which trinucleotide repeat is associated with hd

What are the different types of trinucleotide repeat disorder?

There are several known categories of trinucleotide repeat disorder. Category I includes Huntington's disease (HD) and the spinocerebellar ataxias. These are caused by a CAG repeat expansion in protein-coding portions, or exons, of specific genes.

Does trinucleotide repeat length predict clinical features of Huntington's disease?

The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease Huntington's disease (HD) is associated with the expansion of a CAG trinucleotide repeat in a novel gene.

What is trinucleotide repeat expansion?

Trinucleotide repeat expansion, is a DNA mutation that is responsible for causing any type of disorder classified as a trinucleotide repeat disorder. These disorders are progressive and effect the sequences of the human genome, frequently within the nervous system.

What is the characteristic of anticipation in trinucleotide repeat disorders?

Trinucleotide repeat expansion. This property results in the characteristic of anticipation seen in trinucleotide repeat disorders. Anticipation describes the tendency of age of onset to decrease and severity of symptoms to increase through successive generations of an affected family due to the expansion of these repeats.

Which trinucleotide gets repeated in Huntington's disease?

Highlights. The HTT gene includes trinucleotide repeats ranging from 10 to 35 in the normal population. Huntington's disease is caused when the trinucleotide repeats in the HTT gene expand beyond the normal range.

What causes CAG trinucleotide repeat?

Trinucleotide repeat disorders are caused due to an abnormal number of triplet repeat sequences either in the coding or the non-coding regions and are a result of either maternal or paternal transmission.

What is the CGG triplet repeat?

Expanded trinucleotide repeats underlie a growing number of human diseases. The human FMR1 (CGG)n array can exhibit genetic instability characterized by progressive expansion over several generations leading to gene silencing and the development of the fragile X syndrome.

Is Huntington's disease a repeat expansion mutation?

Repeat expansion diseases include both causes of myotonic dystrophy (DM1 and DM2), the most common genetic cause of amyotrophic lateral sclerosis/frontotemporal dementia (C9ORF72), Huntington disease and eight other polyglutamine disorders including the most common forms of dominantly inherited ataxia, the most common ...

How many CAG repeats are in Huntington's?

People with the adult-onset form of Huntington disease typically have 40 to 50 CAG repeats in the HTT gene, while people with the juvenile form of the disorder tend to have more than 60 CAG repeats.

What is the function of CAG repeats?

CAG repeats in the DNA of adult postmitotic neurons constitute a particular substrate for repair systems, and the regulation of these repair activities is entwined with CAG repeat disease pathogenesis, as discussed below.

What CGG means?

CGG or CGG sequence. Shorthand for the DNA sequence: cytosine-guanine-guanine. Cytosine and guanine are two of the four molecules, otherwise called nucleic acids, that make up DNA. Mentioned in: Fragile X Syndrome. Gale Encyclopedia of Medicine.

What does FMR1 gene stand for?

Fragile X Messenger Ribonucleoprotein 1FMR1 (Fragile X Messenger Ribonucleoprotein 1) is a human gene that codes for a protein called fragile X messenger ribonucleoprotein, or FMRP. This protein, most commonly found in the brain, is essential for normal cognitive development and female reproductive function.

What are CCG repeats?

Abstract. CCG repeats are highly over-represented in exons of the human genome. Usually they are located in the 5′ UTR but are also abundant in translated sequences.

What is Huntington's disease caused by?

Huntington's disease is caused by a mutation in the gene for a protein called huntingtin. The defect causes the cytosine, adenine, and guanine (CAG) building blocks of DNA to repeat many more times than is normal. Each child of a parent with HD has a 50-50 chance of inheriting the HD gene.

Is Huntington's disease the same as Huntington's chorea?

Over time, it became known as “Huntington's chorea” but because not everyone who suffers from the condition experiences chorea, the name was changed to “Huntington's disease.”

How does CAG repeat expand?

CAG, CTG, and CGG repeats form a hairpin. After the hairpin forms, the primer realigns with the 3' end of the newly synthesized strand and continues the synthesis, leading to triplet repeat expansion.

