What we are going to review today: Imprinting Beckwith-Weidman Syndrome Angelman Syndrome Prader-Willi Syndrome

3 DNA Methylation Beckwith-Wiedemann syndrome

4 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

5 Beckwith-Wiedemann syndrome Genetic causes of BWS: –Maternal DMR hypermethylation –UPD –Remainder unknown

6

The Journal of Pathology Volume 211, Issue 3, pages , 18 DEC 2006 DOI: /path Volume 211, Issue 3,

The Journal of Pathology Volume 211, Issue 3, pages , 18 DEC 2006 DOI: /path Volume 211, Issue 3,

9 Genes Dev. Vol. 11, No. 23, pp , December 1, 1997 Mouse mutant embryos overexpressing IGF-II exhibit phenotypic features of the Beckwith-Wiedemann and Simpson-Golabi- Behmel syndromes Jonathan Eggenschwiler,1 Thomas Ludwig,2 Peter Fisher,3 Philip A. Leighton,4,5 Shirley M. Tilghman,4 and Argiris Efstratiadis1,656

14 Prader-Willi and Angelman Syndrome Prader-WilliAngelman Mild mental retardationSevere impairment and loss of speech endocrine abnormalitiesseizures and ataxia temper tantrumsunprovoked laughter Obesityhyperactivity 1 in 15,000

15 Prader-Willi and Angelman Syndrome Angelman syndrome UBE3A Paternally imprinted Prader-Willi syndrome Maternally imprinted genes 15q11-13

16 Prader-Willi and Angelman Syndrome UBE3A is paternally silenced This primarily occurs in brain, other tissues show biallelic expression

17 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…

21 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

22 Prader-Willi and Angelman Syndrome Thus, two different diseases based on the cells “memory” of methylation – alter the memory, alter the phenotype

23 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

24 Prader-Willi and Angelman Syndrome

25 Uniparental Disomy Receive two chromosomes from one parent Eg. Paternal disomy – both of chromosome 15 are from father, thus both have silenced UBE3A

26 Uniparental Disomy How does it happen? Trisomic Rescue - majority Monosomic Duplication

27 Meiosis I

28 Meiosis II

29 Meiosis I Non-disjunction

30 Meiosis I Non-disjunction Fertilization Trisomy Meiosis I non-disjunction always creates a problem

31 Meiosis II Non-disjunction Fertilization Trisomy Normal 2/3 gametes following Meiosis II non-disjunction are normal

32 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

33 Trisomic Rescue following Meiosis I Non-disjunction Two copies of homologous, but not identical, chromosomes + Maternal Paternal M,M 1/3 M,P 1/3 M,P 1/3 Anaphase lag

34 Trisomic Rescue following Meiosis II Non-disjunction + M,M 1/3 M,P 2/3 Two copies of identical chromosomes Anaphase lag

35 Uniparental Disomy How does it happen? Trisomic Rescue - majority Monosomic Duplication

36 Monosomic Duplication + P,P Two identical copies of paternal chromosome - isodisomy

37 Parental Origin Determines Phenotype Prader-Willi Syndrome M,M { 15 M,M Prader-Willi Syndrome P,P Angelman Syndrome

38 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

39 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.

40 Trisomic rescue of Meiosis II non- disjunction can have other problems Anaphase lag { Pair of identical chromosomes (isochromosomes)

41 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 Feb;42(2): CFTR -/+ CFTR +/+ CFTR -/- { Pair of identical Chromosome 7 Harboring CFTR mutation Uniparental isodisomy and reduction to homozygosity