Human Molecular Genetics

Medical and Molecular Genetics, UMDS, Guy's Hospital, London SE1 9RT, UK and ¹Department of Anatomy and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK

Received May 7, 1997

CAG/polyglutamine expansion has been shown to form the molecular basis of an increasing number of inherited neurodegenerative diseases. The mutation is likely to act by a dominant gain of function but the mechanism by which it leads to neuronal dysfunction and cell death is unknown. The proteins harbouring these polyglutamine tracts are unrelated and without exception are widely expressed with extensively overlapping expression patterns. The factors governing the cell specific nature of the neurodegeneration have yet to be understood. Upon a certain size threshold, expanded CAG repeats become unstable on transmission and a modest degree of somatic mosaicism is apparent. Similarly, the molecular basis of the instability and its tissue specificity has yet to be unravelled. Recent reports describing the first mouse models of CAG/polyglutamine disorders indicate that it will be possible to model both the pathogenic mechanism and the CAG repeat instability in the mouse. This has great potential and promise for uncovering the molecular basis of these diseases and developing therapeutic interventions.

INTRODUCTION

Huntington's disease (HD) (1 ) is one of an increasing number of neurodegenerative disorders caused by a CAG/polyglutamine (polygln) repeat expansion, including spinal and bulbar muscular atrophy (SBMA) (2 ), dentatorubral pallidoluysian atrophy (DRPLA) (3 ,4 ) and spinocerebellar ataxia (SCA) types 1 (5 ), 2 (6 -8 ), 3 (9 ) and 6 (10 ). The inheritance patterns are autosomal dominant (with the exception of X-linked SBMA) and in each case, the proteins can tolerate a large variation in the size of the polygln tracts in the normal range but upon a certain size (~37-40 glutamines) these tracts become pathogenic. It is likely that the novel molecular pathways initiated by this mutation have a common basis (except possibly in the case of SCA6 in which the pathogenic threshold is smaller). The proteins harbouring the polygln stretches are mostly novel and otherwise unrelated. In all cases the proteins are widely or ubiquitously expressed, but despite extensively overlapping expression patterns, the neuronal cell death is relatively specific and can differ markedly (reviewed in 11 ).

The molecular events by which a polygln expansion causes cell death remain to be unravelled (reviewed in 12 ). These mutations are likely to act by a dominant gain of function, this mechanism being supported by the identification of the 1C2 antibody which specifically detects polygln expansions, suggestive of a conformational change at a certain size threshold (13 ). In addition, the factors which convey the specific and differing patterns of cell death between these diseases are not understood. Possible mechanisms include differences in expression levels, subcellular localisation of the mutated protein or cell specific subcellular interactions. A number of proteins have now been reported to interact with huntingtin which include HAP 1 (14 ), HIP-1 (15 ), a specific ubiquitin-conjugating enzyme (16 ) and GAPDH (17 ). It is yet to be established whether any of these proteins play a role in the pathogenic mechanism. Huntingtin has also been shown to be specifically cleaved by apopain, a cysteine protease with a key role in the proteolytic events leading to apoptosis (18 ). Similarly, it is not clear if this participates in the chain of events leading to neurodegeneration.

Expanded triplet repeats are invariably unstable when inherited from one generation to the next and they generally show varying degrees of somatic mosaicism. The intergenerational instability forms the molecular basis of anticipation: the observation that the age of onset of a disease decreases and/or the severity increases as the gene is passed from one generation to the next. Repeat instability on transmission has been described in all of the CAG repeat diseases and, in general, repeats tend to be more unstable on paternal transmission. This may present as larger increases on paternal inheritance as in HD (19 ) (reflected in the paternal sex bias to the anticipation) or as a tendency to increase on male and decrease on female transmission as in SCA1 (20 ). A relatively modest degree of somatic repeat instability has been identified in HD, DRPLA, SCA1 and MJD. In general, expansions have been identified in regions of the CNS, with the exception of the cerebellum which presents a smaller repeat relative to the other brain regions tested (21 -26 ). Of non-CNS tissues, instability has consistently been reported in liver and kidney (21 ,24 -26 ) and also in muscle, lung, testis (21 ), leukocytes (23 ) and colon (24 ,26 ). Studies of DRPLA patients also identified a significant correlation between the range of the expanded allele and the age at death of the patient rather than with the onset of disease (25 ). The molecular events governing triplet repeat instability are not understood and possible mechanisms must address both a CAG repeat size threshold and cell specificity.

TRANSGENIC MODELLING OF HUNTINGTON'S DISEASE

It has been proposed for many years that the HD mutation most probably acts through a dominant gain of function. Analysis of mice arising from the first transgenic models of HD, SCA1 and MJD in addition to gene targeted knockouts of the mouse HD gene (Hdh) supports this hypothesis.

