Trinucleotide repeat disorder

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Trinucleotide repeat disorder
Other namesTrinucleotide repeat expansion disorders, Triplet repeat expansion disorders or Codon reiteration disorders

In genetics, trinucleotide repeat disorders, a subset of microsatellite expansion diseases (also known as repeat expansion disorders), are a set of over 30 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 cause developmental, neurological or neuromuscular disorders. [1] [2] [3] 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 production of a toxic protein. [1] [2] In general, the larger the expansion the faster the onset of disease, and the more severe the disease becomes. [1] [2]

Contents

Trinucleotide repeats are a subset of a larger class of unstable microsatellite repeats that occur throughout all genomes.

The first trinucleotide repeat disease to be identified was fragile X syndrome, which has since been mapped to the long arm of the X chromosome. 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. The chromosomal instability resulting from this trinucleotide expansion presents clinically as intellectual disability, distinctive facial features, and macroorchidism in males. The second DNA-triplet repeat disease, fragile X-E syndrome, was also identified on the X chromosome, but was found to be the result of an expanded CCG repeat. [4] The discovery that trinucleotide repeats could expand during intergenerational transmission and could cause disease was the first evidence that not all disease-causing mutations are stably transmitted from parent to offspring. [1]

Trinucleotide repeat disorders and the related microsatellite repeat disorders affect about 1 in 3,000 people worldwide. [5] However, the frequency of occurrence of any one particular repeat sequence disorder varies greatly by ethnic group and geographic location. [6] Many regions of the genome (exons, introns, intergenic regions) normally contain trinucleotide sequences, or repeated sequences of one particular nucleotide, or sequences of 2, 4, 5 or 6 nucleotides. Such repetitive sequences occur at a low level that can be regarded as "normal". [7] Sometimes, a person may have more than the usual number of copies of a repeat sequence associated with a gene, but not enough to alter the function of that gene. These individuals are referred to as "premutation carriers". The frequency of carriers worldwide appears to be 1 in 340 individuals. [5] Some carriers, during the formation of eggs or sperm, may give rise to higher levels of repetition of the repeat they carry. The higher level may then be at a "mutation" level and cause symptoms in their offspring.

Three categories of trinucleotide repeat disorders and related microsatellite (4, 5, or 6 repeats) disorders are described by Boivin and Charlet-Berguerand. [2]

The first main category these authors discuss is repeat expansions located within the promoter region of a gene or located close to, but upstream of, a promoter region of a gene. These repeats are able to promote localized DNA epigenetic changes such as methylation of cytosines. Such epigenetic alterations can inhibit transcription, [8] causing reduced expression of the associated encoded protein. [2] The epigenetic alterations and their effects are described more fully by Barbé and Finkbeiner [9] These authors cite evidence that the age at which an individual begins to experience symptoms, as well as the severity of disease, is determined both by the size of the repeat and the epigenetic state within the repeat and around the repeat. There is often increased methylation at CpG islands near the repeat region, resulting in a closed chromatin state, causing gene downregulation. [9] This first category is designated as "loss of function". [2]

The second main category of trinucleotide repeat disorders and related microsatellite disorders involves a toxic RNA gain of function mechanism. In this second type of disorder, large repeat expansions in DNA are transcribed into pathogenic RNAs that form nuclear RNA foci. These foci attract and alter the location and function of RNA binding proteins. This, in turn, causes multiple RNA processing defects that lead to the diverse clinical manifestations of these diseases. [2]

