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

Large prominent eyesCreases in ear lobesUndescended testiclesSeizures

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

Chromosome 11

Steenman et al. (2000) Genes, Chromosomes & Cancer 28:2.

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