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Fragile X Syndrome

Background Fragile X Syndrome is the second most common form of intellectual disability affecting 1 in 2,000-4,000 men and 1 in 4,000-8,000 women, men being twice as likely to inherit this disability due to their XX chromosomes. This disability arises from a mutation at the end of the X chromosome in the FMR1 gene (Fragile X Mental Retardation Gene) which produces a protein essential for brain development called FMRP. Individuals with Fragile X syndrome experience a variety of symptoms at varying degrees that depend on gender and mutation degree such as attention deficit disorders, irritability, stimuli sensitivity, various anxiety disorders, depression, and/or aggressive behavior. Some treatments for these symptoms seen in individuals with Fragile X syndrome include SSRI’s, antipsychotic medications, stimulants, folic acid, and mood stabilizers. Genetic Causation Sizable expansions of a CGG trinucleotide element are the singular cause of the male genetic disorder called Fragile X Syndrome. In males without Fragile X Syndrome, the CGG repeat number ranges from 53 to 200 while those affected have greater than 200 repeats of this trinucleotide sequence located at the end of the X chromosome on band Xq28.3.1. Carriers that have repeats falling within the 53 to 200 repeat range are said to have “premutation alleles”, as the alleles within this range approach 200, the likelihood of expansion to a full mutation increases, and the mRNA levels are elevated five-fold. Research has shown that individuals with premutation alleles in the low range of 59-69 repeats have about a 30% risk of developing full mutation and those in the higher range of ≥ 90 repeats have almost a 100% chance. Fragile X syndrome carriers (those that fall within the premutation range) typically have unmethylated alleles, normal phenotype, and normal levels of FMR1 mRNA and FMRP protein. Fragile X Syndrome men possess alleles in the full mutation range (>200 repeats) with FMRP protein levels much lower than normal and experience hypermethylation of the promoter region of the FMR1 gene. Some men with alleles in the full mutation range experience partial or no methylation which results in only slightly abnormal phenotypes due to only slight down-regulation of FMR1 gene transcription. Unmethylated and partially methylated alleles in the mutation range experience increased and normal levels of FMR1 mRNA when compared to normal controls. In contrast, when unmethylated alleles reach a repeat number of approximately 300, the transcription levels are relatively unaffected and operate at normal levels; the transcription levels of repeats greater than 300 is currently unknown. Promoter Silencing The CGG trinucleotide repeat expansion is present within the FMR1 mRNA and its interactions are responsible for promoter silencing. The CGG trinucleotide expansion resides within the 5’ untranslated region of the mRNA which undergoes hybridization to form a complementary CGG repeat portion, binding of this genomic repeat to the mRNA results in silencing of the promoter. Beyond this point, the mechanism of promoter silencing is unknown and still being further investigated.

Huntington’s Disease

Background Huntington’s Disease (HD) is a dominantly, paternally inherited neurodegenerative disorder that affects 1 in 15,000-20,000 people in many Western Populations. HD involves the basal ganglia and the cerebral cortex and manifests as symptoms such as cognitive, motor, and/or psychiatric impairment. Causation This autosomal dominant disorder results from expansions of a trinucleotide repeat that involves CAG in exon 1 of the IT15 gene. The majority of all juvenile HD cases stem from the transmission of a high CAG trinucleotide repeat number that is a result of paternal gametogenesis. An individual without HD has a number of CAG repeats that fall within a range between 9 and 37 while an individual with HD has CAG repeats in a range between 37 and 102. Research has shown an inverse relationship between the number of trinucleotide repeats and age of onset and no relationship between trinucleotide repeat numbers and rate of HD progression, an individual's body weight, and/or gender of the carrier parent. Severity of functional decline has been found to be similar across a wide range of individuals with varying numbers of CAG repeats and differing ages of onset, therefore, it is suggested that the rate of disease progression is also linked to factors other than the CAG repeat such as environmental and/or genetic factors.

