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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] In addition to the expansions of these trinucleotide repeats, expansions of one tetranucleotide (CCTG),[4] five pentanucleotide (ATTCT, TGGAA, TTTTA, TTTCA, and AAGGG), three hexanucleotide (GGCCTG, CCCTCT, and GGGGCC), and one dodecanucleotide (CCCCGCCCCGCG) repeat cause 13 other diseases.[5] 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]

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.[6] 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.[citation needed] However, the frequency of occurrence of any one particular repeat sequence disorder varies greatly by ethnic group and geographic location.[7] 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".[8] 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.[citation needed] 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,[9] causing reduced expression of the associated encoded protein.[2] The epigenetic alterations and their effects are described more fully by Barbé and Finkbeiner[10] 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.[10] 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

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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.[11] 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

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Type Gene Normal PolyQ repeats Pathogenic PolyQ repeats
DRPLA (Dentatorubropallidoluysian atrophy) ATN1 or DRPLA 6 - 35 49 - 88
HD (Huntington's disease) HTT 6 - 35 36 - 250
SBMA (Spinal and bulbar muscular atrophy)[12] AR 4 - 34 35 - 72
SCA1 (Spinocerebellar ataxia Type 1) ATXN1 6 - 35 49 - 88
SCA2 (Spinocerebellar ataxia Type 2) ATXN2 14 - 32 33 - 77
SCA3 (Spinocerebellar ataxia Type 3 or Machado-Joseph disease) ATXN3 12 - 40 55 - 86
SCA6 (Spinocerebellar ataxia Type 6) CACNA1A 4 - 18 21 - 30
SCA7 (Spinocerebellar ataxia Type 7) ATXN7 7 - 17 38 - 120
SCA17 (Spinocerebellar ataxia Type 17) TBP 25 - 42 47 - 63

Non-coding trinucleotide repeat disorders

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Type Gene Codon Normal Pathogenic Mechanism[1]
FRAXA (Fragile X syndrome) FMR1 CGG (5' UTR) 6 - 53 230+ abnormal methylation
FXTAS (Fragile X-associated tremor/ataxia syndrome) FMR1 CGG (5' UTR) 6 - 53 55-200 increased expression, and a novel polyglycine product[13]
FRAXE (Fragile XE mental retardation) AFF2 CCG (5' UTR) 6 - 35 200+ abnormal methylation
Baratela-Scott syndrome[14] XYLT1 GGC (5' UTR) 6 - 35 200+ abnormal methylation
FRDA (Friedreich's ataxia) FXN GAA (Intron) 7 - 34 100+ impaired transcription
DM1 (Myotonic dystrophy Type 1) DMPK CTG (3' UTR) 5 - 34 50+ RNA-based; unbalanced DMPK/ZNF9 expression levels
DM2 (Myotonic dystrophy Type 2)[15] CNBP CCTG (3' UTR) 11 - 26 75+ RNA-based; Nuclear RNA accumulation[16]
SCA8 (Spinocerebellar ataxia Type 8) SCA8 CTG (RNA) 16 - 37 110 - 250 ? RNA
SCA12 (Spinocerebellar ataxia Type 12)[17][18] PPP2R2B CAG (5' UTR) 7 - 28 55 - 78 effect on promoter function

Symptoms and signs

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As of 2017, ten neurological and neuromuscular disorders were known to be caused by an increased number of CAG repeats.[11] 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.[19]

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.[20]

Genetics

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Classification of the trinucleotide repeat, and resulting disease status, depends on the number of CAG repeats in Huntington's disease[21]
Repeat count Classification Disease status
<28 Normal Unaffected
28–35 Intermediate Unaffected
36–40 Reduced-penetrance May be affected
>40 Full-penetrance Affected

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.[21] 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.[21] As a result, families that have had Huntington's for many generations show an earlier age of disease onset and faster disease progression.[21]

Non-trinucleotide expansions

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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.[22]

Mechanism

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Triplet expansion is caused by slippage during DNA replication or during DNA repair synthesis.[23] 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.[24] 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.[25][26]

