Objectives 1) Describe imprinting 2) Know the multiple genetic mechanisms of Prader-Willi and Angelman Syndrome 3) Explain how the genetics of Prader-Willi and Angelman Syndrome demonstrate the phenomena of imprinting. - Angelman Syndrome (AS): children are very developmentally disabled, always smiling!- Prader Willi Syndrome (PWS): developmental delay, infants are weak, toddler years= kids develop insatiable eating and obsessive behaviors, obesity.!- Both result from a deletion on chromosme 15q11-13 (de novo)!- PWS/AS critical region!- Only need deletion on 1 chromosome!- Parent of origin effect - PWS: Loss of gene expression from the paternal chromosome 15= had a deletion on chrom 15 that they inherited from their dad!- AS: Loss of gene expression from the maternal chromosome 15= had a deletion on chrom 15 that they inherited from their mom - All of us inherit one copy of each chromosome from each parent. - Imprinting= differential gene expression based on parent of origin,!- Thru imprinting, gene expression can be suppressed.!-->methylation of CpG rich regions, histone mods by deactyl., antisense RNA - Imprinting is normal--about 100 genes are imrinted, but this # is changing.!- Imprinted genes tend to cluster together.!- The way genes are expressed from that imprinted region depends on parent of origin.!- Normal situation-->!- You have a chromosome 15 from dad and one from mom. So you have the pair, but genes X, Y, and Z are only expressed on the chrom from dad, and genes A and B are only expressed on the chrom from mom.!- Prader-Willi Syndrome - Dad had a deletion on his chrom. 15, so when you inherited it, it had a deletion in Gene X, Y, and Z (and A and B, but you wouldn't express them from dad anyways) (for ex.). Mom doesn't have the deletion, so you have a full chromosome 15 from her, but youdon't express X, Y, and Z on a chrom. from mom-->thus you have the phenotype for missing genes X, Y, and Z. = PWS.!- Angelman Syndrome - Mom had a deletion on her chrom. 15, so when you inherited it from her, it had a deletion in genes: A, B, X, Y, and Z, but you wouldn't express XYZ from her anyways, so you are missing A and B from mom. Dad doesn't have the deletion, so you have a full chrom 15 frmo him, but you don't express A and B from dads -->thus you have the pheno for missing gnes A and B= AS. - Other mech. for PWS= Maternal Uniparental Disomy - Where both copies of the same chromosome originate from the same parent.!- Caused by aneuploidy from maternal non-disjunction at conception followed by loss of a chromosome so that only 2 chroms are left.= was initially a trisomic conception - Paternal chrom lost--> uniparental disomy!- a zygote w/3 chroms 15 would die, so the zygote loses one= a post-zygotic event - Paternal Uniparental Disomy can cause AS 1-2% of the time!- non-disjunc. is rare in male meiosis!- Maternally inherited point mutations in UBE3A cause AS in 10% of cases!- If there is a point mutation in UBE3A and the other copy isn't expressed, then all UBE3A expression is lost (essentially Gene A in above ex.)!!!!!!!- No deletion in either chrom 15, no changes in methylation. There is a pt. mutation. If a man has the pt mutation, his kids will be fine, but his daughter could be carriers. The daughters could then have kids with AS--would be 50% chance with each pregnancy if daughters are carriers.!!- Final mechanism: Mutations in the imprinting center (either male or female) on chromosome 15 - At germ cell formation, all imprints are erased!- New imprint is est. thru the imprinting center!- If a new parent appropriate imprint can't be est., then the parent specific genes are methylated and silenced inappropriately!Ex. A woman has 2 chrom. 15's--one from from and one from dad. Chr 15 from dad has a mutation in the paternal imprinting center. When she tries to erase and reset it, she can't do it. So some of the chrom 15's she passes on (50%) will have a male imprint (won't express A and Bgenes). !--> a zygote would have 2 sets of expressed paternal imprinting (X, Y, Z expressed on 1 and X, Y, Z, expressed on the other, no A or B expression) and 0 sets of expressed female chrom. 15 genes from that location.!- The imprinting center is responsible for the appropriate imprint on each chromosome in primordial germ cells. Need IC's to reestablish the appropriate imprint.!- If the mutation in IC occurs in a male, he can't reset to a male imprint in the germ cells that have the IC mutation inherited from his mom. The chromosome with the IC mutation will have a female imprint.!-->can lead to fams w/more than 1 child w/the syndrome!- His germ cells look like this !- have 2 copies, pass on to children!!PWS Theme and Summary - Loss of paternal alleles on chromosome 15!- Mechanisms:!- Deletion of paternal 15q11-13 (70%)!- Maternal uniparental disomy (29%)!- Mutation in paternal imprinting center in the father's maternal chromosome 15 (1%)!!AS Theme and Summary - Loss of maternal alleles on chromosome 15!- Mechanisms:!- Deletion of maternal 15q11-13 (70%)!- Paternal uniparental disomy (1-2%)!- Mutation in maternal imprinting center in the mother's paternal chromosome 15 (5%)!- Mutation in UBE3A (10%)!- Remainder are unknown!- You can AS any way that causes you to not have or not express that section of chrom 15 (A and B genes) that are maternally expressed normally!!- How to test for it: methylation studies (won't pick up UBE3A muts)!- Why is imprinting important?!- Defects: role in diabetes, obesity, cancer!- Can be influenced by envi and nutrition, assisted
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