The third main category of trinucleotide repeat disorders and related microsatellite disorders is due to the translation of repeat sequenced into pathogenic proteins containing a stretch of repeated amino acids. This results in, variously, a toxic gain of function, a loss of function, a dominant negative effect and/or a mix of these mechanisms for the protein hosting the expansion. Translation of these repeat expansions occurs mostly through two mechanisms. First, there may be translation initiated at the usual AUG or a similar (CUG, GUG, UUG, or ACG) start codon. This results in expression of a pathogenic protein encoded by one particular coding frame. Second, a mechanism named "repeat-associated non-AUG (RAN) translation" uses translation initiation that starts directly within the repeat expansion. This potentially results in expression of three different proteins encoded by the three possible reading frames. Usually, one of the three proteins is more toxic than the other two. Typical of these RAN type expansions are those with the trinucleotide repeat CAG. These often are translated into polyglutamine-containing proteins that form inclusions and are toxic to neuronal cells. Examples of the disorders caused by this mechanism include Huntington's disease and Huntington disease-like 2, spinal-bulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, and spinocerebellar ataxia 1–3, 6–8, and 17. [2]

The first main category, the loss of function type with epigenetic contributions, can have repeats located in either a promoter, in 5'untranscribed regions upstream of promoters, or in introns. The second category, toxic RNAs, has repeats located in introns or in a 3' untranslated region of code beyond the stop codon. The third category, largely producing toxic proteins with polyalanines or polyglutamines, has trinucleotide repeats that occur in the exons of the affected genes. [2]

Types

Some of the problems in trinucleotide repeat syndromes result from causing alterations in the coding region of the gene, while others are caused by altered gene regulation. [1] In over half of these disorders, the repeated trinucleotide, or codon, is CAG. In a coding region, CAG codes for glutamine (Q), so CAG repeats result in an expanded polyglutamine tract. [10] 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 can be classified as non-polyQ or non-coding trinucleotide repeat disorders.

Polyglutamine (PolyQ) diseases

TypeGeneNormal PolyQ repeatsPathogenic PolyQ repeats
DRPLA (Dentatorubropallidoluysian atrophy) ATN1 or DRPLA6 - 3549 - 88
HD (Huntington's disease) HTT 6 - 3536 - 250
SBMA (Spinal and bulbar muscular atrophy) [11] AR 4 - 3435 - 72
SCA1 (Spinocerebellar ataxia Type 1) ATXN1 6 - 3549 - 88
SCA2 (Spinocerebellar ataxia Type 2) ATXN2 14 - 3233 - 77
SCA3 (Spinocerebellar ataxia Type 3 or Machado-Joseph disease) ATXN3 12 - 4055 - 86
SCA6 (Spinocerebellar ataxia Type 6) CACNA1A 4 - 1821 - 30
SCA7 (Spinocerebellar ataxia Type 7) ATXN7 7 - 1738 - 120
SCA17 (Spinocerebellar ataxia Type 17) TBP 25 - 4247 - 63

Non-coding trinucleotide repeat disorders

TypeGeneCodonNormalPathogenicMechanism [1]
FRAXA (Fragile X syndrome) FMR1 CGG (5' UTR)6 - 53230+abnormal methylation
FXTAS (Fragile X-associated tremor/ataxia syndrome) FMR1 CGG (5' UTR)6 - 5355-200increased expression, and a novel polyglycine product [12]
FRAXE (Fragile XE mental retardation) AFF2 CCG (5' UTR)6 - 35200+abnormal methylation
Baratela-Scott syndrome [13] XYLT1 GGC (5' UTR)6 - 35200+abnormal methylation
FRDA (Friedreich's ataxia) FXN GAA (Intron)7 - 34100+impaired transcription
DM1 (Myotonic dystrophy Type 1) DMPK CTG (3' UTR)5 - 3450+RNA-based; unbalanced DMPK/ZNF9 expression levels
SCA8 (Spinocerebellar ataxia Type 8) SCA8 CTG (RNA)16 - 37110 - 250 ? RNA
SCA12 (Spinocerebellar ataxia Type 12) [14] [15] PPP2R2B CAG (5' UTR)7 - 2855 - 78effect on promoter function

