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• W2073190649 abstract "Although simple repeats compose a substantial fraction of the eukaryotic genome, their significance has not been understood. The high level of polymorphism of micro- and minisatellites has mostly been used for practical purposes, such as positional cloning of genes associated with diseases, forensic medicine, and phylogenetic studies. The discovery that a number of human diseases are the direct consequence of excessive duplications of trinucleotide repeats, similar to microsatellites but located within genes, has completely changed the picture. Every aspect of the biology of simple repeats is now the object of intensive study. Much of the EMBO workshop on “Trinucleotide Expansion Diseases in the Context of Micro- and Minisatellite Evolution” held at Hammersmith Hospital in London (April 1–3, 1998) was concentrated on three questions: What is the evolutionary significance of simple repeats, and particularly of polyaminoacids, in proteins? What are the mechanisms of the instability of simple repeats? How does the presence of an excessive number of triplets in transcribed DNA lead to disease? The introduction of triplet repeat sequences is likely to have common mechanisms and a similar evolutionary significance whether it occurs within coding or noncoding regions and whether an expansion of the repeats is associated with disease. However, in the case of expansion, the resulting diseases depend on the nature of the triplets and their location in coding regions, 5′ or 3′ untranslated regions, or introns. In eukaryotic proteins, glutamine is the most common amino acid residue in repeats of over 16 residues. Howard Green (Boston) formulated the interesting idea that codon repeats (particularly those encoding polyglutamine) may represent an early stage of protein evolution by generating a new coding sequence, which can then be diversified by nucleotide substitutions and acted upon by natural selection. There are two examples of genes whose entire coding regions are probably derived from repeats of the single ancestral codon CAG: the gene for involucrin, an epidermal precursor of the cornified envelope; and the gene for GRP1, a nuclear protein of unknown function (6Cox G.W Taylor L.S Willis J.D Melillo G White III, R.L Anderson S.K Lin J.J Molecular cloning and characterization of a novel mouse macrophage gene that encodes a nuclear protein comprising polyglutamine repeats and interspersing histidines.J. Biol. Chem. 1996; 271: 25515-25523Crossref PubMed Scopus (10) Google Scholar). The involucrin gene is one of the genes of the “epidermal differentiation complex” (19Mischke D Korge B.P Marenholz I Volz A Ziegler A Genes encoding structural proteins of epidermal cornification and S100 calcium-binding proteins form a gene complex (“epidermal differentiation complex”) on human chromosome 1q21.J. Invest. Dermatol. 1996; 106: 989-992Crossref PubMed Scopus (396) Google Scholar), all genes of which are probably derived by duplications of a single ancestral gene. Although they lack sequence similarity, the linked genes of this complex have the same general structure, including a coding region confined to a single exon and largely composed of short tandem repeats, different in each gene. The evolutionary history of the epidermal differentiation complex might therefore be as follows. The coding region of the ancestral gene was first generated by duplications of CAG. The whole ancestral gene was then duplicated several times. The coding regions of the duplicates were subsequently diverged from each other by nucleotide substitutions, before being further expanded by duplications of short repeats. Diseases of polyglutamine may be viewed as an aberrant consequence of a normal evolutionary process, which has presumably acted on the genes for involucrin and GRP1 at the initial stages of extension of the coding region (13Green, H., and Djian, P. (1998). Amino acid repeats in proteins and the neurological diseases produced by polyglutamine. In Genetic Instabilities and Hereditary Neurological Diseases, R.D. Wells and S.T. Warren, eds. (New York: Academic Press), pp. 739–759.Google Scholar). This is a much debated question, and in many cases, such a function seems improbable. As mentioned by David Rubinsztein (Cambridge) and John Hancock (London), the size of the polyglutamine in proteins potentially able to cause human disease varies greatly within the normal human population and between species: the mouse may contain only two glutamines at a site where the human contains over twenty. Even more compelling were examples in insects provided by Diethard Tautz (Munich). The knirps gene of Drosophila contains a CAG (gln) repeat. In the orthologous gene of Musca domestica, a single nucleotide insertion has shifted the reading frame so that the in-frame repeated codon