Trinucleotide diseases
Hereditary diseases are summarized as trinucleotide repeat diseases or expanding repeat diseases whose common basis for mutation is an intragenic expansion of base triplets and occasionally of DNA sequences consisting of longer multiplets ("expansion disease "). These repetitions show an unstable, i.e. H. usually expanding, inheritance pattern and are responsible for the varying degrees of symptoms in the individual clinical pictures due to the great variability of their repeat length and their tissue distribution . Due to the increasing expansion of the repeats with successive generations, many of the trinucleotide repeater diseases show anticipation .
On the basis of the amino acid sequences encoded from the base triplets , the trinucleotide diseases can be divided into two groups, the coding trinucleotide repeater diseases (polyglutamine diseases, polyalanine diseases) and the non-coding trinucleotide repeater diseases.
Polyglutamine diseases
In polyglutamine diseases, the repetitive codon consists of the sequence CAG and codes for the amino acid glutamine during translation .
| Type | Inheritance | gene | Repeat unit | Repeat location | Normal repeat length | Pathogenic repeat length |
|---|---|---|---|---|---|---|
| Huntington's Disease (HD) | AD | Huntingtin (HDD) | (CAG) n | N terminal | 6-34 | 36-121 |
| Dentatorubro-Pallidoluysic Atrophy (DRPLA) | AD | Atrophin | (CAG) n | N terminal | 7-34 | 49-88 |
| Kennedy type spinobulbar muscular atrophy (SBMA) | XLR | Androgen receptor | (CAG) n | N terminal | 9-36 | 38-62 |
| Spinocerebellar Ataxia Type 1 (SCA1) | AD | Ataxin 1 (ATXN1) | (CAG) n | N terminal | 6-44 | 39-82 |
| Spinocerebellar Ataxia Type 2 (SCA2) | AD | Ataxin 2 (ATXN2) | (CAG) n | N terminal | 15-24 | 32-200 |
| Spinocerebellar ataxia type 3 (Machado-Joseph disease, SCA3) | AD | Ataxin 3 (ATXN3) | (CAG) n | C terminal | 13-36 | 61-84 |
| Spinocerebellar Ataxia Type 6 (SCA6) | AD | CACNA1A | (CAG) n | C terminal | 4-19 | 10-33 |
| Spinocerebellar Ataxia Type 7 (SCA7) | AD | Ataxin 7 (ATXN7) | (CAG) n | N terminal | 4-35 | 37-306 |
| Spinocerebellar Ataxia Type 17 (SCA17) | AD | TBP | (CAG) n | 25-42 | 47-63 |
Polyalanine diseases
In the case of polyalanine diseases, the repetitive codon consists of the sequence GCG and codes for the amino acid alanine during translation .
| Type | Inheritance | gene | Repeat unit | Repeat location | Normal repeat length | Pathogenic repeat length |
|---|---|---|---|---|---|---|
| Oculopharyngeal Muscular Dystrophy (OPMD) | AD (AR) | PABPN1 | (GCG) n | N terminal | 6th | 8-13 |
Non-coding repeater diseases
The non-coding repeater diseases are a heterogeneous group of diseases caused by expanding trinucleotide repeats and occasionally tetra and pentanucleotide repeats. The expanding repeats are outside the reading frame , so they do not code for amino acids and do not lead to a modified protein. Instead, they lead either to reduced protein biosynthesis and / or to an unphysiological binding of essential nuclear proteins to the mutated mRNA (e.g. in DM1 (DMPK) and DM2 (ZNF9)):
| Type | Inheritance | gene | Repeat unit | Repeat location | Normal repeat length | Pathogenic repeat length |
|---|---|---|---|---|---|---|
| Fragile X Syndrome (FRAXA) | XLR (XLD) | FMR1 | (CGG) n | 5'- UTR | 6-60 | > 200 |
| Fragile X Associated Tremor / Ataxia Syndrome (FXTAS) | XLR (XLD) | FMR1 | (CGG) n | 5'- UTR | 6-60 | 60-200 |
| Fragile XE Syndrome (FRAXE) | XLR | FMR2 | (GCC) n | 5'- UTR | 4-39 | 200-900 |
| Friedreich's Ataxia (FRDA) | AR | FXN | (GAA) n | Intron 1 | 6-32 | 200-1700 |
| Myotonic dystrophy type 1 (DM1) | AD | DMPK | (CTG) n | 3'- UTR | 5-37 | 50-10000 |
| Myotonic dystrophy type 2 (DM2) | AD | ZNF9 | (CCTG) n | 10-26 | 75-11000 | |
| Spinocerebellar Ataxia Type 8 (SCA8) | AD | SCA8 | (CTG) n | 16-34 | > 74 | |
| Spinocerebellar Ataxia Type 10 (SCA10) | AD | SCA10 | (ATTCT) n | 10-20 | 500-4500 | |
| Spinocerebellar Ataxia Type 12 (SCA12) | AD | PPP2R2B or SCA12 | (CAG) n | 5'- UTR | 7-45 | 55-78 |
| Huntington's Disease-like 2 ( Neuroacanthocytosis ) (HDL2) | AD | Junctophilin | (CAG) n or (CTG) n | 7-28 | 66-78 |
literature
- Paulson H: Repeat expansion diseases. In: Handb Clin Neurol . tape 147 , 2018, p. 105-123 , doi : 10.1016 / B978-0-444-63233-3.00009-9 , PMID 29325606 .
- Adegbuyiro A, Sedighi F, Pilkington AW 4th, Groover S, Legleiter J: Proteins Containing Expanded Polyglutamine Tracts and Neurodegenerative Disease . In: Biochemistry . tape 56 , no. 9 , May 2017, p. 1199-1217 , doi : 10.1021 / acs.biochem.6b00936 , PMID 28170216 .
- McMurray CT: Mechanisms of trinucleotide repeat instability during human development. In: Nat Rev Genet . tape 11 , no. December 12 , 2010, p. 886 , doi : 10.1038 / nrg2828 , PMID 20953213 .
- Orr HT, Zoghbi HY: Trinucleotide repeat disorders. In: Annual review of neuroscience. Volume 30, 2007, pp. 575-621, ISSN 0147-006X . doi : 10.1146 / annurev.neuro.29.051605.113042 . PMID 17417937 . (Review).
- CJ Cummings, HY Zoghbi: Trinucleotide repeats: mechanisms and pathophysiology. In: Annual review of genomics and human genetics. Volume 1, 2000, pp. 281-328, ISSN 1527-8204 . doi : 10.1146 / annurev.genom.1.1.281 . PMID 11701632 . (Review).
Web links
- HOPES - Huntington's Outreach Project for Education, at Stanford: Trinucleotide Repeat Disorders. (English)
Individual evidence
- ↑ a b c H. T. Orr, HY Zoghbi: Trinucleotide repeat disorders. In: Annual review of neuroscience. Volume 30, 2007, pp. 575-621, ISSN 0147-006X . doi : 10.1146 / annurev.neuro.29.051605.113042 . PMID 17417937 . (Review).