Symptoms and signs

As of 2017, ten neurological and neuromuscular disorders were known to be caused by an increased number of CAG repeats. [10] Although these diseases share the same repeated codon (CAG) and some symptoms, the repeats are found in different, unrelated genes. Except for the CAG repeat expansion in the 5' UTR of PPP2R2B in SCA12, the expanded CAG repeats are translated into an uninterrupted sequence of glutamine residues, forming a polyQ tract, and the accumulation of polyQ proteins damages key cellular functions such as the ubiquitin-proteasome system. A common symptom of polyQ diseases is the progressive degeneration of nerve cells, usually affecting people later in life. However different polyQ-containing proteins damage different subsets of neurons, leading to different symptoms. [16]

The non-polyQ diseases or non-coding trinucleotide repeat disorders do not share any specific symptoms and are unlike the PolyQ diseases. In some of these diseases, such as Fragile X syndrome, the pathology is caused by lack of the normal function of the protein encoded by the affected gene. In others, such as Myotonic Dystrophy Type 1, the pathology is caused by a change in protein expression or function mediated through changes in the messenger RNA produced by the expression of the affected gene. [1] In yet others, the pathology is caused by toxic assemblies of RNA in the nuclei of cells. [17]

Genetics

Classification of the trinucleotide repeat, and resulting disease status, depends on the number of CAG repeats in Huntington's disease [18]
Repeat countClassificationDisease status
<28NormalUnaffected
28–35IntermediateUnaffected
36–40Reduced-penetranceMay be affected
>40Full-penetranceAffected

Trinucleotide repeat disorders generally show genetic anticipation: their severity increases with each successive generation that inherits them. This is likely explained by the addition of CAG repeats in the affected gene as the gene is transmitted from parent to child. For example, Huntington's disease occurs when there are more than 35 CAG repeats on the gene coding for the protein HTT. A parent with 35 repeats would be considered normal and would not exhibit any symptoms of the disease. [18] However, that parent's offspring would be at an increased risk of developing Huntington's compared to the general population, as it would take only the addition of one more CAG codon to cause the production of mHTT (mutant HTT), the protein responsible for disease.

Huntington's very rarely occurs spontaneously; it is almost always the result of inheriting the defective gene from an affected parent. However, sporadic cases of Huntington's in individuals who have no history of the disease in their families do occur. Among these sporadic cases, there is a higher frequency of individuals with a parent who already has a significant number of CAG repeats in their HTT gene, especially those whose repeats approach the number (36) required for the disease to manifest. Each successive generation in a Huntington's-affected family may add additional CAG repeats, and the higher the number of repeats, the more severe the disease and the earlier its onset. [18] As a result, families that have had Huntington's for many generations show an earlier age of disease onset and faster disease progression. [18]

Non-trinucleotide expansions

The majority of diseases caused by expansions of simple DNA repeats involve trinucleotide repeats, but tetra-, penta- and dodecanucleotide repeat expansions are also known that cause disease. For any specific hereditary disorder, only one repeat expands in a particular gene. [19]

Mechanism

Triplet expansion is caused by slippage during DNA replication or during DNA repair synthesis. [20] 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. [21] This may lead to repeated copying of the repeated sequence, expanding the number of repeats. Additional mechanisms involving hybrid RNA:DNA intermediates have been proposed. [22] [23]

Diagnosis

See also

Related Research Articles

A microsatellite is a tract of repetitive DNA in which certain DNA motifs are repeated, typically 5–50 times. Microsatellites occur at thousands of locations within an organism's genome. They have a higher mutation rate than other areas of DNA leading to high genetic diversity. Microsatellites are often referred to as short tandem repeats (STRs) by forensic geneticists and in genetic genealogy, or as simple sequence repeats (SSRs) by plant geneticists.