is now GCA (ala). None of 15 proteins containing repeats in Drosophila, many of which are transcription factors, contain repeats in the flour beetle Tribolium castaneum. It seems that this species does not possess any long amino acid repeats. A likely example of a function for a triplet repeat is involucrin. The polyglutamine encoded by the original involucrin gene would presumably have functioned as a substrate for transglutaminase-catalyzed cross-linking, the same function as the present-day protein. Variations between species in the sizes of the polyCAG sequences associated with human disease are not random. There is a definite trend toward successive CAG repeat additions in primates and particularly in humans (David Rubinsztein; John Hancock). A trend toward expansion is also observed in the 5′ untranslated region of the FMR1 gene, where an increase in the number of CGG triplets beyond twenty has occurred independently in three different primate lineages in association with specific interspersions (Evan Eichler, Cleveland). Bill Amos (Cambridge) seemed inclined to think that microsatellites in general tend to be longer in humans. However, the possibility of ascertainment bias should be kept in mind: many microsatellites were originally cloned in the human, where they are highly polymorphic and would therefore tend to be longer. When protein banks are searched, very few polyaminoacids are found in prokaryotic proteins (Hannah Margalit, Jerusalem). However, this reflects, at least in part, a bias of the banks in favor of E. coli, since repeats are found in other Gram-negative bacteria. Richard Moxon (Oxford) described the important function of short repeats in phase and antigenic variation of pathogenic Gram-negative bacteria. For example, in Hemophilus influenzae, repeats of the tetranucleotide CAAT are present within the 5′ ends of coding regions of genes that encode glycosyl transferases ([CAAT]3 encodes SINQ), which participate in the synthesis of lipopolysaccharides. Changes in the number of repeats occur at high rates (10−2/bacterium), probably by slipped-strand mispairing, and as the repeat is of a tetranucleotide, the upstream initation codons may be shifted in or out of phase with the remainder of the open reading frame, thus switching on and off the translation of the downstream gene, as translational stops result in premature termination (truncation) of the polypeptide. This seems to be true of repeated tetrapeptides encoded by other tetranucleotide repeats in H. influenzae. Variation in the number of repeats can also affect gene transcription in bacteria. Changing the number of repeats of a dinucleotide in the promoter of the H. influenzae pilin gene alters RNA polymerase binding to the overlapping promoters of two divergently transcribed genes and results in reversible on-off transcription of these genes. In Gram-negative bacteria, short tandem repeats are used to adapt the bacterial population to the host at various stages of pathogenesis (7Deitsch K.W Moxon E.R Wellems T.E Shared themes of antigenic variation and virulence in bacterial, protozoal, and fungal infections.Microbiol. Mol. Biol. Rev. 1997; 61: 281-293Crossref PubMed Scopus (196) Google Scholar). According to Gabby Dover (Leicester), repeats would permit “molecular coevolution” between functionally interacting genetic elements. If there are multiple, usually interspersed, binding sites for a transcription factor in the promoter region of a gene, one of the sites can mutate, change in position, orientation, or copy number, and the gene may still be transcribed. Redundancy will give time to select for a mutation in the transcription factor gene, so that it can adjust to the mutated site. A potential example of coevolution is the bicoid-dependent regulation of hunchback between Musca and Drosophila. Both the homeodomain of bicoid and the number and sequences of binding sites of hunchback differ between the two genera (2Bonneton F Shaw P.J Fazakerley C Shi M Dover G.A Comparison of bicoid-dependent regulation of hunchback between Musca domestica and Drosophila melanogaster.Mech. Dev. 1997; 66: 143-156Crossref PubMed Scopus (38) Google Scholar). The homeodomain of the Drosophila protein does not bind the site of Musca. The consequence of G. Dover’s idea is that the nucleotide sequence, number, and orientation of repeats within each species could be important, and yet repeats could vary between species without a drastic change in function. Therefore, the noncorrespondence of repeat regions in homologous genes of two related species does not necessarily imply a lack of function. The consensus view is that the instability of microsatellites is due to slipped-strand mispairing (intrastrand process), while that of minisatellites is due to recombination and gene conversion (interstrand process). The question of the repeat length at which a