Trinucleotide repeat disorders
Encyclopedia
Trinucleotide repeat disorders (also known as trinucleotide repeat expansion disorders, triplet repeat expansion disorders or codon reiteration disorders) are a set of genetic disorders caused by trinucleotide repeat expansion
, a kind of mutation where trinucleotide repeats in certain gene
s exceeding the normal, stable, threshold, which differs per gene. The mutation is a subset of unstable microsatellite repeats that occur throughout all genomic
sequences. If the repeat is present in a healthy gene
, a dynamic mutation
may increase the repeat count and result in a defective gene.
Trinucleotide repeats are sometimes classified as insertion mutations and sometimes as a separate class of mutations.
that has since been mapped to the long arm of the X chromosome
. At this point, there are from 230 to 4000 CGG repeats in the gene that causes fragile X syndrome in these patients, as compared with 60 to 230 repeats in carriers and 5 to 54 repeats in unaffected individuals. The chromosomal instability resulting from this trinucleotide expansion presents clinically as mental retardation
, distinctive facial features, and macroorchidism
in males. The second, related 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. Identifying trinucleotide repeats as the basis of disease has brought clarity to our understanding of a complex set of inherited neurological diseases.
As more repeat expansion diseases have been discovered, several categories have been established to group them based upon similar characteristics. Category I includes Huntington’s disease (HD) and the spinocerebellar ataxias that are caused by a CAG repeat expansion in protein-coding portions of specific genes. Category II expansions tend to be more phenotypically diverse with heterogeneous expansions that are generally small in magnitude, but also found in the exons of genes. 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 outside of the protein-coding regions of the genes.
residues forming what is known as a polyglutamine tract ("polyQ"). Such polyglutamine tracts may be subject to increased aggregation
.
Recent results suggest that the CAG repeats need not always be translated in order to cause toxicity
. Researchers at the University of Pennsylvania
demonstrated that in fruit flies
, a protein previously known to bind CUG repeats (muscleblind, or mbl) is also capable of binding CAG repeats. Furthermore, when the CAG repeat was changed to a repeating series of CAACAG (which also translates to polyQ), toxicity was dramatically reduced. The human homolog
of mbl, MBNL1
, which was originally identified as binding CUG repeats in RNA, has since been shown to bind CAG (and CCG
) repeats as well.
These disorders are characterized by autosomal dominant mode of inheritance (with the exception of spino-bulbar muscular atrophy which shows X-linked inheritance), midlife onset, a progressive course, and a correlation of the number of CAG repeats with the severity of disease and the age at onset. Family studies have also suggested that these diseases are associated with anticipation, the tendency for progressively earlier or more severe expression of the disease in successive generations. Although the causative genes are widely expressed in all of the known polyglutamine diseases, each disease displays an extremely selective pattern of neurodegeneration.
was the first to identify the correlation between trinucleotide repeat expansion and diseases causing neurological dysfunction. At present there are 14 documented trinucleotide repeat disorders that affect humans.
The non-PolyQ diseases do not share any specific symptoms and are unlike the PolyQ diseases.
Trinucleotide repeat disorders generally show genetic anticipation
, where their severity increases with each successive generation that inherits them. This is likely explained by the addition of further CAG-repeats in the gene in the progeny of affected individuals. 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 never exhibit any symptoms of the disease. That parent's offspring, however, would be at an increased risk compared to the general population of developing Huntington's, 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. That said, sporadic cases of Huntington's do occur, and those individuals with a parent who already has a significant number of CAG repeats in their HTT gene, especially if it approaches the number (36) required for the disease to manifest, are at an increased risk of developing Huntington's despite the lack of any history of the disease in their family. Also, the more repeats, the more severe the disease and the earlier its onset. This explains why individuals that have had Huntington's running in their family for a longer period of time show an earlier age of disease onset and faster disease progression, as mutations which add additional CAG codons become more likely with each successive generation.
Trinucleotide repeat disorders are the result of extensive duplication of a single codon. In fact, the cause is trinucleotide expansion up to a repeat number above a certain threshold level. Huntington's is a good example of this phenomenon, as can be seen in the table on the right.
s. If the frameshift mutations altered the expression of developmentally obligatory pathways, then non-trinucleotide repeats may be masked by developmental lethality. Mutations of 3 base pairs, on the other hand, do not cause a catastrophic frameshift mutation
, and unless a stop codon (TAG, TAA, TGA) is the triplet that is added to the gene - which would in almost all cases render the protein coded for useless - a trinucleotide addition to a gene can have no effect at all on the protein, can cripple the protein, or sometimes can make it work even better than it used to. The overwhelming number of mutations are not beneficial, and this article is testimony to the severely detrimental effects trinucleotide additions to the genome can produce. Still, 3 (and multiples of 3) nucleotide expansions to a coding region of the genome are at least somewhat less likely to be detrimental to an organism.
