Cellular and molecular mechanisms in BWS
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Cellular and molecular mechanisms in BWS
Beckwith-Wiedemann syndrome
Carolina CurtoInês G. CostaRui DuarteSandra Cró
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GENETIC BASIS
· Histone modification· Non coding RNAs· DNA methylation
ICs (DMRs)
Genomic Imprinting
Fig1. Ilustrative image of chromossome 11p15.5. Source:http://www.intellmed.eu/cs/mdl/info/lsi-h-ras-orange/index.html
Growth disorder associated with abnormalities in the imprinted domain of chromossome 11p15.5
Gene expression is altered according to the parental origin of the allele.
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GENETIC BASIS
Chromossome 11p15.5
· Histone modification· Non coding RNAs· DNA methylation
ICs (DMRs)
Genomic Imprinting
Fig2. Ilustrative image of the mecanisms of DNA methylation .Source:http://cnx.org/content/m26565/1.1/
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GENETIC BASIS
Maternal expressed genes:CDKN1C; KCNQ1; H19
Methylated IC2 and Non methylated IC1
Paternal expressed genes:IGF2 ; KCNQ10T
Methylated IC1 and Non methylated IC2
Fig3. Schematic representation of chromossome 11p15.5 imprinted region on a normal individual. Source:Rosanna Weksberg,Cheryl Shuman and J. Beckwith: Practical Genetics- Beckwith-Wiedemann syndrome. European Journal of Human Genetics (2010);18,8-14.
Fig4. Schematic representation revelent genes from chromossome 11p15.5.
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GENETIC BASIS
Fig5. Schematic representation of chromossome 11p15.5 imprinted region altered. Source:Rosanna Weksberg,Cheryl Shuman and J. Beckwith: Practical Genetics- Beckwith-Wiedemann syndrome. European Journal of Human Genetics (2010);18,8-14.
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GENETIC BASIS
Paternal uniparental di-somy (20%)
IC1 gain of methylation (7%)
IC2 loss of methylation (50%)
CDKN1C mutations (10%)
Translocations/Inver-sions/Duplications (2%)
Unknown (11%)
Fig6. Distribution of BWS genetic causes.
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GENETIC BASISPaternal
Uniparental Disomy
(Segmental)
Mosaic Distribution
Fig7. Schematic representation of Segmental Uniparental disomy mechanism. Source:http://www.peds.ufl.edu/divisions/genetics/teaching/syndrome_gene_maps.htm
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IC2 LOSS OF METHYLATION
Imprinting control region 2
REGULATES
CDKN1C gene
hypomethylated
Gene activity is reduced
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IC2 LOSS OF METHYLATION
Cyclin-dependent kinase inhibitor 1C
Responsible for restraining growth
Cyclin-dependent kinases regulate the cell cycle. They must be binded to a cyclin in
order to be active.
CDKN1C binds to CDK and distorts cyclin binding
CDKN1C acts as a tumor suppressor
BWS Overgrowth and high risk of tumors
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IC1 GAIN OF METHYLATION
Insulin-like growth factor 2
Promotes cell division before birth
IC2 hypermethylation Increased activity of IGF2 gene
Overgrowth and high risk of tumors(embryonal tumors)
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LOSS OF IMPRINTING
Normally
IGF2Maternal copy
Paternal copy
INACTIVE ACTIVE
LOI
IGF2Maternal copy
Paternal copy
ACTIVE ACTIVE
Over-expression of IGF2 gene, which might stimulate the development of tumor cells
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SYMPTOMS• Macrosomia • Anterior linear ear lobe• Creases/posterior helical ear pits• Macroglossia• Omphalocele/umbilical hernia• Visceromegaly • Embryonal tumors (Wilms tumor,
hepatoblastoma, neuroblastoma, rhabdomyosarcoma) in childhood
• Hemihyperplasia • Cytomegaly of the fetal adrenal cortex
(pathognomonic)• Renal abnormalities including structural
abnormalities, nephromegaly, nephrocalcinosis, later development of medullary sponge kidney
• Placental mesenchymal dysplasia • Cardiomegaly• Hypoglycemia Fig7. Illustrative pictures of symptoms related to this condition.
