Top

Published in:

01-08-2007 | Original Article

Identification of the porcine homologous of human disease causing trinucleotide repeat sequences

Authors: Lone Bruhn Madsen, Bo Thomsen, Christina Ane Elisabeth Sølvsten, Christian Bendixen, Merete Fredholm, Arne Lund Jørgensen, Anders Lade Nielsen

Published in: Neurogenetics | Issue 3/2007

Abstract

Expansion in the repeat number of intragenic trinucleotide repeats (TNRs) is associated with a variety of inherited human neurodegenerative diseases. To study the composition of TNRs in a mammalian species representing an evolutionary intermediate between humans and rodents, we describe in this paper the identification of porcine noncoding and polyglutamine-encoding TNR regions and the comparison to the homologous TNRs from human, chimpanzee, dog, opossum, rat, and mouse. Several of the porcine TNR regions are highly polymorphic both within and between different breeds. The TNR regions are more conserved in terms of repeat length between humans and pigs than between humans and rodents suggesting that TNR lengths could be implicated in mammalian evolution. The TNRs in the FMR2, SCA6, SCA12, and Huntingtin genes are comparable in length to alleles naturally occurring in humans, and also in FMR1, a long uninterrupted CGG TNR was identified. Most strikingly, we identified a Huntingtin allele with 21 uninterrupted CAG repeats encoding a stretch of 24 polyglutamines. Examination of this particular Huntingtin TNR in 349 porcine offspring showed stable transmission. The presence in the porcine genome of TNRs within genes that, in humans, can undergo pathogenic expansions support the usage of the pig as an alternative animal model for studies of TNR evolution, stability, and functional properties.

Everett CM, Wood NW (2004) Trinucleotide repeats and neurodegenerative disease. Brain 127:2385–2405PubMedCrossRef

Pearson CE, Nichol Edamura K, Cleary JD (2005) Repeat instability: mechanisms of dynamic mutations. Nat Rev Genet 6:729–742PubMedCrossRef

Jin P, Zarnescu DC, Zhang F, Pearson CE, Lucchesi JC, Moses K, Warren ST (2003) RNA-mediated neurodegeneration caused by the fragile X premutation rCGG repeats in Drosophila. Neuron 39:739–747PubMedCrossRef

Saveliev A, Everett C, Sharpe T, Webster Z, Festenstein R (2003) DNA triplet repeats mediate heterochromatin-protein-1-sensitive variegated gene silencing. Nature 422:909–913PubMedCrossRef

Cho DH, Thienes CP, Mahoney SE, Analau E, Filippova GN, Tapscott SJ (2005) Antisense transcription and heterochromatin at the DM1 CTG repeats are constrained by CTCF. Mol Cell 20:483–489PubMedCrossRef

Galvao R, Mendes-Soares L, Camara J, Jaco I, Carmo-Fonseca M (2001) Triplet repeats, RNA secondary structure and toxic gain-of-function models for pathogenesis. Brain Res Bull 56:191–201PubMedCrossRef

Wells RD (1996) Molecular basis of genetic instability of triplet repeats. J Biol Chem 271:2875–2878PubMed

Mirkin SM, Smirnova EV (2002) Positioned to expand. Nat Genet 31:5–6PubMedCrossRef

Cleary JD, Nichol K, Wang YH, Pearson CE (2002) Evidence of cis-acting factors in replication-mediated trinucleotide repeat instability in primate cells. Nat Genet 31:37–46PubMedCrossRef

10.

Nenguke T, Aladjem MI, Gusella JF, Wexler NS, Arnheim N (2003) Candidate DNA replication initiation regions at human trinucleotide repeat disease loci. Hum Mol Genet 12:1021–1028PubMedCrossRef

11.

Michlewski G, Krzyzosiak WJ (2004) Molecular architecture of CAG repeats in human disease related transcripts. J Mol Biol 340:665–679PubMedCrossRef

12.

Andres AM, Lao O, Soldevila M, Calafell F, Bertranpetit J (2003) Dynamics of CAG repeat loci revealed by the analysis of their variability. Hum Mutat 21:61–70PubMedCrossRef

13.

Brinkmann B, Klintschar M, Neuhuber F, Huhne J, Rolf B (1998) Mutation rate in human microsatellites: influence of the structure and length of the tandem repeat. Am J Hum Genet 62:1408–1415PubMedCrossRef

14.

Mulvihill DJ, Nichol Edamura K, Hagerman KA, Pearson CE, Wang YH (2005) Effect of CAT or AGG interruptions and CpG methylation on nucleosome assembly upon trinucleotide repeats on spinocerebellar ataxia, type 1 and fragile X syndrome. J Biol Chem 280:4498–4503PubMedCrossRef

15.

Lin Y, Dion V, Wilson JH (2006) Transcription promotes contraction of CAG repeat tracts in human cells. Nat Struct Mol Biol 13:179–180PubMedCrossRef

16.

Lavedan CN, Garrett L, Nussbaum RL (1997) Trinucleotide repeats (CGG)22TGG(CGG)43TGG(CGG)21 from the fragile X gene remain stable in transgenic mice. Hum Genet 100:407–414PubMedCrossRef

17.