<span class="mw-page-title-main">Huntington's disease</span> Inherited neurodegenerative disorder

Huntington's disease (HD), also known as Huntington's chorea, is an incurable neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental/psychiatric abilities. A general lack of coordination and an unsteady gait often follow. It is also a basal ganglia disease causing a hyperkinetic movement disorder known as chorea. As the disease advances, uncoordinated, involuntary body movements of chorea become more apparent. Physical abilities gradually worsen until coordinated movement becomes difficult and the person is unable to talk. Mental abilities generally decline into dementia, depression, apathy, and impulsivity at times. The specific symptoms vary somewhat between people. Symptoms usually begin between 30 and 50 years of age, and can start at any age but are usually seen around the age of 40. The disease may develop earlier in each successive generation. About eight percent of cases start before the age of 20 years, and are known as juvenile HD, which typically present with the slow movement symptoms of Parkinson's disease rather than those of chorea.

Repeated sequences are short or long patterns of nucleic acids that occur in multiple copies throughout the genome. In many organisms, a significant fraction of the genomic DNA is repetitive, with over two-thirds of the sequence consisting of repetitive elements in humans. Some of these repeated sequences are necessary for maintaining important genome structures such as telomeres or centromeres.

<span class="mw-page-title-main">Frameshift mutation</span> Mutation that shifts codon alignment

A frameshift mutation is a genetic mutation caused by indels of a number of nucleotides in a DNA sequence that is not divisible by three. Due to the triplet nature of gene expression by codons, the insertion or deletion can change the reading frame, resulting in a completely different translation from the original. The earlier in the sequence the deletion or insertion occurs, the more altered the protein. A frameshift mutation is not the same as a single-nucleotide polymorphism in which a nucleotide is replaced, rather than inserted or deleted. A frameshift mutation will in general cause the reading of the codons after the mutation to code for different amino acids. The frameshift mutation will also alter the first stop codon encountered in the sequence. The polypeptide being created could be abnormally short or abnormally long, and will most likely not be functional.

In genetics, anticipation is a phenomenon whereby as a genetic disorder is passed on to the next generation, the symptoms of the genetic disorder become apparent at an earlier age with each generation. In most cases, an increase in the severity of symptoms is also noted. Anticipation is common in trinucleotide repeat disorders, such as Huntington's disease and myotonic dystrophy, where a dynamic mutation in DNA occurs. All of these diseases have neurological symptoms. Prior to the understanding of the genetic mechanism for anticipation, it was debated whether anticipation was a true biological phenomenon or whether the earlier age of diagnosis was related to heightened awareness of disease symptoms within a family.

<span class="mw-page-title-main">Spinocerebellar ataxia</span> Medical condition

Spinocerebellar ataxia (SCA) is a progressive, degenerative, genetic disease with multiple types, each of which could be considered a neurological condition in its own right. An estimated 150,000 people in the United States have a diagnosis of spinocerebellar ataxia at any given time. SCA is hereditary, progressive, degenerative, and often fatal. There is no known effective treatment or cure. SCA can affect anyone of any age. The disease is caused by either a recessive or dominant gene. In many cases people are not aware that they carry a relevant gene until they have children who begin to show signs of having the disorder.

<span class="mw-page-title-main">Spinal and bulbar muscular atrophy</span> Medical condition

Spinal and bulbar muscular atrophy (SBMA), popularly known as Kennedy's disease, is a rare, adult-onset, X-linked recessive lower motor neuron disease caused by trinucleotide CAG repeat expansions in exon 1 of the androgen receptor (AR) gene, which results in both loss of AR function and toxic gain of function.

<span class="mw-page-title-main">Huntingtin</span> Gene and protein involved in Huntingtons disease

Huntingtin(Htt) is the protein coded for in humans by the HTT gene, also known as the IT15 ("interesting transcript 15") gene. Mutated HTT is the cause of Huntington's disease (HD), and has been investigated for this role and also for its involvement in long-term memory storage.

<span class="mw-page-title-main">Neurodegenerative disease</span> Central nervous system disease

A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy, tauopathies, and prion diseases. Neurodegeneration can be found in the brain at many different levels of neuronal circuitry, ranging from molecular to systemic. Because there is no known way to reverse the progressive degeneration of neurons, these diseases are considered to be incurable; however research has shown that the two major contributing factors to neurodegeneration are oxidative stress and inflammation. Biomedical research has revealed many similarities between these diseases at the subcellular level, including atypical protein assemblies and induced cell death. These similarities suggest that therapeutic advances against one neurodegenerative disease might ameliorate other diseases as well.