microsatellite becomes a minisatellite does not seem to have a clear answer. Involucrin repeats, which began life as a microsatellite of polyCAG, ended up in the higher primates as a minisatellite containing 10-codon repeats. Since triplet repeats fall into the realm of microsatellites, strand slippage and the formation of hairpins are thought by most (but not all) students of the process to be the mechanism of the instability that produces trinucleotide repeats, their expansion, and disease. A recurrent question during the meeting was whether the level of heterozygosity affects repeat stability. The answer to this question is particularly important for microsatellites, since their instability is thought to be due to slipped-strand mispairing, a purely intrahelical process that should not be affected by heterozygosity. However, Christian Schlötterer (Vienna) pointed out that heterozygotes tend to have a large size difference between alleles and are therefore more likely to have a long and unstable allele than homozygotes. All diseases associated with expansion of a trinucleotide repeat show anticipation: the unstable allele tends to expand further in successive generations. The tendency toward repeat additions rather than deletions might be explained by the orientation of the repeated sequence with respect to the origin of replication (24Wells R.D Molecular basis of genetic instability of triplet repeats.J. Biol. Chem. 1996; 271: 2875-2878Crossref PubMed Scopus (279) Google Scholar). In E. coli, polyCTG is more readily expanded than any other triplet repeat, because polyCTG forms stable hairpins in the nascent lagging strand during DNA replication (Figure 1). Formation of CTG hairpins in the template strand leads to deletions, and in E. coli, large triplet repeats undergo deletions rather than expansions. Induction of transcription through the repeats generates large deletions (Richard Bowater, Houston). Although this bacterial system is of great interest for the study of repeat instability, a number of questions specific to instability of polyCAG sequences associated with human disease remain unanswered. For example, the orientations of the human polyCAG sequences with respect to the replication origins are not known. Also, all triplet repeats associated with human disease are transcribed, and yet they are more subject to expansion than deletion. The stabilizing effect of a mutation in a sequence of triplet repeats had been reported earlier for the SCA1 gene (5Chung M.-y Ranum L.P.W Duvick L.A Servadio A Zoghbi H.Y Orr H.T Evidence for a mechanism predisposing to intergenerational CAG repeat instability in spinocerebellar ataxia type 1.Nat. Genet. 1993; 5: 254-258Crossref PubMed Scopus (419) Google Scholar) and was described at the meeting for the FMR1 gene. The normal CGG repeat of the FMR1 gene is divided by AGG interruptions. As these interruptions are absent from many different haplotypes associated with fragile X syndrome (9Eichler E.E Macpherson J.N Murray A Jacobs P.A Chakravarti A Nelson D.L Haplotype and interspersion analysis of the FMR1 CGG repeat identifies two different mutational pathways for the origin of the fragile X syndrome.Hum. Mol. Genet. 1996; 5: 319-330Crossref PubMed Scopus (94) Google Scholar), it is clear that the absence of interruptions predisposes alleles to instability (Evan Eichler; James Macpherson, Salisbury; Craig Primmer, Helsinki). The stabilizing effect of divergent triplets on trinucleotide repeats has been demonstrated in vitro. Christopher Pearson (Houston) reported the formation of slipped-strand structures during renaturation of SCA1 and FRAXA genomic clones. Increasing numbers of CAG and CGG repeats increased both the amount and the complexity of the structures formed by the SCA1 and FRAXA clones, respectively. The presence of CAT interruptions in the SCA1 repeats or of AGG interruptions in the FRAXA repeats both resulted in a decreased ability to form slipped-strand structures (21Pearson C.E Eichler E.E Lorenzetti D Kramer S.F Zoghbi H.Y Nelson D.L Sinden R.R Interruptions in the triplet repeats of SCA1 and FRAXA reduce the propensity and complexity of slipped strand DNA (S-DNA) formation.Biochemistry. 1998; 37: 2701-2708Crossref PubMed Scopus (130) Google Scholar). It seems certain that the interruptions anchor the repeat tract in register. Slipped-strand mispairing is only possible in the pure tracts between the interruptions, thus placing a limitation on the number of possible slipped isomers and the number of repeats involved in a given slipped structure. In coding regions, most disease-associated triplet repeats are (CAG)n, encoding polyglutamine, while there is one associated with a short (GCG)n, a permutated version of (CGG)n, encoding polyalanine (3Brais B Bouchard J.-P Xie Y.G Rochefort D.L Chrétien N Tomé F.M.S Lafrenière R.G Rommens J.M Uyama E Nohira O et al.Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy.Nat. Genet. 1998; 18: 164-167Crossref PubMed Scopus (600) Google Scholar). In 5′ and 3′ untranslated regions, the two known triplet repeats are of CGG and CTG. This has suggested that polyCXG is more prone to hairpin formation than any other triplet. However, Friedreich ataxia is associated with a polyGAA expansion in an intron. (GAA)n is thought to form triplex structures (Figure 1) (10Gacy A.M Goellner G.M Spiro C Chen X Gupta G Bradbury E.M Dyer R.B Mikesell M.J Yao J.Z Johnson A.J et al.GAA instability in Friedreich’s ataxia shares a common, DNA-directed and intraallelic mechanism with other trinucleotide diseases.Mol. Cell. 1998; 1: 583-593Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar); this suggests that instability may be mediated by different slipped-strand structures, depending on the repeat sequence (20Pearson C.E Sinden R.R Trinucleotide repeat DNA structures dynamic mutations from dynamic DNA.Curr. Opin. Struct. Biol. 1998; in pressGoogle Scholar). Although trinucleotide repeats are generally thought to expand during DNA replication in multiplying cells, it is increasingly believed that expansion could also occur during DNA repair in nonmultiplying cells (see Figure 1). Nicks or gaps may initiate strand slippage/hairpin formation, followed by limited replication to fill in the gap (C. Pearson; M. Hartenstine, Los Angeles). Single-stranded flaps are generated by displacement synthesis when DNA polymerase encounters the 5′ end of a downstream Okazaki fragment. The redundancy contained in the flap could result in duplication on double-stranded DNA either via realignment of a loop on the template or via double-stranded break followed by end-joining. For Dmitry Gordenin (Research Triangle Park), the flap might be the structure responsible for repeat expansion (12Gordenin D.A Kunkel T.A Resnick M.A Repeat expansion-all in a flap?.Nat. Genet. 1997; 16: 116-118Crossref PubMed Scopus (186) Google Scholar), because when the flap contains repeats that are capable of forming stable double-stranded hairpins, triplexes, or tetraplexes (Figure 1), it becomes resistant to repair by RAD27 or its mammmalian homolog, FEN1. It is known from in vitro studies that the FEN1 endonuclease cannot act on paired DNA. Alec Jeffreys described some of the properties of minisatellites, which are extremely unstable in the human, particularly in sperm where the variability is 250 times higher than in blood. Single sperm analysis has shown that instability of minisatellites is due to a complex recombination-based process. Variability is not random, as there is a bias of 3:1 in favor of expansion and as minisatellite growth is polar. Minisatellites add repeats near the 5′ end of the previously existing segment of repeats (polarized variability). From study of the minisatellite MS32, it has been concluded that the minisatellite was not unstable in itself but was rendered unstable by the presence of a flanking hotspot for recombination (mutation regulator). This hotspot is for the most part localized upstream of the repeats, but it extends into the unstable end of the repeat array. It is quite remarkable that although the flanking hotspot appears to cover about 1.5 kb, a single G to C transversion can virtually inactivate it, presumably by abolishing a binding site for a protein. The recombination hotspot acts in cis, as shown in heterozygotes, and suppresses gene conversion in meiosis but has no action on somatic instability. The hotspot appears to control polar germline instability, and it is interesting to speculate that a similar hotspot might have controlled the vectorial expansion of the involucrin segment of repeats during primate and human evolution. Repeat addition in sperm is an interallelic process, a form of gene conversion. In somatic cells, repeat addition is an intraallelic process. Sequences highly unstable in the human are often stable in the mouse. This was known from earlier studies (1Bingham P.M Scott M.O Wang S McPhaul M.J Wilson E.M Garbern J.Y Merry D.E Fischbeck K.H Stability of an expanded trinucleotide repeat in the androgen receptor gene in transgenic mice.Nat. Genet. 