Libby RT, Monckton DG, Fu YH, Martinez RA, McAbney JP, Lau R, Einum DD, Nichol K, Ware CB, Ptacek LJ et al (2003) Genomic context drives SCA7 CAG repeat instability, while expressed SCA7 cDNAs are intergenerationally and somatically stable in transgenic mice. Hum Mol Genet 12:41–50PubMedCrossRef

18.

Alba MM, Guigo R (2004) Comparative analysis of amino acid repeats in rodents and humans. Genome Res 14:549–554PubMedCrossRef

19.

Hancock JM, Worthey EA, Santibanez-Koref MF (2001) A role for selection in regulating the evolutionary emergence of disease-causing and other coding CAG repeats in humans and mice. Mol Biol Evol 18:1014–1023PubMed

20.

Andres AM, Soldevila M, Lao O, Volpini V, Saitou N, Jacobs HT, Hayasaka I, Calafell F, Bertranpetit J (2004) Comparative genetics of functional trinucleotide tandem repeats in humans and apes. J Mol Evol 59:329–339PubMedCrossRef

21.

Yu F, Sabeti PC, Hardenbol P, Fu Q, Fry B, Lu X, Ghose S, Vega R, Perez A, Pasternak S et al (2005) Positive selection of a pre-expansion CAG repeat of the human SCA2 gene. PLoS Genet 1:e41PubMedCrossRef

22.

Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215PubMedCrossRef

23.

Brook JD, McCurrach ME, Harley HG, Buckler AJ, Church D, Aburatani H, Hunter K, Stanton VP, Thirion JP, Hudson T et al (1992) Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3′ end of a transcript encoding a protein kinase family member. Cell 69:385PubMed

24.

Harley HG, Brook JD, Rundle SA, Crow S, Reardon W, Buckler AJ, Harper PS, Housman DE, Shaw DJ (1992) Expansion of an unstable DNA region and phenotypic variation in myotonic dystrophy. Nature 355:545–546PubMedCrossRef

25.

Mahadevan M, Tsilfidis C, Sabourin L, Shutler G, Amemiya C, Jansen G, Neville C, Narang M, Barcelo J, O’Hoy K et al (1992) Myotonic dystrophy mutation: an unstable CTG repeat in the 3′ untranslated region of the gene. Science 255:1253–1255PubMedCrossRef

26.

Fu YH, Pizzuti A, Fenwick RG Jr, King J, Rajnarayan S, Dunne PW, Dubel J, Nasser GA, Ashizawa T, de Jong P et al (1992) An unstable triplet repeat in a gene related to myotonic muscular dystrophy. Science 255:1256–1258PubMedCrossRef

27.

Tsilfidis C, MacKenzie AE, Mettler G, Barcelo J, Korneluk RG (1992) Correlation between CTG trinucleotide repeat length and frequency of severe congenital myotonic dystrophy. Nat Genet 1:192–195PubMedCrossRef

28.

Holmes SE, O’Hearn EE, McInnis MG, Gorelick-Feldman DA, Kleiderlein JJ, Callahan C, Kwak NG, Ingersoll-Ashworth RG, Sherr M, Sumner AJ et al (1999) Expansion of a novel CAG trinucleotide repeat in the 5′ region of PPP2R2B is associated with SCA12. Nat Genet 23:391–392PubMedCrossRef

29.

Fu YH, Kuhl DP, Pizzuti A, Pieretti M, Sutcliffe JS, Richards S, Verkerk AJ, Holden JJ, Fenwick RG Jr, Warren ST et al (1991) Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. Cell 67:1047–1058PubMedCrossRef

30.

Verkerk AJ, Pieretti M, Sutcliffe JS, Fu YH, Kuhl DP, Pizzuti A, Reiner O, Richards S, Victoria MF, Zhang FP et al (1991) Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65:905–914PubMedCrossRef

31.

Eichler EE, Kunst CB, Lugenbeel KA, Ryder OA, Davison D, Warren ST, Nelson DL (1995) Evolution of the cryptic FMR1 CGG repeat. Nat Genet 11:301–308PubMedCrossRef

32.

Knight SJ, Flannery AV, Hirst MC, Campbell L, Christodoulou Z, Phelps SR, Pointon J, Middleton-Price HR, Barnicoat A, Pembrey ME et al (1993) Trinucleotide repeat amplification and hypermethylation of a CpG island in FRAXE mental retardation. Cell 74:127–134PubMedCrossRef

33.

Bowman AB, Lam YC, Jafar-Nejad P, Chen HK, Richman R, Samaco RC, Fryer JD, Kahle JJ, Orr HT, Zoghbi HY (2007) Duplication of Atxn1l suppresses SCA1 neuropathology by decreasing incorporation of polyglutamine-expanded ataxin-1 into native complexes. Nat Genet 39:373–379PubMedCrossRef

34.

Orr HT, Chung MY, Banfi S, Kwiatkowski TJ Jr, Servadio A, Beaudet AL, McCall AE, Duvick LA, Ranum LP, Zoghbi HY (1993) Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nat Genet 4:221–226PubMedCrossRef

35.

