Download NF2/Merlin and Neurofibromatosis 2

NF2/Merlin and
Neurofibromatosis 2
March 25, 2003
By: Caroline Clendenin
Neurofibromatosis:
An Overview
• NF is the most common neurological disorder caused by
a single gene.
• It is subdivided into two distinct types: NF1 and NF2,
which are caused by different genes on different
chromosomes.
• NF1 is more common, affecting 1:4,000 births
throughout the world; while NF2 affects about 1:40,000
people worldwide.
• These diseases affect more than 100,000 Americans—
making NF more prevalent than Cystic Fibrosis,
hereditary Muscular Dystrophy, Huntington’s Disease,
and Tay Sachs combined.
Neurofibromatosis:
An Overview:
• Both forms of NF are inherited by
autosomal dominant mechanisms.
• NF can also arise from spontaneous
mutations in sperm or eggs.
• In this presentation we will focus on
NF2 and its role in the cell.
NF2: Signs and Symptoms
• Bilateral tumors on the eighth cranial nerve
• Problems with balance, secondary to dysfunction of the vestibular
nerve
• Hearing loss and tinnitus, secondary to dysfunction of the auditory
nerve
• Schwannomas—tumors arising from Schwann cells
• Symptoms of schwannomas depend on location: those on cranial
nerves affect only the head and neck unless they grow and put
pressure on the brainstem—which can be life threatening.
• Those on nerves as they exit the spinal cord may cause numbness
in a region of the body or weakness and numbness in the legs if the
tumor places pressure on the spine, itself.
• Peripheral schwannomas rarely cause neurological symptoms, but
may be disfiguring.
• Facial weakness
• Headache
NF2: Diagnosis
• Bilateral tumors of eighth
cranial nerve OR
• A parent, sibling, or child with
NF2 and a unilateral tumor on
the eighth cranial nerve OR
• A parent, sibling or child with
NF2 and two of the following:
– Glioma
– Meningioma
– Neurofibroma
– Schwannoma
– Early onset cataract
Clinical Onset of NF2
• The identification of the NF2 gene product
allows genetic testing for families with
documented cases of NF2 in order to confirm
diagnosis.
• Prenatal testing by amniocentesis and chorionic
villi sampling is also available for those at risk.
• The mean age of onset is in the early 20’s.
• Those who present earlier with clinical
symptoms tend to have more rapid, aggressive
tumors with a greater number of tumors present.
• Those who present later exhibit a less severe
disease course with fewer tumors.
Treatments:
• At present, treatments
are aimed at controlling
the symptoms.
• Diagnostic technologies
such as MRI and CT can
reveal tumors as small as
a few millimeters in
diameter, thus allowing
early treatment.
• Surgical removal of the
tumors—may result in
hearing loss.
• Partial removal of tumors
• Radiation therapy
(radiosurgery)
• Watchful waiting—if
tumors are not
progressing rapidly or if
the patient has other
serious medical issues.
The NF2 Gene:
What is its normal function?
• This tumor suppressor
gene was identified by
positional cloning and
loss of heterozygosity
studies.
• The protein encoded by
NF2 is called merlin (or
schwannomin).
• It is a member of the
ERM (ezrin, radixin,
moesin) family of
cytoskeleton:membrane
linker proteins.
Bretscher, et. al.
In what tissues is NF2 found?
• In human and fetal
mouse tissues, it is
found in:
–
–
–
–
–
–
Heart
Brain
Liver
Spleen
Skeletal muscle
Kidney
• In adult mice NF2 is
NOT found in:
–
–
–
–
Spinal cord
Brain
Liver
Pancreas
What does it do?
• NF2 gene product is
essential for
extraembryonic
development just prior to
gastrulation.
• Homozygous mutant
mouse embryos die
between day 6.5 and day
7.
• They show collapsed
extraembryonic region
and an absence of
organized extraembryonic
ectoderm.
• Conditional
homozygous NF2
knockout mice show
characteristics of NF2
disorder.
Giovannini, et. al.
The NF2 Gene:
Domains
•
•
Reed & Gutmann
Three domains:
1. FERM
2. alpha helix
3. C-terminus
It is missing Nterminal actin
binding domain that
is present in all
other ERM proteins.
Conformations of NF2
• “closed” vs. “open”
• Binding sites for
interactions with
CD44 and HRS
(hepatocyte growth
factor-regulated
tyrosine kinase
substrate)
• Proposed mechanism
of interaction.
Gutmann
Uncertainties:
Although the molecular basis of merlin’s
growth-suppressing activity is not known,
the recent identification of merlininteracting proteins, and advances in
understanding the molecular function of
related ERM proteins, suggest that merlin
may function to control the localization of
signaling molecules through its effects on
cytoskeletal reorganization.
Model of Activation of ERM
Proteins and Merlin
Gautreau, et. al.
• For ERM proteins, phosphorylation of c-terminal residue
mediated by the Rho pathway induces transition from
inactive oligomers to active monomers.
• For merlin, the Rac pathway mediates phosphorylation
of a c-terminal residue which causes inactivation of its
tumor suppressor activity.
• Dephosphorylation of both ERM and merlin allows
interdomain association to occur.
How does merlin mess up?
• As a tumor suppressor, merlin is affected by
Knudson’s Two Hit Hypothesis. Both copies of
the gene must be mutated to remove its
function.
• Generally, mutations in NF2 involve deletions
that cause the formation of truncated proteins.
• As with Rb, a person with a mutated copy of the
NF2 gene (NF2+/NF2-) will almost invariably
develop acoustic neuromas associated with
neurofibromatosis 2.
• The NF2 mutation is about 98% penetrant.
Merlin Mutations in Mice
McClatchey, et. al.
• Mutant mice exhibited formation of metastatic
osteosarcomas, whereas in humans tumor growth is
usually benign schwannomas which are localized.
• This difference is probably due to the fact that that p53 is
highly linked to the NF2 gene in mice, but not in humans.
The Future of NF2:
It is hoped that through these studies of
molecular genetics that nonsurgical or
pharmacologic treatments can be
employed to slow and suppress the growth
of tumors associated with the
neurofibromatoses.
Summary:
• NF2 is a tumor suppressor gene that encodes
the protein merlin.
• Merlin is a member of the ERM family of
membrane:cytoskeletal linker proteins.
• It requires “two hits” to eliminate its function on
the cellular level, although the NF2 disorder is
inherited in an autosomal dominant fashion,
similar to Rb.
• Mice have been used to study this protein’s
function.
• Although the specific pathway for this gene is
not fully understood, it is presumed that it acts
on cytoskeletal reorganization to cause tumors.