What are the two major features of trinucleotide repeat mutations?

Clinical and Genetic Features Collectively, the common clinical features of trinucleotide diseases include neurodegeneration, ataxia, mental retardation, and muscle weakness or wasting [1]. The average age of onset differs for each disorder and ranges from infancy to adulthood.

How is Huntington's disease inherited?

Huntington's disease is autosomal dominant, meaning inheritance of just a single copy of an abnormal chromosome from a biological parent is enough to cause it. If one parent carries the abnormal gene, each of their biological children has a 50 percent chance of Huntington's disease inheritance.

Can someone be a carrier for a dominant disorder?

Although the term 'carrier' is commonly used in reference to recessive disorders, it can also be used in the context of dominant conditions.

How is Huntington's disease inherited what is the mode of inheritance?

Huntington's disease is an autosomal dominant disorder, which means that a person needs only one copy of the nontypical gene to develop the disorder. With the exception of genes on the sex chromosomes, a person inherits two copies of every gene — one copy from each parent.

Where are trinucleotide repeats found?

Trinucleotide repeat mutations are not always found in coding regions of genes; they have also been detected within introns as well as within noncoding exons of the 5′- and 3′-untranslated regions in mature mRNA. Moderate expansions of trinucleotide tracts that do not code for amino acids are often asymptomatic, as seen in fragile X syndrome, myotonic dystrophy, and Friedreich's ataxia. The moderate expansions generate ‘pre-mutation’ alleles – highly unstable trinucleotide tracts that may undergo massive expansions, adding hundreds to thousands of triplet repeats during transmission from parent to offspring. These massive expansions can become pathogenic by silencing transcription, inhibiting translation, altering mRNA splicing, or impeding RNA export from the nucleus (Wells and Warren, 1998). In fragile X syndrome, as the triplet repeat expands into the premutation range, more disease-causing ‘full-mutation’ alleles arise through transmission to offspring, which explains the increased penetrance of fragile X syndrome in successive generations and thus the Sherman paradox. The full-mutation CGG tract, which is near the promoter, becomes a target for DNA methylation thereby silencing transcription (Cummings and Zoghbi, 2000). In myotonic dystrophy, the transcribed expanded CUG repeat in the DMPK mRNA 3′ UTR is believed to sequester CUG-binding proteins, thereby squelching proteins away from other cellular mRNAs and impairing general cellular RNA splicing and export (Cummings and Zoghbi, 2000). Massive GAA expansions in intron 1 of the X25 gene are believed to impair transcription or possibly splicing of the expanded intron, reducing the cellular level of mature frataxin (Cummings and Zoghbi, 2000 ).

Where are shorter trinucleotide repeats unstable?

Alternatively, shorter trinucleotide repeat tracts are unstable only if located in the appropriate genomic environment, within a large transgenic fragment of human genomic DNA [73, 76, 84, 85, 96 ], or at the endogenous locus in knock-in mice

What is the ATTCT repeat?

Short ATTCT repeat sequences undergo repeat-length mutations in plasmids. Unlike other repeats in plasmids, the ATTCT repeat expansion involves complex events, including inversion and transition. The number of the ATTCT repeat unit may increase or decrease. Most expansion mutations accompany an inversion of the repeat containing 5′ (TATTC)n (GAATA)n3′ in either orientation. All plasmids were head to tail dimers, containing an A•T to G•C transition at the 3′ end within the AGAAT repeat. These characteristics may have resulted from an inter- or intra-molecular strand switch ( Potaman et al., 2006 ). Whether these plasmid data of relatively short ATTCT repeats (less than 50 ATTCTs) are relevant to expanded ATTCT repeat in humans is not clear. However, inter- and intra-molecular strand switches may be relevant to the complex interruptions of the expanded ATTCT repeat observed in patients with SCA10.

What is the effect of huntingtin mutations on the gene coding region?