(Q), resulting in a polyglutamine tract
. These diseases are commonly referred to as polyglutamine (or PolyQ) diseases. The remaining disorders repeated codons do not code for glutamine and are classified as non-polyglutamine diseases.
mutation
responsible for causing any type of disorder
categorized as a trinucleotide repeat disorder. These are labelled in dynamical genetics
as dynamic mutation
s.
Triplet expansion is caused by slippage during DNA replication. Due to the tandem repeats in the DNA sequence and the instability of the sequence in these regions, 'loop out' structures may form during DNA replication while maintaining complementary base paring between the parent strand and daughter strand being synthesized. Essentially, a nick one side of the DNA strand is caused by cleavage by endonuclease whereby the repetitive triplet is extended and sealed by DNA polymerase and DNA ligase respectively. If the loop out structure is formed from 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. 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.
In 2006,a model of expanding the triplets by involving RNA:DNA intermediate formed in repeat transcription or in post-transcription was proposed., and similar ideas turned to be a fashion ongoing issue of the mechanism studies ever since
In 2007 a new disease model was produced to explain the progression of Huntington's Disease
and similar trinucleotide repeat disorders
, which, in simulations, seems to accurately predict age of onset and the way the disease will progress in an individual, based on the number of repeats of a genetic mutation
.
Trinucleotide repeat expansion
Trinucleotide repeat expansion, also known as 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...
, a kind of mutation where trinucleotide repeats in certain gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s exceeding the normal, stable, threshold, which differs per gene. The mutation is a subset of unstable microsatellite repeats that occur throughout all genomic
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
sequences. If the repeat is present in a healthy gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
, a dynamic mutation
Dynamic mutation
In genetics, a dynamic mutation is an unstable heritable element where the probability of expression of a mutant phenotype is a function of the number of copies of the mutation. That is, the replication product of a dynamic mutation has a different likelihood of mutation than its predecessor...
may increase the repeat count and result in a defective gene.
Trinucleotide repeats are sometimes classified as insertion mutations and sometimes as a separate class of mutations.
Summary
Since the early '90s, a new class of molecular disease has been characterized based upon the presence of unstable and abnormal expansions of DNA-triplets (trinucleotides). The first triplet disease to be identified was fragile X syndromeFragile X syndrome
Fragile X syndrome , Martin–Bell syndrome, or Escalante's syndrome , is a genetic syndrome that is the most commonly known single-gene cause of autism and the most common inherited cause of intellectual disability...
that has since been mapped to the long arm of the X chromosome
X chromosome
The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...
. At this point, there are from 230 to 4000 CGG repeats in the gene that causes fragile X syndrome in these patients, as compared with 60 to 230 repeats in carriers and 5 to 54 repeats in unaffected individuals. The chromosomal instability resulting from this trinucleotide expansion presents clinically as mental retardation
Mental retardation
Mental retardation is a generalized disorder appearing before adulthood, characterized by significantly impaired cognitive functioning and deficits in two or more adaptive behaviors...
, distinctive facial features, and macroorchidism
Macroorchidism
Macroorchidism is the medical term used to describe a genetic disorder found in males where a subject has abnormally large testes. The condition is commonly inherited in connection with fragile X syndrome, which is also the second most common genetic cause of mental disabilities...
in males. The second, related 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. Identifying trinucleotide repeats as the basis of disease has brought clarity to our understanding of a complex set of inherited neurological diseases.
As more repeat expansion diseases have been discovered, several categories have been established to group them based upon similar characteristics. Category I includes Huntington’s disease (HD) and the spinocerebellar ataxias that are caused by a CAG repeat expansion in protein-coding portions of specific genes. Category II expansions tend to be more phenotypically diverse with heterogeneous expansions that are generally small in magnitude, but also found in the exons of genes. Category III includes fragile X syndrome, myotonic dystrophy
Myotonic dystrophy
Myotonic dystrophy is a chronic, slowly progressing, highly variable inherited multisystemic disease. It is characterized by wasting of the muscles , cataracts, heart conduction defects, endocrine changes, and myotonia. Myotonic dystrophy can occur in patients of any age...
