00:01
There's a few genetic principles
that I'd like for you to know about
both NF1, NF2,
and tuberous sclerosis.
00:07
And the first is
Knudson's Two-hit hypothesis.
00:12
And this is an important hypothesis
for understanding
why tumors develop
in tumor suppressor syndromes?
When we think about a tumor,
there are two ways
to develop a tumor,
an oncogene
or a tumor suppressor gene.
00:25
The oncogene is like
putting your foot on the gas.
00:28
One mutation in one oncogene is
sufficient to cause a tumor to grow.
00:32
Tumor suppressor genes
are like feet on the brakes,
and you have two feet
on the brake.
00:39
Mutation in one gene is insufficient
to cause a tumor to grow,
you really need
that second hit.
00:44
And this is going to be a diagram
that discusses and details,
how that to hit occurs?
As we know, we contain genes
from both our mom and our dad.
00:55
Alleles from mom and dad
for each gene in our body.
00:58
And you can see here at the top,
this individual,
this parent at the top has
two alleles at the NF1 locus.
01:05
A normal allele that's a plus
and an abnormal allele
or a mutated of allele,
that's represented by the minus.
01:14
That parent will give those
alleles to offspring.
01:17
And so we can see one
offspring has an NF+/+,
they've inherited the normal allele
from mom and dad.
01:24
And the other offspring has NF -/+,
they've inherited
that abnormal copy.
01:29
So we see here, the abnormal copy
from one parent,
the normal copy
from the other parent,
and this patient has
acquired neurofibromatosis
or an abnormality in the NF1 gene.
01:42
And this accounts for about
50% of cases of NF1.
01:46
The patient inherits the abnormal
copy of NF1 from a parent.
01:51
And that's both
at a genetic condition
and an inherited condition.
01:55
But that's not the only way
patients develop NF1, and NF2.
02:00
Sometimes the parent
has both normal copies of NF1.
02:04
Both allele's are normal.
02:05
There is no mutated copy of NF1
in the parent,
and yet the child still develops
neurofibromatosis.
02:13
And that results from
a mutation in this gene
that's acquired at
the time of conception.
02:17
When that gamete is formed,
as a result of DNA replication,
there is a mutation
in the NF1 gene.
02:26
The NF1 gene is one
of the largest genes in the body.
02:28
So it's really common that we see
sporadic or spontaneous mutations.
02:32
And it turns out
that de novo mutations in NF1
account for about 50% of patients
with neurofibromatosis.
02:39
So while all NF patients
have a genetic condition,
about half are acquired from a
parent and are inherited,
and half are sporadic
or de novo.
02:49
That's an important principle
that I want you to know.
02:53
And one key principle in genetics
that we think about with NF 1 and 2
is complete penetrance.
02:59
What is complete penetrance?
Well, this is a genetic condition
in which all patients
who have the disease
causing mutation
will show a sign of the disease.
03:08
So if those cells, if the germline
contains a mutation in NF1,
there will be
clinical signs or symptoms.
03:15
That's an important
genetic principle to take away
from these conditions.
03:20
We talked about the first hit.
What's the second hit?
All the cells in the body
as we can see here depicted
have a normal NF1 copy
and an abnormal NF1 copy.
03:32
Those cells we call
heterozygous.
03:34
They're heterozygous
at the NF1 allele.
03:37
And heterozygosity is not sufficient
to cause tumor growth,
but is sufficient to cause
a number of symptoms.
03:43
And we'll talk about
some of the minor symptoms in NF
that can develop as a result
of this haploinsufficiency
having one normal copy,
and one abnormal copy.
03:51
As a result of life and
acquired mutations in living,
some cells will acquire
a second hit.
03:58
A mutation in that one remaining
normal NF1 copy
that one foot that is on the brake
and preventing tumor growth,
and we call that
loss of heterozygosity.
04:08
There's no longer a heterozygous
allele at the NF1 locus,
and that cell is NF1 -/-
and this is sufficient
for tumor growth.
04:18
So NF1 patients have symptoms that
both result from haploinsufficiency,
things like learning disabilities,
scoliosis, short stature,
and these things called UBO's,
or Focal Areas of Signal Intensity
that we'll talk about.
04:32
And tumors.
04:34
In the tumors are a result
of that second hit.
04:36
Loss of the second break,
on tumor growth or cell growth.
04:40
And that's why we see things like
neurofibromas, optic pathway,
gliomas, sphenoid wing dysplasia,
and tibial pseudarthrosis.
04:49
We also see in this a concept
that's called variable expressivity.
04:54
This is another important
genetic principle.
04:57
What is variable expressivity?
Well, this is the degree
to which a phenotype,
a clinical phenotype
is expressed by individuals
that have a
particular genotype.
05:08
Those are a lot of words.
What is that mean?
Well, in other words, patients
with the same genetic mutation
may have different
severity of disease.
05:16
A mom and a daughter may both have
the same NF1 mutation,
but one may have
severe disease and one may not.
05:23
A brother and sister, both may have
the same mutation in the NF1 gene,
and one may have more
severe or less severe disease.
05:31
And this is because
of that second hit,
the loss of heterozygosity.
05:35
The acquired mutation that occurs
for no other reason than chance.
05:40
The environment gives it to us,
and that results in variable
expression of these conditions.
05:46
So important genetic principles that
I want you to be able to take away
from this lecture.