Transcript P57: Beckwith-Wiedemann Syndrome

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.
www.nlm.nih.gov/medlineplus/ency/article/001186.htm
Symptoms of BWS
Microcephaly- abnormal
smallness of the head
Macroglossia- enlarged
tongue
Umbilical herniaprotrusion of the
intestines through the
abdominal wall in the
navel region
www.nlm.nih.gov/medlineplus/ency/article/001186.htm
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 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)
active
CDK
Cyclin
inactive
+
p21
CDK
p21
Cyclin
p27Kip1
Cyclin A
CDK2
Jeffrey et al. (1995) Nature 376:313
CDK2
Cyclin A
Russo et al. (1996) Nature 382:325
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 10:2989-3000.
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
Phenotype
BWS
p57KIP2 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