<span class="mw-page-title-main">Slipped strand mispairing</span> Nucleotide duplications created by DNA polymerase during DNA replication

Slipped strand mispairing is a mutation process which occurs during DNA replication. It involves denaturation and displacement of the DNA strands, resulting in mispairing of the complementary bases. Slipped strand mispairing is one explanation for the origin and evolution of repetitive DNA sequences.

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.

<span class="mw-page-title-main">Ataxin 1</span> Protein-coding gene in the species Homo sapiens

Ataxin-1 is a DNA-binding protein which in humans is encoded by the ATXN1 gene.

<span class="mw-page-title-main">Atrophin 1</span> Protein-coding gene in the species Homo sapiens

Atrophin-1 is a protein that in humans is encoded by the ATN1 gene. The encoded protein includes a serine repeat and a region of alternating acidic and basic amino acids, as well as the variable glutamine repeat. The function of Atrophin-1 has not yet been determined. There is evidence provided by studies of Atrophin-1 in animals to suggest it acts as a transcriptional co-repressor. Atrophin-1 can be found in the nuclear and cytoplasmic compartments of neurons. It is expressed in nervous tissue.

<span class="mw-page-title-main">Ataxin-2</span> Mammalian protein found in Homo sapiens

Ataxin-2 is a protein that in humans is encoded by the ATXN2 gene. Mutations in ATXN2 cause spinocerebellar ataxia type 2 (SCA2).

<span class="mw-page-title-main">Ataxin 3</span> Protein-coding gene in the species Homo sapiens

Ataxin-3 is a protein that in humans is encoded by the ATXN3 gene.

<span class="mw-page-title-main">JPH3</span> Protein-coding gene in the species Homo sapiens

Junctophilin-3 (JPH3) is a protein in humans that is encoded by the JPH3 gene. The gene is approximately 97 kilobases long and is located at chromosomal position 16q24.2. Junctophilin proteins are associated with the formation of junctional membrane complexes, linking the plasma membrane with the endoplasmic reticulum in excitable cells. JPH3 is localized to the brain and is associated with motor coordination and memory neurons.

<span class="mw-page-title-main">Dentatorubral–pallidoluysian atrophy</span> Congenital disorder of nervous system

Dentatorubral–pallidoluysian atrophy (DRPLA) is an autosomal dominant spinocerebellar degeneration caused by an expansion of a CAG repeat encoding a polyglutamine tract in the atrophin-1 protein. It is also known as Haw River Syndrome and Naito–Oyanagi disease. Although this condition was perhaps first described by Smith et al. in 1958, and several sporadic cases have been reported from Western countries, this disorder seems to be very rare except in Japan.

A polyglutamine tract or polyQ tract is a portion of a protein consisting of a sequence of several glutamine units. A tract typically consists of about 10 to a few hundred such units.

<span class="mw-page-title-main">Epigenetics of neurodegenerative diseases</span> Field of study

Neurodegenerative diseases are a heterogeneous group of complex disorders linked by the degeneration of neurons in either the peripheral nervous system or the central nervous system. Their underlying causes are extremely variable and complicated by various genetic and/or environmental factors. These diseases cause progressive deterioration of the neuron resulting in decreased signal transduction and in some cases even neuronal death. Peripheral nervous system diseases may be further categorized by the type of nerve cell affected by the disorder. Effective treatment of these diseases is often prevented by lack of understanding of the underlying molecular and genetic pathology. Epigenetic therapy is being investigated as a method of correcting the expression levels of misregulated genes in neurodegenerative diseases.

Repeat Associated Non-AUG translation, or RAN translation, is an irregular mode of mRNA translation that can occur in eukaryotic cells.

References

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