Mutant huntingtin exerts its pathological effects via abnormal protein aggregation, transcriptional dysregulation, mitochondrial dysfunction, excitotoxicity, and abnormal cellular trafficking, leading to neuronal loss particularly in the dorsal substratum [555].

Why does DNA expand?

DNA expansions that occur within trinucleotide tracts are attributable to the unique biochemical difficulties of performing DNA replication within long stretches of repeat DNA. Mounting in vitro evidence suggests that triplets are deleted or added to long repetitive tracts as the cellular machinery tries to replicate ...

When were unstable trinucleotide repeats discovered?

Unstable trinucleotide repeats are a novel disease mechanism, first discovered in 1991, and an important cause of neurogenetic disease. A feature of these conditions is anticipation, with earlier onset and more severe phenotype in successive generations, which appears to correlate with increasing repeat size during gamete formation. Two different classes of expansion have been identified:

What controls the direction of repeat size variation?

The direction of repeat size variation may also be controlled by unidentified sex-specific trans- acting factors. For example, the metabolism of trinucleotide repeats may be intrinsically different during female and male gametogenesis, as suggested by observations in humans and mice.

What are the different types of trinucleotide repeat disorder?

There are several known categories of trinucleotide repeat disorder. Category I includes Huntington's disease (HD) and the spinocerebellar ataxias. These are caused by a CAG repeat expansion in protein-coding portions, or exons, of specific genes. Category II expansions are also found in exons, and tend to be more phenotypically diverse with heterogeneous expansions that are generally small in magnitude. Category III includes fragile X syndrome, myotonic dystrophy, two of the spinocerebellar ataxias, juvenile myoclonic epilepsy, and Friedreich's ataxia. These diseases are characterized by typically much larger repeat expansions than the first two groups, and the repeats are located in introns rather than exons.

What happens when a trinucleotide repeat is unstable?

Depending on its location, the unstable trinucleotide repeat may cause defects in a protein encoded by a gene; change the regulation of gene expression; produce a toxic RNA, or lead to chromosome instability. In general, the larger the expansion the faster the onset of disease, and the more severe the disease becomes.

What is a CAG repeat?

In a coding region, CAG codes for glutamine (Q), so CAG repeats result in a polyglutamine tract. These diseases are commonly referred to as polyglutamine (or polyQ) diseases. The repeated codons in the remaining disorders do not code for glutamine, and these are classified as non-polyglutamine diseases.

How many CGG repeats are in fragile X syndrome?

Patients carry from 230 to 4000 CGG repeats in the gene that causes fragile X syndrome, while unaffected individuals have up to 50 repeats and carriers of the disease have 60 to 230 repeats.

Why do DNA repeats have identical sequences?

Because the tandem repeats have identical sequence to one another, base pairing between two DNA strands can take place at multiple points along the sequence. This may lead to the formation of 'loop out' structures during DNA replication or DNA repair synthesis.

What is a triplet repeat expansion disorder?

Trinucleotide repeat disorders, also known as microsatellite expansion diseases, are a set of over 50 genetic disorders caused by trinucleotide repeat expansion, a kind of mutation in which repeats of three nucleotides ...

What is a Category III disease?

Category III includes fragile X syndrome, myotonic dystrophy, two of the spinocerebellar ataxias, juvenile myoclonic epilepsy, and Friedreich's ataxia. These diseases are characterized by typically much larger repeat expansions than the first two groups, and the repeats are located in introns rather than exons.

What is a triplet repeat?

A trinucleotide repeat expansion, also known as a triplet repeat expansion, is the DNA mutation responsible for causing any type of disorder categorized as a trinucleotide repeat disorder. These are labelled in dynamical genetics as dynamic mutations. Triplet expansion is caused by slippage during DNA replication, also known as "copy choice" DNA replication. Due to the repetitive nature of the DNA sequence in these regions, 'loop out' structures may form during DNA replication while maintaining complementary base pairing between the parent strand and daughter strand being synthesized. If the loop out structure is formed from the sequence on the daughter strand this will result in an increase in the number of repeats. However, if the loop out structure is formed on the parent strand, a decrease in the number of repeats occurs. It appears that expansion of these repeats is more common than reduction. Generally, the larger the expansion the more likely they are to cause disease or increase the severity of disease. Other proposed mechanisms for expansion and reduction involve the interaction of RNA and DNA molecules.