Diagnosis

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See also

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References

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  1. ^ a b c d e f g Orr HT, Zoghbi HY (2007). "Trinucleotide repeat disorders". Annual Review of Neuroscience. 30 (1): 575–621. doi:10.1146/annurev.neuro.29.051605.113042. PMID 17417937.
  2. ^ a b c d e f g h i Boivin M, Charlet-Berguerand N (2022). "Trinucleotide CGG Repeat Diseases: An Expanding Field of Polyglycine Proteins?". Front Genet. 13: 843014. doi:10.3389/fgene.2022.843014. PMC 8918734. PMID 35295941.
  3. ^ Depienne, Christel; Mandel, Jean-Louis (2021). "30 years of repeat expansion disorders: What have we learned and what are the remaining challenges?". Am J Hum Genet. 108 (5): 764–785. doi:10.1016/j.ajhg.2021.03.011. PMC 8205997. PMID 33811808.
  4. ^ Papp, David; Hernandez, Luis A; Mai, Theresa A; Haanen, Terrance J; O’Donnell, Meghan A; Duran, Ariel T; Hernandez, Sophia M; Narvanto, Jenni E; Arguello, Berenice; Onwukwe, Marvin O; Mirkin, Sergei M; Kim, Jane C (2024-02-07). Rhind, N (ed.). "Massive contractions of myotonic dystrophy type 2-associated CCTG tetranucleotide repeats occur via double-strand break repair with distinct requirements for DNA helicases". G3: Genes, Genomes, Genetics. 14 (2). doi:10.1093/g3journal/jkad257. ISSN 2160-1836. PMC 10849350. PMID 37950892.
  5. ^ Khristich, Alexandra N.; Mirkin, Sergei M. (March 2020). "On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability". Journal of Biological Chemistry. 295 (13): 4134–4170. doi:10.1074/jbc.rev119.007678. ISSN 0021-9258. PMC 7105313. PMID 32060097.
  6. ^ "Fragile XE syndrome". Genetic and Rare Diseases Information Center (GARD). Archived from the original on 9 March 2013. Retrieved 14 September 2012.
  7. ^ Ramakrishnan S, Gupta V. Trinucleotide Repeat Disorders. 2023 Aug 22. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–. PMID 32644680.
  8. ^ Tóth G, Gáspári Z, Jurka J (July 2000). "Microsatellites in different eukaryotic genomes: survey and analysis". Genome Res. 10 (7): 967–81. doi:10.1101/gr.10.7.967. PMC 310925. PMID 10899146.
  9. ^ Irvine RA, Lin IG, Hsieh CL (October 2002). "DNA methylation has a local effect on transcription and histone acetylation". Mol Cell Biol. 22 (19): 6689–96. doi:10.1128/MCB.22.19.6689-6696.2002. PMC 134040. PMID 12215526.
  10. ^ a b Barbé L, Finkbeiner S (2022). "Genetic and Epigenetic Interplay Define Disease Onset and Severity in Repeat Diseases". Front Aging Neurosci. 14: 750629. doi:10.3389/fnagi.2022.750629. PMC 9110800. PMID 35592702.
  11. ^ a b Adegbuyiro A, Sedighi F, Pilkington AW, Groover S, Legleiter J (March 2017). "Proteins Containing Expanded Polyglutamine Tracts and Neurodegenerative Disease". Biochemistry. 56 (9): 1199–1217. doi:10.1021/acs.biochem.6b00936. PMC 5727916. PMID 28170216.
  12. ^ Laskaratos A, Breza M, Karadima G, Koutsis G (June 2021). "Wide range of reduced penetrance alleles in spinal and bulbar muscular atrophy: a model-based approach". Journal of Medical Genetics. 58 (6): 385–391. doi:10.1136/jmedgenet-2020-106963. PMID 32571900. S2CID 219991108.
  13. ^ Gao FB, Richter JD (January 2017). "Microsatellite Expansion Diseases: Repeat Toxicity Found in Translation". Neuron. 93 (2): 249–251. doi:10.1016/j.neuron.2017.01.001. PMID 28103472.