Source:http://www.perinataljournal.com/20110193008;http://atlasgeneticsoncology.org/Kprones/HemihyperplasiaID10046.html;http://www.pediatricsconsultant360.com/article/newborn-macroglossia-mass-umbilical-area-and-hypoglycemia
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DIAGNOSISBlood analysisAbdominal X-RaysMRIs and EcosGenetic Studies
Clinical Evaluation
Methylation sensitive
MLPA
Southern blotting
Q-PCR determination
of copy numberGUSB
Fig8. Different techniques used in BWS diagnosis. Source: Algar E, Dagar V, Sebaj M, Pachter N. An 11p15 imprinting center region 2 deletion in a family with Beckwith-Wiedemann syndrome provides insights into imprinting control at CDKN1C.PLoS One. 2011;6:e29034. doi: 10.1371/journal.pone.0029034.
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DIAGNOSIS
Fig9. Schematic representation of the approches used to diagnose BWS . Source:Rosanna Weksberg,Cheryl Shuman and J. Beckwith: Practical Genetics- Beckwith-Wiedemann syndrome. European Journal of Human Genetics (2010);18,8-14.
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TREATMENT
Standard supportive medical and surgical stratagiesDosing of α-fetoproteinTumor surveillance
Prenatal diagnosis
Fig10. Surgical treatment for macroglossia. Source:http://curiosoebizarroo.blogspot.pt/2010/08/macroglossia.html
Fig11. CT scan image of bilateral Wilms Tumor. Source:http://med.brown.edu/pedisurg/Brown/IBImages/Abdomen/BilatWilms.html
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BIBLIOGRAPHYhttp://atlasgeneticsoncology.org/Kprones/HemihyperplasiaID10046.htmlhttp://cnx.org/content/m26565/1.1/http://emedicine.medscape.com/article/919477-clinical#a0218http://ghr.nlm.nih.govhttp://med.brown.edu/pedisurg/Brown/IBImages/Abdomen/BilatWilms.htmlhttp://www.bv.fapesp.br/pt/bolsas/137779/investigacao-molecular-funcao-cdkn1c-p57kip2/http://www.chc.min-saude.pt/servicos/Genetica/beckwith-wiedemann.htmhttp://www.intellmed.eu/cs/mdl/info/lsi-h-ras-orange/index.htmlhttp://www.ncbi.nlm.nih.gov/pubmed/15811927http://www.pediatricsconsultant360.com/article/newborn-macroglossia-mass-umbilical-area-and-hypoglycemiahttp://www.peds.ufl.edu/divisions/genetics/teaching/syndrome_gene_maps.htmhttp://www.perinataljournal.com/20110193008Rosanna Weksberg,Cheryl Shuman and J. Beckwith: Practical Genetics- Beckwith-Wiedemann syndrome. European Journal of Human Genetics (2010);18,8-14.Jacqueline R Engel, Alan Smallwood, Antonita Harper, Michael J Higgins, Mitsuo Oshimura,Wolf Reik, Paul N Schofield, Eamonn R Maher: Epigenotype-phenotype correlations in Beckwith-Wiedemann syndrome; J Med Genet 2000;37:921–926Shaffer LG, Agan N, Goldberg JD, Ledbetter DH, Longshore JW, Cassidy SB. American College of Medical Genetics statement of diagnostic testing for uniparental disomy. Available online. 2001. Accessed 6-26-12.Algar E, Dagar V, Sebaj M, Pachter N. An 11p15 imprinting center region 2 deletion in a family with Beckwith-Wiedemann syndrome provides insights into imprinting control at CDKN1C.PLoS One. 2011;6:e29034. doi: 10.1371/journal.pone.0029034.