
memory, alter the phenotype
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Prader-Willi and Angelman
Syndrome
• How do you “lose” chromosome 15?
– Microdeletion of 15q11-13 on one chromsome – 70%
– Single gene mutation – 15% of AS
– Defect in imprinting centre (IC) – 5%
– Uniparental Disomy – 30% of PWS, 5% AS
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Prader-Willi and Angelman
Syndrome
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Uniparental Disomy
• Receive two chromosomes from one
parent
• Eg. Paternal disomy – both of
chromosome 15 are from father, thus both
have silenced UBE3A
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Uniparental Disomy
• How does it happen?
• Trisomic Rescue - majority
• Monosomic Duplication
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Meiosis I
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Meiosis II
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Meiosis I Non-disjunction
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Meiosis I Non-disjunction
Fertilization
Trisomy
Meiosis I non-disjunction
always creates a problem
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Meiosis II Non-disjunction
Fertilization
Fertilization
Trisomy
Normal
2/3 gametes
following Meiosis
II non-disjunction
are normal
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Trisomy
• Trisomy for most autosomal chromosomes
is lethal
• BIG exception: Trisomy 21, smallest autosomal
chromosome, fewest genes, not lethal
• Under rare conditions, some autosomal
trisomies can escape – Trisomic Rescue
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Trisomic Rescue following Meiosis I
Non-disjunction
+
Two copies of homologous, but
not identical, chromosomes
Maternal
Anaphase lag
Maternal
Paternal
M,M
1/3
M,P
1/3
M,P
1/3
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Trisomic Rescue following Meiosis II
Non-disjunction
+
Two copies of
identical
chromosomes
Anaphase lag
M,M
1/3
M,P
2/3
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Uniparental Disomy
• How does it happen?
• Trisomic Rescue - majority
• Monosomic Duplication
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Monosomic Duplication
+
Two identical copies of
paternal chromosome isodisomy
P,P
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Parental Origin Determines
Phenotype
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{
Prader-Willi Syndrome
M,M
Prader-Willi Syndrome
M,M
Angelman Syndrome
P,P
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Prader-Willi and Angelman
syndrome
• Non-disjunction is more common in Meiosis I in
females
• In human females, Meiosis I starts before birth but is arrested
at diplotene stage (late prophase I)
• Oocytes sit like this for decades
• Complete meiosis II once each month
• While arrested at the diplotene stage, the tetrad chromosomes
are held together by chiasmata (formed during recombination)
• If a pair of chromosomes don’t undergo recombination, the
lack of chiasmata can contribute to non-disjunction
• Uniparental Disomy – 30% of PWS, 5% AS
Maternal non-disjunction and trisomic rescue
leading to the pair of maternal chromosomes
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Uniparental Disomy and Human
Disease
Eric Engel. Some lessons from uniparental disomy (UPD) in the framework of contemporary cytogenetics and molecular biology.
Atlas Genet Cytogenet Oncol Haematol. December 2003.
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Trisomic rescue of Meiosis II nondisjunction can have other problems
{
Anaphase lag
Pair of identical
chromosomes
(isochromosomes)
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Uniparental disomy as a mechanism
for human genetic disease.
Spence JE, Perciaccante RG, Greig GM, Willard HF, Ledbetter DH,
Hejtmancik JF, Pollack MS, O'Brien WE, Beaudet AL.
Am J Hum Genet. 1988 Feb;42(2):217-26.
CFTR-/+
CFTR-/-
{
CFTR+/+
Uniparental
isodisomy and
reduction to
homozygosity
Pair of identical
Chromosome 7
Harboring CFTR mutation
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