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p57: Beckwith-Wiedemann Syndrome. Presented By: Jameeka Carrington. Symptoms of BWS. Large body size (macrosomia) Large tongue (macroglossia) Large organs (visceromegaly) Abdominal wall defects (i.e. umbilical hernia ) Hypoglycemia (low blood sugar). Symptoms of BWS. - PowerPoint PPT Presentation
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Symptoms of BWS
Large body size (macrosomia) Large tongue (macroglossia) Large organs (visceromegaly)Abdominal wall defects (i.e.
umbilical hernia )Hypoglycemia (low blood sugar)
Symptoms of BWS
Metopic Ridge- a ridge of bone or suture line on the forehead between the two halves of the frontal bone. The ridging is caused when the two halves close prematurely.
www.nlm.nih.gov/medlineplus/ency/article/001186.htm
Symptoms of BWSMicrocephaly-
abnormal smallness of the head
Macroglossia- enlarged tongue
Umbilical hernia- protrusion of the intestines through the abdominal wall in the navel region
www.nlm.nih.gov/medlineplus/ency/article/001186.htm
Symptoms of BWSIncreased predisposition to tumor
developmentWilms’ tumorAdrenocortical carcinomaRhabdomyosarcomaHepatoblastoma
Tests for BWS
Bone X-rayBlood tests for low sugarUltrasound of the abdomenX-ray of the abdomenMRI of the abdomenChromosome studies
Genetic Basis of BWS85% of cases are sporadicInherited in autosomal dominant fashionMapped to chromosome 11p15
Translocation breakpoints found within chromosome map to three distinct regions
Region 1, BWSCR1, contains 5 translocation breakpoints, which all disrupt the KCNQ1 gene and is the region of primary concern
p57 Member of the Cip/Kip
family of mammalian CKI’s along with p21 and p27
Differs from p21 and p27 in structure by insert of proline/alanine rich or acidic motifs following the Cdk inhibitory domain
Inhibits G1 cyclin-Cdk complexes by binding to cyclin and blocking the catalytic site of the associated Cdk
Expressed during embryonic development
The p21 Family of CDK inhibitors(p21CIP1/WAF1, p27KIP1, p57KIP2)
CDK
Cyclin
active
p21+
inactive
CDK
Cyclinp21
p27Kip1
Cyclin ACDK2
Russo et al. (1996) Nature 382:325
Cyclin A
CDK2
Jeffrey et al. (1995) Nature 376:313
IGFIIInsulin-like growth factor II, or IGFII, is a
single chain polypeptide that is 47% homologous with insulin
FunctionsMediates growth hormone actionStimulates the growth of cultured cellsStimulates the action of insulinInvolved in development and growthAutocrine regulator of cell proliferation
Imprinting of p57 and IGFII
p57 is paternally imprinted in the genome IGFII is maternally imprinted in the genomeGenomic imprinting is the reversible modification
of DNA that causes differential expression of maternally or paternally inherited genes
A gene which is imprinted, is inactivated, by being methylated
Imprinting suppresses gene transcription and takes place during gametogenesis
Chromosome 11 is one of only nine chromosomes that are suspected to have imprinted regions
p57 and IGFII Act as Antagonists
Several studies have also shown that IGFII expression down regulates the activity of p57
p57 is a negative regulator of cell proliferation
IGFII is a positive regulator of cell proliferation
Both over expression of IGFII and inhibited expression of p57 result in BWS symptoms
Together, p57 and IGFII act antagonistically
Grandjean et al. (2000) PNAS 97:5281.
Loss of Imprinting (LOI) and BWS
Imprinting defects of IGFII is the most prominent cause of the development of BWS
LOI of IGFII results in biallelic expression of IGFII, which down regulates expression of p57 at an increased level
Paternal duplication of IGFII and the presence of a defective maternal p57 allele contributes to the development of BWS as well
Weksburg et al. (2001) Human Molecular Genetics 10:2989-3000.
p57 and BWSTwo separate studies
were conducted using mutant mice carrying deletions of the beginning of the p57 gene
Resultant defects common between both studies correlate with symptoms of BWS
PhenotypePhenotype BWSBWS p57p57KIP2KIP2 mutantsmutants
IGFII IGFII transgenicstransgenics
Macroglossia + _ nd
Gigantism + _ +*
Abdominal defect
+ + nd
Hypoglycemia + _ +
Visceromegaly + + +
Renal dysplasia +/- + nd
Adrenal cytomegaly
+ + nd
Intestinal malrotation
+/- + nd
Cleft palate +/- + nd
Neoplasia +/- _ +*
Skeletal anomalies
+/- + nd
Lens defect +/- + nd
Key: +, observed commonly; +/-, less commonly observed; -, not observed; nd, not determined; *, observed only in some reports
Swanger, W. Jherek, Roberts, James M. (1997) BioEssays 19:840.
SummaryBWS is an autosomal dominant disorder
characterized by overgrowth and predisposition to tumor development
p57 and IGFII, both located on chromosome 11, are believed to be highly associated with the development of BWS
Defects in the imprinting of p57 and IGFII have been experimentally shown to reproduce BWS symptoms in mutant mice