Knockouts of the mouse Hhd gene

Three research groups have independently generated knockouts of the mouse HD gene (Hdh) (27 -29 ). In all cases the nullizygous phenotype was embryonic lethal, clearly demonstrating that the HD gene plays an important role in development. In two of these studies, heterozygous mice expressing only one copy of Hdh were phenotypically normal (28 ,29 ). In contrast, Nasir et al. (27 ) reported that heterozygotes showed increased motor activity and cognitive deficits with a significant neuronal loss in the subthalamic nucleus. To explain this discrepancy, it has been suggested that the targeted allele (targeted to replace exon 5) may allow the production of a truncated protein which could conceivably cause a dominant effect in the heterozygous mice, generating a phenotype. Together, these studies demonstrate that HD is not caused by haplo-insufficiency (loss of function of one copy of the gene) or a simple dominant-negative mechanism. In the first case, loss of one allele and in the second case, loss of both alleles, would be expected to generate a model of HD.

Transgenic models of HD

A dominant gain of function mechanism would predict that a mouse model of a polygln neurodegenerative disorder could be generated by the introduction into the mouse germ line of a mutant copy of the gene in question, irrespective of the presence of two copies of the endogenous mouse homologue. The first description of HD transgenic mice used a full length cDNA construct under the control of a CMV promoter carrying (CAG)₄₄ (30 ). Of the HD transgenes, 2/6 founders expressed high levels of transgene mRNA but a transgene protein was not detected. Whilst these results could be interpreted as providing evidence that translation of the CAG repeat into a polygln expansion is necessary for pathogenesis, the repeat expansion in this experiment is comparatively modest and it is possible that larger expansions are necessary to generate a phenotype with an age of onset that falls within the lifetime of a mouse.

Genomic clones are frequently more successful at generating transgenic models than cDNAs as they often direct an expression profile that mimics the endogenous gene. The large size of the HD gene (170 kb) necessitates that genomic constructs are prepared and manipulated in the form of yeast artificial chromosomes (YACs). Using YAC technology, Hodgson et al. (31 ) have successfully generated mice that are transgenic for the normal human HD gene. They have crossed the human HD transgene onto an Hdh nullizygous background and shown that the human YAC can rescue the embryonic lethal phenotype. This indicates that the transgene is expressed appropriately and predicts that the introduction of a mutant version of the human YAC would be successful in generating a model of HD.

Mice transgenic for a mutant version of exon 1 of the HD gene

We have described four lines of mice that are transgenic for exon 1 of the HD gene carrying CAG expansions of 115-156 (R6/1, R6/2, R6/5 and R6/0) and a further two lines transgenic for the same construct carrying 18 repeats (HDex6 and HDex27) (32 ). The transgene is ubiquitously expressed at both the RNA and protein levels in all lines except R6/0, in which no evidence of expression has been detected (32 ,33 ). The transgene protein contains the first 69 amino acids of huntingtin in addition to the number of residues encoded by the CAG repeat (i.e. ~3% of huntingtin).

A progressive neurological phenotype has been observed in three lines: R6/1, (CAG)₁₁₅; R6/2, (CAG)₁₄₅; and R6/5, (CAG)_130-155. Line R6/2 has an onset of ~2 months, line R6/1 at ~5 months and R6/5 hemizygotes do not show symptoms after >1 year. Lines R6/1 and R6/5 show an earlier age of onset and more rapid progression of the disease when bred to homozygosity. The phenotype includes an irregular gait, resting tremor, stereotypic and abrupt, irregularly timed movements and epileptic seizures. Coincident with the onset of the motor disorder there is a progressive reduction in body weight in the transgenes as compared with their littermate controls. The absence of a phenotype in lines R6/0, HDex6 and HDex27 suggests that expression of the polygln expansion forms the molecular basis of the phenotype rather than the expression of a novel peptide. It is notable that the R6 phenotype does not include an overt cerebellar ataxia as described for the spinocerebellar ataxia lines (34 ,35 ) (see below). Extensive neuropathological analysis has been performed on the brains of R6/2 mice. At 12 weeks, the only difference that could be identified between the transgene and control brains was that the R6/2 brains were ~20% smaller, and that this reduction in brain size occurred across all structures with an apparently normal neuronal density. This is consistent with early changes that occur in the brains of HD patients. More recently, immunocytochemistry with huntingtin N-terminal antibodies has identified the presence of neuronal intranuclear inclusions (NII) in the brains of symptomatic transgenic mice (33 ).