Limprasert P, Nouri N, Nopparatana C, Deininger PL, Keats BJ (1997) Comparative studies of the CAG repeats in the spinocerebellar ataxia type 1 (SCA1) gene. Am J Med Genet 74:488–493PubMedCrossRef

36.

Pulst SM, Nechiporuk A, Nechiporuk T, Gispert S, Chen XN, Lopes-Cendes I, Pearlman S, Starkman S, Orozco-Diaz G, Lunkes A et al (1996) Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2. Nat Genet 14:269–276PubMedCrossRef

37.

Choudhry S, Mukerji M, Srivastava AK, Jain S, Brahmachari SK (2001) CAG repeat instability at SCA2 locus: anchoring CAA interruptions and linked single nucleotide polymorphisms. Hum Mol Genet 10:2437–2446PubMedCrossRef

38.

Takiyama Y, Nishizawa M, Tanaka H, Kawashima S, Sakamoto H, Karube Y, Shimazaki H, Soutome M, Endo K, Ohta S et al (1993) The gene for Machado-Joseph disease maps to human chromosome 14q. Nat Genet 4:300–304PubMedCrossRef

39.

Kawaguchi Y, Okamoto T, Taniwaki M, Aizawa M, Inoue M, Katayama S, Kawakami H, Nakamura S, Nishimura M, Akiguchi I et al (1994) CAG expansions in a novel gene for Machado–Joseph disease at chromosome 14q32.1. Nat Genet 8:221–228PubMedCrossRef

40.

Limprasert P, Nouri N, Heyman RA, Nopparatana C, Kamonsilp M, Deininger PL, Keats BJ (1996) Analysis of CAG repeat of the Machado–Joseph gene in human, chimpanzee and monkey populations: a variant nucleotide is associated with the number of CAG repeats. Hum Mol Genet 5:207–213PubMedCrossRef

41.

Zhuchenko O, Bailey J, Bonnen P, Ashizawa T, Stockton DW, Amos C, Dobyns WB, Subramony SH, Zoghbi HY, Lee CC (1997) Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel. Nat Genet 15:62–69PubMedCrossRef

42.

David G, Abbas N, Stevanin G, Durr A, Yvert G, Cancel G, Weber C, Imbert G, Saudou F, Antoniou E et al (1997) Cloning of the SCA7 gene reveals a highly unstable CAG repeat expansion. Nat Genet 17:65–70PubMedCrossRef

43.

Koide R, Ikeuchi T, Onodera O, Tanaka H, Igarashi S, Endo K, Takahashi H, Kondo R, Ishikawa A, Hayashi T et al (1994) Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA). Nat Genet 6:9–13PubMedCrossRef

44.

Nakamura K, Jeong SY, Uchihara T, Anno M, Nagashima K, Nagashima T, Ikeda S, Tsuji S, Kanazawa I (2001) SCA17, a novel autosomal dominant cerebellar ataxia caused by an expanded polyglutamine in TATA-binding protein. Hum Mol Genet 10:1441–1448PubMedCrossRef

45.

La Spada AR, Roling DB, Harding AE, Warner CL, Spiegel R, Hausmanowa-Petrusewicz I, Yee WC, Fischbeck KH (1992) Meiotic stability and genotype-phenotype correlation of the trinucleotide repeat in X-linked spinal and bulbar muscular atrophy. Nat Genet 2:301–304PubMedCrossRef

46.

The Huntington’s Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72:971–983CrossRef

47.

Matsuyama N, Hadano S, Onoe K, Osuga H, Showguchi-Miyata J, Gondo Y, Ikeda JE (2000) Identification and characterization of the miniature pig Huntington’s disease gene homolog: evidence for conservation and polymorphism in the CAG triplet repeat. Genomics 69:72–85PubMedCrossRef

48.

Clark RM, Bhaskar SS, Miyahara M, Dalgliesh GL, Bidichandani SI (2006) Expansion of GAA trinucleotide repeats in mammals. Genomics 87:57–67PubMedCrossRef

Title: Identification of the porcine homologous of human disease causing trinucleotide repeat sequences
Authors: Lone Bruhn Madsen
Bo Thomsen
Christina Ane Elisabeth Sølvsten
Christian Bendixen
Merete Fredholm
Arne Lund Jørgensen
Anders Lade Nielsen
Publication date: 01-08-2007
Publisher: Springer-Verlag
Published in: Neurogenetics / Issue 3/2007
Print ISSN: 1364-6745
Electronic ISSN: 1364-6753
DOI: https://doi.org/10.1007/s10048-007-0088-y

At a glance: The STEP trials

Springer Medicine

Identification of the porcine homologous of human disease causing trinucleotide repeat sequences

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2007

Confirmation of region-specific patterns of gene expression in the human brain

Association of progesterone receptor with migraine-associated vertigo

Association study of cholesterol-related genes in Alzheimer’s disease

The cholesteryl ester transfer protein (CETP) gene and the risk of Alzheimer’s disease

Influence of CCR5-Δ32 genotype in Spanish population with multiple sclerosis

A de novo SPAST mutation leading to somatic mosaicism is associated with a later age at onset in HSP