Biology Fact-Sheet on ‘Fragile X Syndrome’

CHARECTERISTICS

Fragile X syndrome is an X-linked dominant disorder causing mental and emotional disabilities. This disorder is heritable and can be passed from one generation to another. The persons suffering from this disorder show phenotypes like prominent ears, long face, autism and behavioral problems (Fragile X Syndrome). It is called “fragile X syndrome” because the affected X chromosomes are narrowed at the end when observed under high resolution microscope. (Fragile X Syndrome, 2007)

 Since the gene causing is present on the X chromosome, the number of affected males is higher than the number of affected females. It is so because, males have only one X chromosome present (XY chromosome) while females have two X chromosomes (XX chromosomes). Most of the females with fragile X syndrome have one normal X chromosome and one defective X chromosome but they have only one functional copy of X chromosome. During protein formation cell randomly chooses only one X chromosome for translation, therefore sometimes females with a defective X chromosome also have normal phenotype. Where as in males the X chromosome is always utilized in protein formation and the disorder is expressed. (Fragile X Syndrome)

CAUSES

It is caused by the mutation in a gene that encodes for the Fragile X Mental Retardation Protein (FMRP) required for the brain to carry out normal functions. Due to the transcriptional silencing of the Fragile X Mental Retardation 1 (FMR1) gene the expression is inhibited. (Garber 2008)

The promoter region of the FMR1 gene consists of a repeated CGG sequence. A normal FMR1 gene has about 6 to 40 CGG repeats where a mutated FMR1 may have more than 200 repeats. The number of repeats vary from person to person.  A mutation ranging from 55 to 200 repeats is called “Premutation” where as a mutation with more than 200 repeats in a gene is known as “Full Mutation” and the phenomenon is called as methylation. (Fragile X Syndrome)

 Due to extended CGG repeats in the untranslated 5′- region the gene is inactivated and production of FMRP is halted. FMRP is a protein which selectively binds to RNA and carries out the negative regulation of protein synthesis in neuronal dendrites (Hagerman 2005). When FMRP is not present, the transcripts regulated by FMRP are over translated resulting in the abundance of proteins. The protein abundance reduces the synaptic strength due to trafficking of AMPA receptor (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor). Because AMPA receptors get inhibited, the synaptic transmission to the Central Nervous System is reduced leading to synaptic plasticity and mental abnormalities. Because synaptic plasticity is responsible for learning and memory, its alteration results into fragile X syndrome. (Garber 2008)

TREATMENT

There are several ongoing research projects funded by National Institute of Child Health and Human Development (NICHD), which aim to find a suitable cure for this disorder. NICHD has established three research centers across the country for the treatment of Fragile X Disorder.  The disorder can be determined by carryings genetic testing. In order to find the treatment, the research is carried out on several model analogous to human brain the possible outcomes are discussed as follows: (Fragile X Syndrome)

1.    Production of certain chemical in the brain that repairs the mutated, extended FMR1 gene.
2.    A drug that initiates reverse methylation.
3.    Replacing the mutated FMR1 gene with a normal gene.
4.    To introduce FMRP artificially into brain via pills or injections.
5.    To find a substitute for FMRP that carries out similar function.