Where are triplet repeats found?

In terms of location, these triplet repeats can be found in both coding and non-coding regions. CAG and GCN repeats, which lead to polyglutamine and polyalanine tracts respectively, are normally found in the coding regions. At the 5’ untranslated region, CGG and CAG repeats are found and responsible for fragile X syndrome and spinocerebellar ataxia 12. At the 3’ untranslated region, CTG repeats are found, while GAA repeats are located in the intron region. Other disease-causing repeats, but not triplet repeats, have been located in the promoter region. Once the number of repeats exceeds normal levels, Triplet Repeat Expansions (TRE) become more likely and the number of triplet repeats can typically increase to around 100 in coding regions and up to thousands in non-coding regions. This difference is due to overexpression of glutamine and alanine, which is selected against due to cell toxicity.

How are DM1 and FXS similar?

Many similarities can be drawn between DM1 and FXS involving aspects of mutation. Full maternal inheritance is present within DM1, repeat expansion length is linked to maternal age and the earliest instance of expansions is seen in the two-cell stage of preimplantation embryos. There is a positive correlation between male inheritance and allele length. A study of mice found the exact timing of CTG repeat expansion to be during development of spermatogonia. In DM1 and FXS, it is hypothesized that expansion of TNRs occurs by means of multiple missteps by DNA polymerase in replication. An inability of DNA polymerase to properly move across the TNR may cause transactivation of translesion polymerases (TLPs), which will attempt to complete the replication process and overcome the block. It is understood that as the DNA polymerase fails in this way, the resulting single-stranded loops left behind in the template strand undergo deletion, affecting TNR length. This process leaves the potential for TNR expansions to occur.

How do CGG repeats form?

A CGG repeat will form a G-quadruplex due to Hoogsteen base pairing, while a GAA repeat forms a triplex due to negative supercoiling. CAG, CTG, and CGG repeats form a hairpin. After the hairpin forms, the primer realigns with the 3’ end of the newly synthesized strand and continues the synthesis, leading to triplet repeat expansion. The structure of the hairpin is based on a stem and a loop that contains both Watson-Crick base pairs and mismatched pairs. In CTG and CAG repeats, the number of nucleotides present in the loop depends on if the number of triplet repeats is odd or even. An even number of repeats forms a tetraloop structure, while an odd number leads to the formation of a triloop.

What happens to DNA when it is damaged?

In addition to occurring during DNA replication, trinucleotide repeat expansion can also occur during DNA repair. When a DNA trinucleotide repeat sequence is damaged, it may be repaired by processes such as homologous recombination, non-homologous end joining, mismatch repair or base excision repair.

Why is DNA replication error important?

DNA replication errors are predicted to be the main perpetrator of trinucleotide repeat expansion transmission in many predicted models due to the difficulty of Trinucleotide Repeat Expansion (TRE). TREs have been shown to occur during DNA replication in both in vitro and in vivo studies, allowing for these long tracts of triplet repeats to assemble rapidly in different mechanisms that can result in either small scale or large scale expansions.

Where is the CGG repeat located?

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. The 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.

How many trinucleotide repeat disorders are there?

Some of these 14 trinucleotide repeat disorders are more alike than others. While the symptoms and the affected body parts vary by disease, scientists consider two illnesses to be similar if they share the same repeated codon as their cause. Six of the 14 trinucleotide repeat disorders have little or no apparent similarity to each other, or to the 8 remaining diseases. These 6 are described in brief at the end of this section. The 8 remaining disorders, one of which is Huntington’s Disease, all share the same repeated codon as their cause: CAG. Since CAG codes for an amino acid called glutamine, these 8 trinucleotide repeat disorders are collectively known as polyglutamine diseases (“poly” being the Greek word for “many”). (For background information on codons and amino acids click here .)

