The Jake Porter StoryThe Jake Porter StoryJake 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 half-field journey demonstrated the true meaning of the human spirit.

The Causes, Patterns The Causes, Patterns and Symptoms ofand Symptoms of

Fragile X SyndromeFragile X Syndrome

What is it?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 Karyotype of a Male Exhibiting Fragile X Exhibiting Fragile X

ChromosomeChromosome

Brief background onBrief background on X-linked inheritance X-linked inheritance

► Generally, Females have two copies of the X Generally, Females have two copies of the X chromosome, males have and X and a Y.chromosome, males have and X and a Y.

► Females who have one bad X copy and one Females who have one bad X copy and one normal X copy are considered heterozygous for normal X copy are considered heterozygous for the trait and if it is recessive, it will not show in the trait and if it is recessive, it will not show in the phenotype. They would however, be the phenotype. They would however, be considered a carrier for the trait.considered a carrier for the trait.

► Males receiving one bad copy of an X Males receiving one bad copy of an X chromosome will be affected. For this reason chromosome will be affected. For this reason the phenotypic expression of this trait in males the phenotypic expression of this trait in males is higher.is higher.

A family pedigree showing a history of X-linked Mendelian

inheritance

Normal Female

Normal Male Positive Male

Positive Female

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 A model showing FMRP as part of a ribonucleoprotein particle. If the FMRP ribonucleoprotein particle. If the FMRP protein is mutated through replication protein is mutated through replication

(multiple copies of CGG producing (multiple copies of CGG producing FMR1) The complex cannot function. 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 ReplicationFMR1 Replication CGG may be repeated up to several times CGG may be repeated up to several times

at it’s locus in the X chromosome. There at it’s locus in the X chromosome. There are three important classifications.are three important classifications.

When the gene repeats at a range of 5-50, When the gene repeats at a range of 5-50, it is normal and thus the phenotype of the it is normal and thus the phenotype of the individual is normal. At this point DNA individual is normal. At this point DNA replication will be normalreplication will be normal

If the gene repeats 50-200 times, the If the gene repeats 50-200 times, the individual is deemed a carrier. Carriers individual is deemed a carrier. Carriers exhibit a more likely chance of having DNA exhibit a more likely chance of having DNA polymerase slip during replication, thus polymerase slip during replication, thus amplifying the amount of gene copies. amplifying the amount of gene copies.

Sufferers are those with more than 200 Sufferers are those with more than 200 repeats. repeats.

InheritanceInheritanceMales in the range of 50-200 repeats are called “normal transmitting males”. The “pre-mutation” 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 FMR1 AmplificationAmplification There are some interesting aspects to the There are some interesting aspects to the

amplification process of the FMR1 gene.amplification process of the FMR1 gene. Through meiosis, mutations may occur in the Through meiosis, mutations may occur in the

gene during replication (slippage) or through gene during replication (slippage) or through unequal crossing-over. In either situation, the unequal crossing-over. In either situation, the amount of CGG copies may increase explosively amount of CGG copies may increase explosively through any single replication.through any single replication.

It is often the case that problematic replications It is often the case that problematic replications occur when there is a small deletion in the occur when there is a small deletion in the promoter region.promoter region.

Generally, the more repeats an individual has Generally, the more repeats an individual has (past 200) the earlier the phenotype manifests (past 200) the earlier the phenotype manifests itself in the individual. itself in the individual.

Normal individuals may contribute gametes in Normal individuals may contribute gametes in which repeats become expanded to their children, which repeats become expanded to their children, as is often the scenario. as is often the scenario.

Oddly, tri-nucleotide CGG amplification occurs Oddly, tri-nucleotide CGG amplification occurs exclusively in the female germ-line.exclusively in the female germ-line.

Errors During DNA Errors During DNA ReplicationReplication

Formation of Okazaki Fragments occurs during DNA Replication

Direction of DNA replication

Polymerase cannot work in this

Direction so it must overlap

Polymerase can work freely in this direction

Origin of replication

Moderate to extreme mental Moderate to extreme mental retardationretardation

Dysmorphology of the face. Prominent Dysmorphology of the face. Prominent forehead, large jaw, large ears.forehead, large jaw, large ears.

Possible behavioral abnormalities. Possible behavioral abnormalities. (Autistic behavior, poor social contact)(Autistic behavior, poor social contact)

Poor muscular control or connective Poor muscular control or connective tissue dysfunction.tissue dysfunction.

The conditions are almost always less The conditions are almost always less severe in females.severe in females.

A Method called Atomic A Method called Atomic Force Microscopy shows the Force Microscopy shows the detailed view of a fragile X detailed view of a fragile X

chromosomechromosomeLocate 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 Diagnosis and TreatmentTreatment

Since phenotypic symptoms differ greatly in their range and specificity, accurate diagnosis can only be made through genetic testing. 99% of cases

show tri-nucleotide 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 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

iGeneticsPeter J. Russell© 2002 Pearson Education, Inc