Transcript Document

MUTANTS
genetic variation in human development
Lecture 8
Fall 2006
Bennington College
Some Disorders linked to bone growth
cleidocranial dysplasia
thanatophoric dysplasia
sclerosteosis
fibrodysplasia ossificans progressiva (FOP)
pseuodoachondroplasia
achondroplasia
osteogenesis imperfecta
osteoporosis
osteopetrosis
pycnodysostosis
cleidocranial dysplasia
A rare condition inherited as an autosomal dominant trait and
characterized by partial or complete absence of the clavicles,
defective ossification of the skull, and faulty occlusion due to missing,
misplaced, or supernumerary teeth.
cleidocranial dysplasia
Current evidence suggests
cause is mutation in the
Cbfa1 transcription factor
(Core binding factor a1)
Bone is always a “work in progress” - not a static entity
Bone is derived from the same embryonic tissues that make
the flesh surrounding bones (connective tissue, muscle)
all derived from the mesoderm
Osteogenesis - the formation of bones
Two major modes of osteogenesis:
intramembranous ossification - direct conversion of
tissue into bone; this is how flat bones, such as the cranium,
are formed.
endochondral ossification - cells first differentiate into
a cartilage intermediate which is later replaced by bone;
this is how long bones, such as the femur and humerus,
are formed
Intramembranous ossification: layer of osteoblasts secrete a protein
matrix. Calcium phosphate forms on this matrix and then encloses the
osteoblasts (at which point they become osteocytes)
endochondral ossification: chondrocytes produce cartilage as a
template for future bone. osteoblasts ultimately come along and
turn the cartilage into bone.
zoom-in of endochondral ossification
Back to the role of cbfa1 in cleidocranial dysplasia…Cbfa1 is a transcription factor
that promotes the differentiation of bone-producing cells (osteoblasts and
chondrocytes) from mesoderm (mesenchymal cells)
If you have one mutant copy of Cbfa1, the result is cleidocranial dysplasia
If you have two mutant copies of Cbfa1, the result is death immediately
following birth…
Defective Cbfa1 means defective bone formation - no bones and all
cartilage means no ribs to support the ability of the lungs to expand
and contract - this results in asphyxiation.
endochondral ossification is what results from the
observed “condensations” during embryogenesis.
what tells these condensations that they will become
bone is BMP (bone morphogenetic protein)
BMP tells the mesenchymal cells (cells from the mesoderm)
to become bone instead of muscle or connective tissue
you may recall, earlier in embryogenesis, BMP was telling
the developing embryo to form front, not back (while noggin
was telling it to form back, not front)
Later in life if we get a fracture - BMP4 will appear
and say “make bone”
Basically, BMPs can induce bone wherever they are…
Chiba et al., Histological study of effect of bone morphogenetic protein
derived from bovine tooth on periosteum in rats. Journal of Bone and
Mineral Metabolism. 8(3): 24-29. 1990.
control injection
into femur
BMP injection
into femur
Too little bone is a problem…too much bone is also a problem
Sclerosteosis - a rare, potentially lethal, autosomal recessive,
progressive sclerosing (hardening) bone dysplasia with characteristic
facial and skeletal features.
Usually results in massive, thick skulls
May become lethal if excess bone crushes a vital nerve
Balemans et al. Increased bone density in sclerosteosis is due to the deficiency of
a novel secreted protein (SOST). Human Molecular Genetics 10(5): 537-543, 2001.
Identified a gene, SOST (sclerostin), that
is the cause of sclerosteosis.
sclerostin is a negative regulator of BMPs.
Figure 1. Lateral view of a patient from the Brazilian sclerosteosis family showing the
characteristic high forehead and the protruding large chin.
BMP4
SOST
SOSTBMP4
SOST
SOSTBMP4
A
SOST
B
SOST
BMP4
B
BMP4
BMP4
BMP4
BMP4
A
B
B
go make
bone now!
fibrodysplasia ossificans progressiva (FOP)
An extremely rare disease (~250 worldwide cases known)
in which connective tissue and muscle tends to ossify
(turn into bone) over time. Also, any injury is repaired
with osteoblasts, increasing bone formation. Ultimately
leads to complete immobilization of the patient.
Harry Eastlack
1930-1973
Appeared normal until he fractured his leg at 5.
Soon got stiff in the hip and knee - doctors found
bony deposits on his adductor and quadricep muscles
By 1946, left leg and hip were frozen.
Back muscles were turning into sheets of bone
(Torso permanently bent at 33° angle)
Any attempts to remove excess bone only
made it come back - and get worse
By the age of 23 his jaws had entirely seized up
and he could only partake of a liquid diet.
Had to be institutionalized for care.
At the time of his death (due to pneumonia)
he could move only his lips.
Donated his body to science.
Victor Chandler Twitty
1901-1967
Twitty aimed to discover where the information
governing limb growth came from
Experiment: Use a larger species and a smaller species of
salamander. Chop off a limb from each.
When the limb bud regenerates, excise it and
transplant it to the other salamander.