1995; 9: 191-196Crossref PubMed Scopus (123) Google Scholar), but Karen Usdin (Bethesda) reported a very remarkable case. Versions of the 5′ region of the human FMR1 gene bearing long CGG repeats were introduced into mice. The corresponding human alleles show 100% probability of expansion when inherited from the mother, but the same repeats showed virtually no instability in mice, even after five generations. In a separate discussion, Alec Jeffreys (Leicester) mentioned the great stability of minisatellites in the germline of the mouse as compared to that of the human. In the latter, the instability of a given minisatellite in pedigrees corresponds to mutation rates observed in single sperm analysis, whereas in the mouse, the variability of minisatellites can be very high in the population and yet no variability is observed in the sperm. It is thought that the very short generation time of the mouse and its large population size can lead to high levels of heterozygosity in spite of the relative stability of minisatellites in sperm. This means that factors other than the repeat itself control instability (Karen Usdin). If the mouse might not be the right animal for studying instability of simple repeats in the germline, it could be the right animal for studying instability of repeats in somatic tissues. Mice containing a fragment of the myotonic dystrophy protein kinase (DMPK) cDNA with 162 CTGs show high levels of tissue-specific, age-dependent, and expansion-biased somatic instability (Darren Monckton, Glasgow). As only one of three transgenic lines showed somatic instability, the important determinant seems to be the site of integration of the transgene containing the expanded polyCTG. Triplet repeat expansion can produce disease by different mechanisms. Fragile X syndrome is due to loss of function of the FMR1 gene through hypermethylation and altered chromatin structure, while in neuronal proteins, an excessively long polyglutamine sequence produces a gain of function that results in neuronal lethality (13Green, H., and Djian, P. (1998). Amino acid repeats in proteins and the neurological diseases produced by polyglutamine. In Genetic Instabilities and Hereditary Neurological Diseases, R.D. Wells and S.T. Warren, eds. (New York: Academic Press), pp. 739–759.Google Scholar). PolyQ-containing fragments of the proteins associated with disease of polyglutamine cause disease more readily than the intact protein (15Ikeda H Yamaguchi M Sugai S Aze Y Narumiya S Kakizuka A Expanded polyglutamine in the Machado-Joseph disease protein induces cell death in vitro and in vivo.Nat. Genet. 1996; 13: 196-202Crossref PubMed Scopus (497) Google Scholar). Cleavage of huntingtin by apopain in vitro has been reported (11Goldberg Y.P Nicholson D.W Rasper D.M Kalchman M.A Koide H.B Graham R.K Bromm M Kazemi-Esfarjani P Thornberry N.A Vaillancourt J.P Hayden M.R Cleavage of huntingtin by apopain, a proapoptotic cystein protease, is modulated by the polyglutamine tract.Nat. Genet. 1996; 13: 442-449Crossref PubMed Scopus (491) Google Scholar), and the presence of fragments of huntingtin in affected areas of the brain of patients with Huntington disease has been observed (8DiFiglia M Sapp E Chase K.O Davies S.W Bates G.P Vonsattel J.P Aronin N Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain.Science. 1997; 277: 1990-1993Crossref PubMed Scopus (2175) Google Scholar). It is thought that fragments form toxic aggregates more readily than the intact protein, either by polar-zipper hydrogen bonding or by transglutaminase-catalyzed cross-linking. Jean-Marc Gallo (London) reported the specific cleavage of the androgen receptor containing an expanded polyglutamine sequence in COS cells and in a neuroblastoma cell line (4Butler R Leigh P.N McPhaul M.J Gallo J.-M Truncated forms of the androgen receptor are associated with polyglutamine expansion in X-linked spinal and bulbar muscular atrophy.Hum. Mol. Genet. 1998; 7: 121-127Crossref PubMed Scopus (68) Google Scholar). Enhanced proteolysis of proteins containing an excessively long polyglutamine sequence might be an important aspect of the pathogenesis of diseases of polyglutamine. The gene is autosomal and dominant, and the disease is the most common muscular dystrophy in adults. There were two very interesting talks on the subject by Keith Johnson and Darren Monckton, both from Glasgow. The cause of myotonic dystrophy is the expansion of a polyCTG sequence located in the 3′untranslated region of the DMPK gene and expressed in numerous tissues. The polyCTG expansion probably affects the function of several neighboring genes. One such gene is the myotonic dystrophy-associated homeodomain protein gene (DMHAP). Alteration of DMPK gene expression, as a result of the expansion of the polyCTG, does not seem an adequate explanation for the human disease. Homozygous knockout mice show only minor changes in muscles (16Jansen G Groenen P.J Bachner D Jap P.H Coerwinkel M Oerlemans F van den Broek W Gohlsch B Pette D Plomp J.J Molenaar P.C Nederhoff M.G van Echteld C.J Dekker M Berns A Hameister H Wieringa B Abnormal myotonic dystrophy protein kinase levels produce only mild myopathy in mice.Nat. Genet. 1996; 13: 316-324Crossref PubMed Scopus (267) Google Scholar) or a late onset progressive skeletal myopathy (23Reddy S Smith D.B Rich M.M Leferovich J.M Reilly P Davis B.M Tran K Rayburn H Bronson R Cros D Balice-Gordon R.J Housman D Mice lacking the myotonic dystrophy kinase develop a late onset progressive myopathy.Nat. Genet. 