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 half- field 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 Normal MalePositive 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 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. 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 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 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. If the gene repeats 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. Sufferers are those with more than 200 repeats.

Inheritance Males in the range of 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 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 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 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 retardation Moderate to extreme mental retardation Dysmorphology of the face. Prominent forehead, large jaw, large ears. Dysmorphology of the face. Prominent forehead, large jaw, large ears. Possible behavioral abnormalities. (Autistic behavior, poor social contact) Possible behavioral abnormalities. (Autistic behavior, poor social contact) Poor muscular control or connective tissue dysfunction. Poor muscular control or connective tissue dysfunction. The conditions are almost always less severe in females. 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 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 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          Children with Fragile X Syndrome. A Parent’s Guide Jayne Dixon Webber © 2000 Woodbine House  iGenetics Peter J. Russell © 2002 Pearson Education, Inc