What happens? Does the donor (and therefore the limb
bud) control the ultimate size of the limb?
Or does information from the host (hormones,
other signaling pathways) tell the limb what size
it should become for that particular species?
Results of Twitty’s limb bud grafting experiment
The limb bud grafted
from the donor contained
all the information to
govern the ultimate size
of the limb.
The host, and therefore
the host’s hormones,
did not influence this
process.
Twitty thus demonstrated local control of bone growth
But how does the bone know how long it should grow to be?
Perhaps by studying what happens when they fail to do so
we can gain some insight…
dwarfism
Shortly after the time that Twitty spent in Hans Spemann’s
laboratory in Germany, another young scientist was beginning
his career at the Kaiser Wilhelm Institute of Anthropology.
This student was Josef Mengele
1935 dissertation described work measuring
hundreds of jawbones looking for distinctive
racial differences
The world does not remember Mengele for
his doctoral work, but for the horrific career
path he then followed.
Mengele was encouraged by his mentor, von Verschuer, to go and take
advantage of the “extraordinary research opportunities” at Auschwitz.
The medical practice paradigm during the Hitler period saw the physician as a
"selector" acting on behalf of the state in order to improve the “health of the nation”
(Volksgesundheit). People defined as “underclass” and therefore a “risk to the genetic
or racial health of the population”. These people could be selected for enforced
sterilization, incarceration, and eventual extermination.
Research on eugenics and racial hygiene was conducted in university research
institutes and those of the Kaiser-Wilhelm organization.
The helpless human quarry incarcerated by the state was viewed by medical science
as a unique opportunity for the kinds of research which under German law were not
even permitted on animals. These victims were exploited in the name of “science”
both before death for inhuman research, and their bodies were exploited after death.
When Mengele arrived at Aushwitz in May 1943,
there were >100,000 prisoners. Killing took place daily.
Aushwitz survivors usually remember Mengele he was a very complicated entity:
- very attractive
- well groomed
- charming
- could speak nicely to a child then
send it off to the gas chamber
(sociopathic?)
Mengele often performed the initial “sorting” to life or death
of prisoners arriving by train. He kept the most interesting
“specimens” for his “research”
One such “lucky” (or unlucky?) group of “subjects” was a family
afflicted with dwarfism.
The father of the Ovitz family had a type of dwarfism known
as psuedoachondroplasia
Of his 9 children, 7 were dwarfed. After his unexpected death,
the mother got the children musical training to engineer a way
for them to earn a living.
They hid their Jewish heritage for a few years, but were eventually
captured and sent to Auschwitz - much to the delight of Mengele
They became Mengele’s favorite experimental subjects
-those who were married were subjected to gynecological experiments
uterine injections, blood samples, other tissue samples
-all subjected to numerous other “medical” tests including
extraction of spinal fluid, flushing of ears with extremely hot or
cold water, hair extraction, painful brain and face examinations.
-forced to stand naked on display while Mengele lectured about
them to Nazi higher-ups
Auschwitz was liberated in January 1945.
The Ovitz family survived with their lives
(but at what cost?)
Mengele was also fascinated with other subjects,
especially twins, who he would kill just to dissect
and compare the similarity of their organs.
Mengele was never tried for his crimes against humanity.
He died on a beach in Brazil in 1979.
psuedoachondroplasia
Dominantly inherited form of dwarfism. The gene mutated in this
condition is cartilage oligomeric protein (COMP).
Growth plates are the active sites of bone growth at the
ends of developing/growing bones.
Growth plates remain uncalcified until around the age of 18
(when we stop growing).
normally, there are columns
of chondrocytes that secrete
a cartilagenous matrix, then
die.
if COMP is mutated, it fails
to be secreted to the matrix
and prematurely kills the
chondrocytes in the process
(halting growth )
therefore, COMP and other proteins
that control the activity of the
growth plate play a large role
in determining the final length
of the bone.
achondroplasia
Inherited in an autosomal dominant fashion, but over 80% of
cases arise from spontaneous mutation. Phenotypically characterized
by short stature with disproportionately short arms and legs, a large
head, and characteristic facial features
achondroplasia
The mutation responsible is a single amino acid change
in FGFR3resulting in a glycine to arginine change at
position 380.
glycine
arginine
achondroplasia
The mutation responsible is a single amino acid change
in FGFR3resulting in a glycine to arginine change at
position 380.
This mutation makes the Fibroblast Growth Factor Receptor
inappropriately active (mimics excess FGF)
Too much FGF would inhibit chondrocytes from travelling up
the growth plate - thus this mutation results in lack
of bone growth from the growth plates.
(no chondrocytes, no secreted matrix, no future bone)
thanatophoric dysplasia
This disorder is lethal. It is caused by different mutations
in the same FGFR3 receptor. Condition occurs if both copies of
the receptor carry the mutation.
extremely short limbs
folds of extra skin
on the arms and legs
narrow chest
short ribs
underdeveloped lungs
enlarged head with a large forehead
wide-spaced eyes.
HAVE A NICE WEEKEND!!!