How long does polyglutamine degeneration last?

After 10-20 years, many of the affected nerve cells die. The major symptoms of these diseases are similar to one another and they usually affect people around the same time, in mid-life (although childhood cases have also been reported, as in the case of juvenile HD ).

What is DRPLA in medical terms?

Like other trinucleotide repeat disorders, DRPLA (Dentatorubropallidoluysian Atrophy ) affects both the mind and body. It is characterized by abrupt muscle jerking, involuntary movements, and eventual dementia. Although these symptoms are common in the men and women of all ages who have DRPLA, young people with the disease may also be affected by progressive intellectual decline.

What is the protein product of the DRPLA gene?

The protein product of the DRPLA gene is called atrophin-1. Although scientists are not sure about its function, the leading theory is that atrophin-1 is involved in the pathway that helps insulin take effect in the body’s cells. Since insulin helps determine how cells utilize their energy, it is essential that this pathway work smoothly so that cells can function efficiently. If there is a kink in the plan, it could spell disaster for an affected nerve cell.

What are the parts of the brain that are affected by DRPLA?

Together, these very important regions of the brain are collectively known as the basal ganglia. The basal ganglia are important because they help plan movements and thus have a large effect on motor control. Working with other parts of the brain such as the red nucleus and the dentate nucleus (which are also damaged in people with DRPLA), the basal ganglia help to regulate each and every movement we make. When neurons in this area are damaged due to DRPLA, it’s no wonder that muscle jerks and involuntary movements become common. (For a more detailed description of the basal ganglia – written in regards to Huntington’s Disease – click here ). (See Figure F-1.)

Is polyglutamine a repeat disorder?

As noted in the introduction to this chapter, polyglutamine diseases are only a subset of the trinucleotide repeat disorders. As of this writing (summer 2001), researchers have identified six non- polyglutamine diseases that also fall under the category of trinucleotide repeat disorders. Because each disease involves a unique repeated codon, the six non- polyglutamine diseases show relatively little resemblance to one another. More importantly, none of them appear to have any strong similarity to Huntington’s Disease or the other polyglutamine diseases. For this reason, we provide only brief descriptions of these non- polyglutamine disorders. The descriptions follow below.

Do polyglutamines have the same repeats?

It deserves to be reiterated that while the polyglutamine diseases are similar to each other, they are not identical. Although they share the same repeated codon (CAG), the repeats for the different polyglutamine diseases occur on different chromosomes, and thus on entirely different segments of DNA. (For more info on chromosomes, click here .) Despite this fact, scientists are excited about research in any of the polyglutamine diseases because finding a way to stop the CAG repeat from occurring in one disease may help lead to a cure for the other 7 as well. While this is by no means a certainty, the possibility offers wonderful incentive to be persistent in research; eight for the price of one would certainly be a great deal!

Where are trinucleotide repeats found?

Trinucleotide repeat mutations are not always found in coding regions of genes; they have also been detected within introns as well as within noncoding exons of the 5′- and 3′-untranslated regions in mature mRNA. Moderate expansions of trinucleotide tracts that do not code for amino acids are often asymptomatic, as seen in fragile X syndrome, myotonic dystrophy, and Friedreich's ataxia. The moderate expansions generate ‘pre-mutation’ alleles – highly unstable trinucleotide tracts that may undergo massive expansions, adding hundreds to thousands of triplet repeats during transmission from parent to offspring. These massive expansions can become pathogenic by silencing transcription, inhibiting translation, altering mRNA splicing, or impeding RNA export from the nucleus (Wells and Warren, 1998 ). In fragile X syndrome, as the triplet repeat expands into the premutation range, more disease-causing ‘full-mutation’ alleles arise through transmission to offspring, which explains the increased penetrance of fragile X syndrome in successive generations and thus the Sherman paradox. The full-mutation CGG tract, which is near the promoter, becomes a target for DNA methylation thereby silencing transcription ( Cummings and Zoghbi, 2000 ). In myotonic dystrophy, the transcribed expanded CUG repeat in the DMPK mRNA 3′ UTR is believed to sequester CUG-binding proteins, thereby squelching proteins away from other cellular mRNAs and impairing general cellular RNA splicing and export ( Cummings and Zoghbi, 2000 ). Massive GAA expansions in intron 1 of the X25 gene are believed to impair transcription or possibly splicing of the expanded intron, reducing the cellular level of mature frataxin ( Cummings and Zoghbi, 2000 ).

