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 eyes  Creases in ear lobes  Undescended testicles  Seizures

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.

Symptoms of BWS  Microcephaly- abnormal smallness of the head  Macroglossia- enlarged tongue  Umbilical hernia- protrusion of the intestines through the abdominal wall in the navel region

Symptoms of BWS  Increased predisposition to tumor development  Wilms’ tumor  Adrenocortical carcinoma  Rhabdomyosarcoma  Hepatoblastoma

Tests for BWS  Bone X-ray  Blood tests for low sugar  Ultrasound of the abdomen  X-ray of the abdomen  MRI of the abdomen  Chromosome studies

Genetic Basis of BWS  85% of cases are sporadic  Inherited in autosomal dominant fashion  Mapped 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 G 1 cyclin-Cdk complexes by binding to cyclin and blocking the catalytic site of the associated Cdk  Expressed during embryonic development

IGFII  Insulin-like growth factor II, or IGFII, is a single chain polypeptide that is 47% homologous with insulin  Functions  Mediates growth hormone action  Stimulates the growth of cultured cells  Stimulates the action of insulin  Involved in development and growth  Autocrine regulator of cell proliferation

Imprinting of p57 and IGFII  p57 is paternally imprinted in the genome  IGFII is maternally imprinted in the genome  Genomic 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:

p57 and BWS  Two 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 PhenotypeBWS p57 KIP2 mutants IGFII transgenics 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.

Summary  BWS 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