, two of the spinocerebellar ataxias, juvenile myoclonic epilepsy
Myoclonic epilepsy
Myoclonic epilepsy refers to a family of epilepsies which present with myoclonus.They are divided into two main families:* progressive myoclonic epilepsy* juvenile myoclonic epilepsy...
, and Friedreich's ataxia
Friedreich's ataxia
Friedreich's ataxia is an inherited disease that causes progressive damage to the nervous system, resulting in symptoms ranging from gait disturbance to speech problems; it can also lead to heart disease and diabetes....
. These diseases are characterized by typically much larger repeat expansions than the first two groups, and the repeats are located outside of the protein-coding regions of the genes.
CAG Repeats
Currently, nine neurologic disorders are known to be caused by an increased number of CAG repeats, typically in coding regions of otherwise unrelated proteins. During protein synthesis, the expanded CAG repeats are translated into a series of uninterrupted glutamineGlutamine
Glutamine is one of the 20 amino acids encoded by the standard genetic code. It is not recognized as an essential amino acid but may become conditionally essential in certain situations, including intensive athletic training or certain gastrointestinal disorders...
residues forming what is known as a polyglutamine tract ("polyQ"). Such polyglutamine tracts may be subject to increased aggregation
Protein aggregation
Protein aggregation is the aggregation of mis-folded proteins, and is thought to be responsible for many degenerative diseases, such as Alzheimer's. It has also been implicated in CAG repeat diseases....
.
Recent results suggest that the CAG repeats need not always be translated in order to cause toxicity
Toxicity
Toxicity is the degree to which a substance can damage a living or non-living organisms. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a substructure of the organism, such as a cell or an organ , such as the liver...
. Researchers at the University of Pennsylvania
University of Pennsylvania
The University of Pennsylvania is a private, Ivy League university located in Philadelphia, Pennsylvania, United States. Penn is the fourth-oldest institution of higher education in the United States,Penn is the fourth-oldest using the founding dates claimed by each institution...
demonstrated that in fruit flies
Drosophila melanogaster
Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...
, a protein previously known to bind CUG repeats (muscleblind, or mbl) is also capable of binding CAG repeats. Furthermore, when the CAG repeat was changed to a repeating series of CAACAG (which also translates to polyQ), toxicity was dramatically reduced. The human homolog
Homology (biology)
Homology forms the basis of organization for comparative biology. In 1843, Richard Owen defined homology as "the same organ in different animals under every variety of form and function". Organs as different as a bat's wing, a seal's flipper, a cat's paw and a human hand have a common underlying...
of mbl, MBNL1
MBNL1
Muscleblind-like , also known as MBNL1, is a protein that in humans is encoded by the MBNL1 gene. It has been implicated in Myotonic dystrophy and has been shown to autoregulate its transcript.-Further reading:...
, which was originally identified as binding CUG repeats in RNA, has since been shown to bind CAG (and CCG
Proline
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...
) repeats as well.
These disorders are characterized by autosomal dominant mode of inheritance (with the exception of spino-bulbar muscular atrophy which shows X-linked inheritance), midlife onset, a progressive course, and a correlation of the number of CAG repeats with the severity of disease and the age at onset. Family studies have also suggested that these diseases are associated with anticipation, the tendency for progressively earlier or more severe expression of the disease in successive generations. Although the causative genes are widely expressed in all of the known polyglutamine diseases, each disease displays an extremely selective pattern of neurodegeneration.
History
Anita HardingAnita Harding
Anita Harding was a British neurologist. She was born in Birmingham and educated at the King Edward VI High School for Girls and the Royal Free Hospital Medical School, where she qualified in 1975. She married neurology professor P.K...
was the first to identify the correlation between trinucleotide repeat expansion and diseases causing neurological dysfunction. At present there are 14 documented trinucleotide repeat disorders that affect humans.
Symptoms
A common symptom of PolyQ diseases is characterized by a progressive degeneration of nerve cells usually affecting people later in life. Although these diseases share the same repeated codon (CAG) and some symptoms, the repeats for the different polyglutamine diseases occur on different chromosomes.The non-PolyQ diseases do not share any specific symptoms and are unlike the PolyQ diseases.