1996; 13: 325-335Crossref PubMed Scopus (277) Google Scholar); no myotonia is observed, and heterozygotes are normal. Overexpression of a DMPK transgene results in cardiomyopathy and male sterility, but there is neither muscle atrophy nor myotonia. Alteration of DMHAP expression would appear particularly relevant, since the gene encodes a transcription factor found in all tissues affected by myotonic dystrophy (14Heath S.K Carne S Hoyle C Johnson K.J Wells D.J Characterization of expression of mDMHAP, a homeodomain-encoding gene at the murine DM locus.Hum. Mol. Genet. 1997; 6: 651-657Crossref PubMed Scopus (36) Google Scholar) and since the polyCTG of the DMPK gene coincides with the promoter of the DMHAP gene. An enhancer for the DMHAP gene has been identified, downstream of the polyCTG sequence (17Klesert T.R Otten A.D Bird T.D Tapscott S.J Trinucleotide repeat expansion at the myotonic dystrophy locus reduces expression of DMHAP.Nat Genet. 1997; 16: 402-406Crossref PubMed Scopus (213) Google Scholar), within a very large CpG island. Expansion of the polyCTG sequence is thought to condense chromatin at the DMHAP enhancer, thereby hindering access of trans-acting factors to the enhancer. Progressive increase in the length of the polyCTG sequence would lead to progressively greater impairment of the transcription of the DMHAP gene and to increasing haploinsufficiency. In some cases, haploinsufficiency is known to produce morphogenetic defects, such as the aniridia due to a 50% decrease in PAX6. A prominant feature of myotonic dystrophy is the extraordinarily high level of somatic mosaicism (18Lavedan C Hofmann-Radvanyi H Shelbourne P Rabes J.P Duros C Savoy D Dehaupas I Luce S Johnson K Junien C Myotonic dystrophy size- and sex-dependent dynamics of CTG meiotic instability, and somatic mosaicism.Am. J. Hum. Genet. 1993; 52: 875-883PubMed Google Scholar). Expanded alleles show little variability early in life, but the average size and the degree of mosaicism increase progressively with age, particularly in affected tissues, such as muscle. In this disease, the tissue specificity of the symptoms and the progressive nature of the disease are probably related to tissue-specific somatic instability of the expanded repeat sequence. An important question is whether expansion of the polyCTG repeat in muscle takes place in satellite cells during their multiplication or whether it is independent of DNA replication (Howard Green). PolyCTG repeat expansion is observed in brain, but proof of expansion in (nondividing) neurons is lacking. It is not known which of the numerous possibilities for slipped-strand expansion of triplet repeats observed in vitro operate in vivo. Slipped-strand mispairing alone cannot explain some of the features of repeat expansion in vivo. For example, why is there a difference in stability of triplet repeats in the germline of the two sexes, and why are repeats that are unstable in the germline of the human, stable in that of the mouse? Why is expanded polyCAG always located in the sense strand? Why are triplets often added at a precise location? Do recombination-based processes, which are believed to operate in minisatellite expansion, play a role in trinucleotide repeat expansion? Some of the proteins causing disease of polyglutamine are specifically aggregated in affected parts of the central nervous system, and it is believed that the aggregates cause neuronal lethality. Although recent studies have shown that both transglutaminase-catalyzed cross-linking and hydrogen-bonded polar-zipper formation can be mechanisms of aggregation in vitro, it is not clear whether only one or both mechanisms might be operating in vivo. Another question is why, within the brain, the diseases affect different neuronal subpopulations, although most of the disease-causing proteins are found in all neurons? In the case of myotonic dystrophy, splicing regulated by a CUG-binding protein is altered in muscle of patients, presumably because of inappropriate binding of the protein to the expanded polyCUG repeat of the DMPK mRNA (22Philips A.V Timchenko L.T Cooper T.A Disruption of splicing regulated by a CUG-binding protein in myotonic dystrophy.Science. 1998; 280: 737-741Crossref PubMed Scopus (658) Google Scholar). The relative contributions of a trans-dominant effect of the DMPK mRNA and of haploinsufficiency of the DMHAP protein remain to be determined. We are very grateful to Drs. Howard Green, Richard Bowater, Gabby Dover, Evan Eichler, Jean-Marc Gallo, Dmitry Gordenin, Geneviève Gourdon, John Hancock, Alec Jeffreys, Keith Johnson, Darren Monckton, Richard Moxon, Christopher Pearson, and Diethard Tautz for their comments on the manuscript." @default.
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• W2073190649 title "Evolution of Simple Repeats in DNA and Their Relation to Human Disease" @default.
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