What are the structures of trinucleotide repeats?

Most trinucleotide repeats show non-B DNA structures. CAG/CTG repeats are known to form hairpins with slipped strands, which may play an important role in the mechanism of repeat-size instability (Pearson et al., 1998, 2003 ). GAA repeats at the FRDA locus have been shown to form the “sticky DNA” structure ( Sakamoto et al., 1999 ). In contrast, in vitro studies provided evidence that ATTCT repeats take unpaired structures, in which two strands are separated ( Potaman et al., 2003 ). Two-dimension (2D) agarose gel electrophoresis of plasmid topoisomers containing (ATTCT)11–46 repeats suggested that the repeats form uncoiled DNA under superhelical tension. Atomic force microscopy confirmed unpairing of the two strands in these ATTCT repeats. Furthermore, chloroacetylaldehyde bound the repeat region of the supercoiled plasmid, indicating accessibility of this reagent to the uncoiled region ( Potaman et al., 2003 ). Although the unpaired DNA structure may induce chromosome fragility and DNA methylation, our cytogenetic study, in collaboration with Dr. Lisa G. Shaffer of Washington State University showed no evidence of chromosome-22 fragility in leukocytes obtained from SCA10 patients (unpublished data). Our Southern blot analysis of genomic SCA10 DNA digested with methylation-dependent and -independent enzymes showed no evidence of aberrant methylation in the SCA10 region (data not shown).

What is the effect of huntingtin mutations on the gene coding region?

Mutant huntingtin exerts its pathological effects via abnormal protein aggregation, transcriptional dysregulation, mitochondrial dysfunction, excitotoxicity, and abnormal cellular trafficking, leading to neuronal loss particularly in the dorsal substratum [555].

Why does DNA expand?

DNA expansions that occur within trinucleotide tracts are attributable to the unique biochemical difficulties of performing DNA replication within long stretches of repeat DNA. Mounting in vitro evidence suggests that triplets are deleted or added to long repetitive tracts as the cellular machinery tries to replicate ...

When were unstable trinucleotide repeats discovered?

Unstable trinucleotide repeats are a novel disease mechanism, first discovered in 1991, and an important cause of neurogenetic disease. A feature of these conditions is anticipation, with earlier onset and more severe phenotype in successive generations, which appears to correlate with increasing repeat size during gamete formation. Two different classes of expansion have been identified:

What controls the direction of repeat size variation?

The direction of repeat size variation may also be controlled by unidentified sex-specific trans- acting factors. For example, the metabolism of trinucleotide repeats may be intrinsically different during female and male gametogenesis, as suggested by observations in humans and mice.

What enzyme is responsible for removing the flap of single stranded DNA?

Flap endonuclease 1, FEN1, is an enzyme responsible for removing the ‘flap’ of single-stranded DNA ( Warren and Sherman, 2000). This allows end-to-end ligation of the Okazaki fragments and conserves the wild-type DNA sequence. In trinucleotide repeat tracts, the single-strand flap DNA may form a stable hairpin structure and remain in ...

Overview

Trinucleotide repeat disorders, also known as microsatellite expansion diseases, are a set of over 50 genetic disorders caused by trinucleotide repeat expansion, a kind of mutation in which repeats of three nucleotides (trinucleotide repeats) increase in copy numbers until they cross a threshold above which they become unstable. Depending on its location, the unstable trinucleotide repeat may cause defects in a protein encoded by a gene; change the regulation of gene expression; prod…

Symptoms and signs

Genetics

Mechanism

See also

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