Transcript The Causes, patterns and symptoms of Fragile X syndrome

The Jake Porter Story
Jake Porter rumbled 49 yards in 10 seconds to
secure the final touchdown of the game. All around
him men and women jumped, cheered and cried. It’s
amazing how ten seconds are all that are needed to
change the lives of so many forever.
The amazing part of the story is that Porter’s long
run did not win Northwest High the game. They were
not even close. He also set no records that day.
What Jake Porter did was more important. His halffield journey demonstrated the true meaning of the
human spirit.
The Causes, Patterns
and Symptoms of
Fragile X Syndrome
What is it?
First discovered in 1965, fragile X syndrome (aka
Martin-Bell Syndrome) is a heritable X-linked
recessive trait that affects roughly 1/1250 males
and 1/2500 females.
It is the most common heritable form of mental
retardation and is produced by mutations in a
specific gene thus modifying the protein that it
produces.
The protein entitled FMRP (Fetal Mental
Retardation Protein) can become changed creating
a host of problems during DNA replication. The
mutated gene, called FMR1, can generate powerful
effects on the individual.
Karyotype of a Male Exhibiting
Fragile X Chromosome
Brief background on
X-linked inheritance
► Generally,
Females have two copies of the X
chromosome, males have and X and a Y.
► Females who have one bad X copy and one normal X
copy are considered heterozygous for the trait and
if it is recessive, it will not show in the phenotype.
They would however, be considered a carrier for
the trait.
► Males receiving one bad copy of an X chromosome
will be affected. For this reason the phenotypic
expression of this trait in males is higher.
A family pedigree showing a history of
X-linked Mendelian inheritance
Normal Female
Positive Female
Normal Male
Positive Male
Fragile X Loci (Xq27.3) found on both
male and female chromosomes
Notice the weak formation of the tail end of the X
chromosome (arrow).
A model showing FMRP as part of a
ribonucleoprotein particle. If the FMRP
protein is mutated through replication
(multiple copies of CGG producing FMR1)
The complex cannot function.
The purpose of the FMRP protein is
still somewhat a mystery to
scientists. It is believed by many,
however that it shuttles between the
cytoplasm and the nucleus, visiting
ribosomes. If this is true, it may be
involved in protein synthesis. After
CGG’s become repeated over 200
times, a methyl cap is placed over the
gene and FMRP is not produced. The
lack of FMRP causes fragile x
syndrome.
FMR1 Replication
CGG may be repeated up to several times at it’s
locus in the X chromosome. There are three
important classifications.
 When the gene repeats at a range of 5-50, it is
normal and thus the phenotype of the individual
is normal. At this point DNA replication will be
normal
 If the gene repeats 50-200 times, the individual
is deemed a carrier. Carriers exhibit a more
likely chance of having DNA polymerase slip
during replication, thus amplifying the amount of
gene copies.
 Sufferers are those with more than 200 repeats.
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Inheritance
Males in the range of 50-200 repeats are
called “normal transmitting males”. The “premutation” for FMR1 is inherited by all of their
daughters and none of their sons. The
grandchildren of these males are at-risk.
Females in the range of 50-200 repeats will
show a 50% risk of transmitting abnormal
copies of the gene. These females show a
greater risk of amplification in their germ line.
FMR1 Amplification
 There are some interesting aspects to the
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amplification process of the FMR1 gene.
Through meiosis, mutations may occur in the gene
during replication (slippage) or through unequal
crossing-over. In either situation, the amount of CGG
copies may increase explosively through any single
replication.
It is often the case that problematic replications
occur when there is a small deletion in the promoter
region.
Generally, the more repeats an individual has (past
200) the earlier the phenotype manifests itself in the
individual.
Normal individuals may contribute gametes in which
repeats become expanded to their children, as is
often the scenario.
Oddly, tri-nucleotide CGG amplification occurs
exclusively in the female germ-line.
Errors During DNA Replication
Direction of DNA replication
Origin of
replication
Polymerase cannot work in this
Direction so it must overlap
Polymerase can work freely in
this direction
Formation of Okazaki Fragments occurs
during DNA Replication
Moderate to extreme mental retardation
 Dysmorphology of the face. Prominent
forehead, large jaw, large ears.
 Possible behavioral abnormalities.
(Autistic behavior, poor social contact)
 Poor muscular control or connective tissue
dysfunction.
 The conditions are almost always less
severe in females.

A Method called Atomic Force
Microscopy shows the detailed
view of a fragile X chromosome
Locate the position of the
fragile x chromosome at the arrow
Pedigree showing the number
of repeats of the GCC gene
Less than 50 repeats
Status: Normal
50-200 repeats
Status: Normal
Over 200 repeats
Status: Fragile X Syndrome
Diagnosis and Treatment
Since phenotypic symptoms differ greatly in their range
and specificity, accurate diagnosis can only be made
through genetic testing. 99% of cases show trinucleotide CGG expansion on chromosomal locus Xg27.3.
There is no specific treatment for fragile X syndrome.
Therapy for children sufferers consist of but is not
limited to:
a) Behavioral techniques
b) Educational intervention
c) Drug control of behavioral issues
d) Genetic counseling for families
Related “Amplifying”
Conditions
 Myotonic
Dystrophy
 Huntington’s Disease
 Spinobulbar Muscular Atrophy
Credits
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http://www.eur.nl/fgg/kgen/research/gbndfragx.html
http://www.faseb.org/genetics/acmg/pol-16.htm
http://www.geneclinics.org
http://www.medceu.com
www.autism.org/fragilex.html
http://plantsciences.montana.edu
http://www.diseasedir.org.uk/genetic/genex03.htm
http://abc.net.au/science/news/stories/s70065.htm
Children with Fragile X Syndrome. A Parent’s Guide
Jayne Dixon Webber
© 2000 Woodbine House
iGenetics
Peter J. Russell
© 2002 Pearson Education, Inc