Genetics
| Repeat count | Classification | Disease status |
|---|---|---|
| <28 | Normal | Unaffected |
| 28–35 | Intermediate | Unaffected |
| 36–40 | Reduced Penetrance | +/- Affected |
| >40 | Full Penetrance | Affected |
Trinucleotide repeat disorders generally show genetic anticipation
Anticipation (genetics)
In genetics, anticipation is a phenomenon whereby the symptoms of a genetic disorder become apparent at an earlier age as it is passed on to the next generation. In most cases, an increase of severity of symptoms is also noted. Anticipation is common in trinucleotide repeat disorders such as...
, where their severity increases with each successive generation that inherits them. This is likely explained by the addition of further CAG-repeats in the gene in the progeny of affected individuals. For example, Huntington's disease
Huntington's disease
Huntington's disease, chorea, or disorder , is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and dementia. It typically becomes noticeable in middle age. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea...
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 never exhibit any symptoms of the disease. That parent's offspring, however, would be at an increased risk compared to the general population of developing Huntington's, 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. That said, sporadic cases of Huntington's do occur, and those individuals with a parent who already has a significant number of CAG repeats in their HTT gene, especially if it approaches the number (36) required for the disease to manifest, are at an increased risk of developing Huntington's despite the lack of any history of the disease in their family. Also, the more repeats, the more severe the disease and the earlier its onset. This explains why individuals that have had Huntington's running in their family for a longer period of time show an earlier age of disease onset and faster disease progression, as mutations which add additional CAG codons become more likely with each successive generation.
Trinucleotide repeat disorders are the result of extensive duplication of a single codon. In fact, the cause is trinucleotide expansion up to a repeat number above a certain threshold level. Huntington's is a good example of this phenomenon, as can be seen in the table on the right.
Why three nucleotides?
An interesting question is why three nucleotides are expanded, rather than two or four or some other number. Dinucleotide repeats are a common feature of the genome in general, as are larger repeats (e.g. VNTRs - Variable Number Tandem Repeats). One possibility is that repeats that are not a multiple of three would not be viable. Trinucleotide repeat expansions tend to be near coding regions of the genome, and therefore repeats that are not multiples of three could cause frameshift mutationFrameshift mutation
A frameshift mutation is a genetic mutation caused by indels of a number of nucleotides that is not evenly divisible by three from a DNA sequence...
s. If the frameshift mutations altered the expression of developmentally obligatory pathways, then non-trinucleotide repeats may be masked by developmental lethality. Mutations of 3 base pairs, on the other hand, do not cause a catastrophic frameshift mutation
Frameshift mutation
A frameshift mutation is a genetic mutation caused by indels of a number of nucleotides that is not evenly divisible by three from a DNA sequence...
, and unless a stop codon (TAG, TAA, TGA) is the triplet that is added to the gene - which would in almost all cases render the protein coded for useless - a trinucleotide addition to a gene can have no effect at all on the protein, can cripple the protein, or sometimes can make it work even better than it used to. The overwhelming number of mutations are not beneficial, and this article is testimony to the severely detrimental effects trinucleotide additions to the genome can produce. Still, 3 (and multiples of 3) nucleotide expansions to a coding region of the genome are at least somewhat less likely to be detrimental to an organism.
Types
In over half of these disorders, the repeated codon is CAG , which in a coding region , codes for glutamineGlutamine
Glutamine is one of the 20 amino acids encoded by the standard genetic code. It is not recognized as an essential amino acid but may become conditionally essential in certain situations, including intensive athletic training or certain gastrointestinal disorders...
(Q), resulting in a polyglutamine tract
Polyglutamine tract
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....
. These diseases are commonly referred to as polyglutamine (or PolyQ) diseases. The remaining disorders repeated codons do not code for glutamine and are classified as non-polyglutamine diseases.
