Fragile X

As you all know, sex is determined by your X and Y chromosomes: you have XX if you are a female and XY if you are a male. Many people do not know, however, that your X and Y chromosomes do more than just determine what sex you are, they also carry genes that encode for certain proteins as well. With every gene, there is a potential for something to be inherited that causes a dysfunction. Fragile X syndrome is an example of a dysfunction caused by inheriting an abnormal gene. This disease encodes for a gene that is located on the X chromosome and can be inherited through a stroke of bad luck.

Fragile X syndrome (FXS) is an X-linked dominant disorder that is characterized by mental disability, autistic-like behaviors, developmental delay, vulnerability of seizures, and macroorchidism in males. Being an X-linked dominant disorder means that you only need to inherit one bad copy of the gene for this disease to be expressed. This disease is caused by a single mutation in the Fragile X Mental Retardation 1 gene (FMR1). In normal functioning people this gene is expressed allowing for the production of Fragile X Mental Retardation Protein (FMRP); these individuals express normal mental capabilities. However, the mutation within FXMD1 causes silencing of gene expression which ultimately leads to cognitive impairment and other disease symptoms.

To clarify, FXS is caused by gene expansion of FMRI. The CGG repeat sequence located at the 5' untranslated region (UTR) gets expanded leading to hypermethylation of the repeat sequence and the promoter region. This hypermethylation plays a part in not allowing for translation of the FMRP. The severity of the disease can be in part caused by how many expansions are added to the CGG repeat sequence. The normal allele has about 5-44 CGG repeats, the borderline allele has 45-54 repeats, premutation (PM) allele has 55-200 repeats, and the full mutation (FM) allele has greater than 200 repeats. Within these repeats are AGG interruption; this allows for the strand to be anchored during replication where they won't slip. PM alleles do not have these AGG interruptions causing the DNA to be unstable when it gets inherited to the offspring; the possibility of this turning into a FM is very high and there is a change that the baby will show signs of this disease. With that being said, carriers of PM alleles do not show any signs of FXS, while individuals who carry the FM allele will show signs and symptoms of FXS.

Another factor in the severity of FXS symptoms is the sex of the individual. Males tend to express the disease more often (1 in 4000) since males only posses one X chromosome. Males can only inherit this disease from their mothers since they receive the Y chromosome from the father. If they carry the full mutation then they will always be infected. However, females posses two X chromosomes and only about 1 in 8000 females show prevalence of this disease. Due to random X-inactivation, which is when one of the X chromosomes is randomly deactivated to stop females from expressing twice as many X chromosome genes as males do, females who carry the FM allele, can go their entire life time without ever expressing FXS. The severity is inversely related to the activation ratio between the  normal FMR1 allele and its product meaning that however much FMRP is produced, correlates how bad the disease will be if FM FMRI allele is present.