  14. ^ LaCroix AJ, Stabley D, Sahraoui R, Adam MP, Mehaffey M, Kernan K, et al. (January 2019). "GGC Repeat Expansion and Exon 1 Methylation of XYLT1 Is a Common Pathogenic Variant in Baratela-Scott Syndrome". American Journal of Human Genetics. 104 (1): 35–44. doi:10.1016/j.ajhg.2018.11.005. PMC 6323552. PMID 30554721.
  15. ^ Schoser, Benedikt (1993), Adam, Margaret P.; Feldman, Jerry; Mirzaa, Ghayda M.; Pagon, Roberta A. (eds.), "Myotonic Dystrophy Type 2", GeneReviews®, Seattle (WA): University of Washington, Seattle, PMID 20301639, retrieved 2024-07-02
  16. ^ Meola, Giovanni; Cardani, Rosanna (2015-07-22). "Myotonic Dystrophy Type 2: An Update on Clinical Aspects, Genetic and Pathomolecular Mechanism". Journal of Neuromuscular Diseases. 2 (Suppl 2): S59 – S71. doi:10.3233/JND-150088. ISSN 2214-3599. PMC 5240594. PMID 27858759.
  17. ^ Srivastava AK, Takkar A, Garg A, Faruq M (January 2017). "Clinical behaviour of spinocerebellar ataxia type 12 and intermediate length abnormal CAG repeats in PPP2R2B". Brain. 140 (1): 27–36. doi:10.1093/brain/aww269. PMID 27864267.
  18. ^ O'Hearn E, Holmes SE, Margolis RL (2012-01-01). "Chapter 34 - Spinocerebellar ataxia type 12". In Subramony SH, Dürr A (eds.). Handbook of Clinical Neurology. Ataxic Disorders. Vol. 103. Elsevier. pp. 535–547. doi:10.1016/b978-0-444-51892-7.00034-6. ISBN 9780444518927. PMID 21827912. S2CID 25745894. Retrieved 2022-12-07.
  19. ^ Fan HC, Ho LI, Chi CS, Chen SJ, Peng GS, Chan TM, et al. (May 2014). "Polyglutamine (PolyQ) diseases: genetics to treatments". Cell Transplantation. 23 (4–5): 441–458. doi:10.3727/096368914X678454. PMID 24816443.
  20. ^ Sanders DW, Brangwynne CP (June 2017). "Neurodegenerative disease: RNA repeats put a freeze on cells". Nature. 546 (7657): 215–216. Bibcode:2017Natur.546..215S. doi:10.1038/nature22503. PMID 28562583.
  21. ^ a b c d Walker FO (January 2007). "Huntington's disease". Lancet. 369 (9557): 218–228. doi:10.1016/S0140-6736(07)60111-1. PMID 17240289. S2CID 46151626.
  22. ^ Mirkin SM (June 2007). "Expandable DNA repeats and human disease". Nature. 447 (7147): 932–940. Bibcode:2007Natur.447..932M. doi:10.1038/nature05977. PMID 17581576. S2CID 4397592.
  23. ^ Usdin K, House NC, Freudenreich CH (2015). "Repeat instability during DNA repair: Insights from model systems". Critical Reviews in Biochemistry and Molecular Biology. 50 (2): 142–167. doi:10.3109/10409238.2014.999192. PMC 4454471. PMID 25608779.
  24. ^ Petruska J, Hartenstine MJ, Goodman MF (February 1998). "Analysis of strand slippage in DNA polymerase expansions of CAG/CTG triplet repeats associated with neurodegenerative disease". The Journal of Biological Chemistry. 273 (9): 5204–5210. doi:10.1074/jbc.273.9.5204. PMID 9478975.
  25. ^ McIvor EI, Polak U, Napierala M (2010). "New insights into repeat instability: role of RNA•DNA hybrids". RNA Biology. 7 (5): 551–558. doi:10.4161/rna.7.5.12745. PMC 3073251. PMID 20729633.
  26. ^ Salinas-Rios V, Belotserkovskii BP, Hanawalt PC (September 2011). "DNA slip-outs cause RNA polymerase II arrest in vitro: potential implications for genetic instability". Nucleic Acids Research. 39 (17): 7444–7454. doi:10.1093/nar/gkr429. PMC 3177194. PMID 21666257.
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