Myotonic Dystrophy

Background Myotonic Dystrophy is a rare muscular disorder in which numerous bodily systems are affected. There are four forms of Myotonic Dystrophy: mild phenotype and late-onset, onset in adolescence/young adulthood, early childhood featuring only learning disabilities, and a congenital form. Individuals with Myotonic Dystrophy experience severe, debilitating physical symptoms such as muscle weakness, heartbeat issues, and difficulty breathing that can be improved through treatment to maximize patients' mobility and everyday activity to alleviate some stress of their caretakers. The muscles of individuals with Myotonic Dystrophy feature an increase of type 1 fibers as well as an increased deterioration of these type 1 fibers. In addition to these physical ailments, individuals with Myotonic Dystrophy have been found to experience varying internalized disorders such as anxiety and mood disorders as well as cognitive delays, attention deficit disorders, autism spectrum disorders, lower IQ’s, and visual-spatial difficulties. Research has shown that there is a direct correlation between expansion repeat number, IQ, and an individual's degree of visual-spatial impairment. Causation Myotonic Dystrophy results from a (CTG)n trinucleotide repeat expansion that resides in a 3’ untranslated region of a serine/threonine kinase coding transcript. This repeat is located within leukocytes and the repeat length, as well as age, is directly related to disease progression and type 1 fiber predominance. Age and (CTG)n length only have small correlation coefficients to disease progression, research suggests that various other factors play a role in disease progression such as changes in signal transduction pathway, somatic expression, and cell heterogeneity in (CTG)n repeats.

Intergenerational Instability '

Parental Influence Research suggests that there is a direct, important correlation between the sex of the parent that transmits the mutation and the degree and phenotype of disorder in the child. , The degree of repeat expansion and whether or not an expansion will occur has been directly linked to the sex of the transmitting parent in both non-coding and coding trinucleotide repeat disorders. For example, research regarding the correlation between Huntington’s Disease CAG trinucleotide repeat and parental transmission has found that there is a strong correlation between the two with differences in maternal and paternal transmission. Maternal transmission has been observed to only consist of an increase in repeat units of 1 while the paternal transmission is typically anywhere from 3 to 9 extra repeats. Paternal transmission is almost always responsible for large repeat transmission resulting in the early onset of Huntington’s Disease while maternal transmission results in affected individuals experiencing symptom onset mirroring that of their mother. , While this transmission of a trinucleotide repeat expansion is regarded to be a result of “meiotic instability”, the degree to which meiosis plays a role in this process and the mechanism is not clear and numerous other processes are predicted to simultaneously play a role in this process. Proposed Mechanisms 

Unequal Homologous Exchange The mechanisms that make-up trinucleotide expansion are hardly understood, but there are a few models that propose contributing mechanisms. One proposed but highly unlikely mechanism that plays a role in trinucleotide expansion transmission occurs during meiotic or mitotic recombination. It is suggested that during these processes it is possible for a homologous repeat misalignment, commonly known for causing alpha-globin locus deletions, causes the meiotic instability of a trinucleotide repeat expansion. This process is unlikely to contribute to the transmission and presence of trinucleotide repeat expansions due to differences in expansion mechanisms. Trinucleotide repeat expansions typically favor expansions of the CAG region but, in order for the unequal homologous exchange to be a plausible suggestion, these repeats would have to go through expansion and contraction events at the same time. In addition, numerous diseases that result from transmitted trinucleotide repeat expansions, such as Fragile X syndrome, involve unstable trinucleotide repeats on the X chromosome that cannot be explained by meiotic recombination. Research has shown that although unequal homologous recombination is unlikely to be the sole cause of transmitted trinucleotide repeat expansions, this homologous recombination likely plays a minor role in the length of some trinucleotide repeat expansions. DNA Replication DNA replication errors are predicted to be the main perpetrator of trinucleotide repeat expansion transmission in many predicted models due to the difficulty of replication of trinucleotide repeats. In DNA replication of trinucleotide repeat expansions, it is necessary that replication is done starting at the lagging strand which is followed by the release of Okazaki fragments that are then associated to generate the lagging strand copy. Okazaki fragments are a key element of the proposed error in DNA replication. It is suggested that the small size of Okazaki fragments, typically between 150 and 200 nucleotides long, makes them more likely to fall off or “slip” off the lagging strand which creates room for trinucleotide repeats to attach to the lagging strand copy. In addition to this possibility of trinucleotide repeat expansion changes occurring due to slippage of Okazaki fragments, the ability of CG-rich trinucleotide repeat expansion sequences to form a special hairpin, toroid, and triplex DNA structures contributes to this model suggesting error occurs during DNA replication. Hairpin structures can form as a result of the freedom of the lagging strand during DNA replication and are typically observed to form in extremely long trinucleotide repeat sequences. Research has found that this hairpin formation depends on the orientation of the trinucleotide repeats within each CAG/CTG trinucleotide strand. Strands that have duplex formation by CTG repeats in the leading strand are observed to result in extra repeats, while those without CTG repeats in the leading strand result in repeat deletions.

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