Polyglutamine (PolyQ) Diseases
| Type | Gene | Normal PolyQ repeats | Pathogenic PolyQ repeats >- | DRPLA (Dentatorubropallidoluysian atrophy) |
ATN1 ATN1 ATN1 is a protein found in nervous tissue.It is associated with a form of trinucleotide repeat disorder known as "dentatorubral-pallidoluysian atrophy" or "dentatorubropallidoluysian atrophy".-Interactions:... or DRPLA |
6 - 35 | >- | HTT (Huntingtin Huntingtin The Huntingtin gene, also called HTT or HD gene, is the IT15 gene which codes for a protein called the huntingtin protein... ) |
10 - 35 | >- | Androgen receptor Androgen receptor The androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus... on the X chromosome X chromosome The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system... . |
9 - 36 | >- | ATXN1 | 6 - 35 | >- | ATXN2 ATXN2 Ataxin-2 is a protein that in humans is encoded by the ATXN2 gene.-Further reading:-External Links:*... |
14 - 32 | >- | ATXN3 | 12 - 40 | >- | CACNA1A | 4 - 18 | >- | ATXN7 | 7 - 17 | >- | TBP | 25 - 42 | 47 - 63 |
Non-Polyglutamine Diseases
| Type | Gene | Codon | Normal/wildtype | Pathogenic >- | FRAXA (Fragile X syndrome Fragile X syndrome Fragile X syndrome , Martin–Bell syndrome, or Escalante's syndrome , is a genetic syndrome that is the most commonly known single-gene cause of autism and the most common inherited cause of intellectual disability... ) |
FMR1 FMR1 FMR1 is a human gene that codes for a protein called fragile X mental retardation protein, or FMRP. This protein, most commonly found in the brain, is essential for normal cognitive development and female reproductive function... , on the X-chromosome |
CGG | 6 - 53 | >- | FMR1 FMR1 FMR1 is a human gene that codes for a protein called fragile X mental retardation protein, or FMRP. This protein, most commonly found in the brain, is essential for normal cognitive development and female reproductive function... , on the X-chromosome |
CGG | 6 - 53 | >- | AFF2 AFF2 AF4/FMR2 family member 2 is a protein that in humans is encoded by the AFF2 gene.-Further reading:... or FMR2, on the X-chromosome |
GCC | 6 - 35 | >- | FXN or X25, (frataxin Frataxin Frataxin is a protein that in humans is encoded by the FXN gene.Frataxin is localized to the mitochondrion. The function of frataxin is not entirely clear, but it seems to be involved in assembly of iron-sulfur clusters... ) |
GAA | 7 - 34 | >- | DMPK | CTG | 5 - 37 | >- | OSCA or SCA8 | CTG | 16 - 37 | >- | PPP2R2B PPP2R2B Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B beta isoform is an enzyme that in humans is encoded by the PPP2R2B gene.-External Links:* -Further reading:... or SCA12 |
nnn On 5' end | 7 - 28 | 66 - 78 |
Trinucleotide repeat expansion
Trinucleotide repeat expansion, also known as triplet repeat expansion, is the DNADNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
responsible for causing any type of disorder
Disease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...
categorized as a trinucleotide repeat disorder. These are labelled in dynamical genetics
Dynamical genetics
Dynamical genetics concerns the study and the interpretation of those phenomena in which physiological enzymatic protein complexes alter the DNA, in a more or less sophisticated way....
as dynamic mutation
Dynamic mutation
In genetics, a dynamic mutation is an unstable heritable element where the probability of expression of a mutant phenotype is a function of the number of copies of the mutation. That is, the replication product of a dynamic mutation has a different likelihood of mutation than its predecessor...
s.
Triplet expansion is caused by slippage during DNA replication. Due to the tandem repeats in the DNA sequence and the instability of the sequence in these regions, 'loop out' structures may form during DNA replication while maintaining complementary base paring between the parent strand and daughter strand being synthesized. Essentially, a nick one side of the DNA strand is caused by cleavage by endonuclease whereby the repetitive triplet is extended and sealed by DNA polymerase and DNA ligase respectively. If the loop out structure is formed from 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. 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.
In 2006,a model of expanding the triplets by involving RNA:DNA intermediate formed in repeat transcription or in post-transcription was proposed., and similar ideas turned to be a fashion ongoing issue of the mechanism studies ever since
In 2007 a new disease model was produced to explain the progression of Huntington's Disease
Huntington's disease
Huntington's disease, chorea, or disorder , is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and dementia. It typically becomes noticeable in middle age. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea...
and similar trinucleotide repeat disorders
Trinucleotide repeat disorders
Trinucleotide repeat disorders are a set of genetic disorders caused by trinucleotide repeat expansion, a kind of mutation where trinucleotide repeats in certain genes exceeding the normal, stable, threshold, which differs per gene...
, which, in simulations, seems to accurately predict age of onset and the way the disease will progress in an individual, based on the number of repeats of a genetic mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
.