COMPARISON WITH OTHER CAG/POLYGLN MOUSE MODELS

Mice transgenic for both SCA1 (34 ) and MJD (35 ) constructs have also been reported to develop a phenotype. A summary of the main features of these and the R6 transgenes is presented in Table 1 . The SCA1 transgenes were the first demonstration that modelling a polygln repeat disorder would be possible in the mouse. They included mice transgenic for the SCA1 cDNA carrying either a normal interrupted allele of (CAG)₁₂CATCAGCAT(CAG)₁₅ (PS-30) or an expanded uninterrupted allele of (CAG)₈₂ (PS-82) under the control of the pcp2 promoter (Purkinje cell-specific) (34 ). Five of six PS-82 lines showed RNA expression between 10- and 100-fold of endogenous levels. In the original report, transgene protein could not be detected but this has since been shown to be present by immunocytochemistry (H.Orr and H.Zoghbi, personal communication). Mice from all five lines developed ataxia. Onset varied from 12 to 26 weeks and a dosage effect was apparent: in two lines studied, homozygotes were more severely affected than hemizygotes. Neuropathological analysis showed significant loss of the Purkinje cell population, with Bergmann glial proliferation, and shrinkage and gliosis of the molecular layer. Ectopic Purkinje cells were present in the molecular layer and occasionally the granular layer and the dendritic arrays also appeared to be abnormal.

Ikeda et al. (35 ) used expression constructs containing the MJD cDNA carrying 79 CAG repeats (MJD79), the CAG repeat followed by only the C-terminus of the MJD gene with both 79 and 35 CAG repeats (Q₇₉C and Q₃₅C) and a 79 CAG repeat in isolation (Q₇₉) under the control of a Purkinje cell-specific promoter. Ataxia was observed in 3/3 Q₇₉C and 2/6 Q₇₉ transgenic mice, occurring as early as 1 month of age after full activation of the promoter. In contrast, a phenotype was not observed in any of the ten Q₃₅C or four MJD79 transgenic mice as of 7 and 5 months, respectively. Neuropathological analysis of a 2 month old ataxic Q79C mouse showed a very atrophic cerebellum, in which all three layers were affected. The authors suggest that comparison of their data with that of Burright et al. (34 ) indicates that the polygln tracts are more toxic when present in isolation or in the context of a truncated protein. In the absence of any data relating to expression levels it is difficult to come to strong conclusions with regard to the comparative toxicity of the full length and truncated constructs. However, these conclusions were strongly supported by a series of transient transfections of COS cells described in the same paper (35 ).

MOUSE MODELS OF CAG/CTG REPEAT STABILITY

Repeat stability studies carried out on the first mice transgenic for CAG repeat expansions showed no evidence of instability and suggested that the molecular mechanism underlying triplet repeat instability in humans may not exist in the mouse. These initial studies included (CAG)₄₅ in the androgen receptor cDNA (36 ), (CAG)₄₄ in the HD cDNA (30 ), (CAG)₈₂ in the SCA1 cDNA (34 ) and (CAG)₇₉ in constructs based on the MJD/SCA3 cDNA (35 ).

Triplet repeat instability in lines transgenic for the HD mutation (R6)

The R6 lines transgenic for exon 1 of the HD gene carrying (CAG)₁₁₅-(CAG)₁₅₅ expansions showed both intergenerational and somatic repeat instability (32 ,37 ). The repeats were clearly unstable on transmission in lines R6/1, R6/2 and R6/5, although this was less clear in line R6/0 as the changes observed in this line could be accounted for by errors in sizing. In line R6/2, the degree of instability increases with the age of the transmitting male (as R6/2 females are sterile it was not possible to look for an age effect on female transmission). R6/5 was the only line in which an extensive comparison of instability on both male and female transmission was conducted and the repeats had a tendency to increase on male transmission and decrease on female transmission (37 ). This trend was supported by the intergenerational instability observed in the other lines. The CAG expansions introduced into these mice are considerably larger than are normally seen in HD patients. The change in size of the repeat on transmission in the mice is smaller than would be expected from comparison with size changes associated with highly expanded CAG repeats seen in humans. The discrepancy in the degree of instability between humans and mice may reflect the difference in their life span, a model supported by the observation that the size of the intergenerational expansion increased with the age of the transmitting male.

Somatic instability was detected in lines R6/1, R6/2 and R6/5 but not in line R6/0 (Fig. 1 ). In all three lines, onset of instability was at ~6 weeks and the CAG repeat range increased with the age of the mouse. This argues against a pathogenic role for repeat instability as the age of onset of symptoms in these lines differs markedly. The pattern of instability was more widespread in some lines than others although on the whole it was first present and most prominent in brain regions. Peripheral tissues that consistently showed instability included liver and kidney. Overall the somatic instability was comparable with that described in individuals carrying CAG expansions (21 -26 ). The major difference between line R6/0, in which instability was not apparent, and the other lines was the absence of transgene expression. This is probably due to gene silencing by a position effect as the R6/0 transgene has clearly integrated into a region of unusual genomic structure (32 ).

Other mouse models of triplet repeat instability

Triplet repeat instability has also been reported in two series of lines transgenic for the myotonic dystrophy (DM) mutation (CTG on the sense strand) (37 ,38 ). The integration fragments used in these lines were a genomic fragment (Dmt162) from the myotonic dystrophy (DM) locus containing a small portion of the coding region and the 3'UTR with (CTG)₁₆₂ (38 ) and a cosmid (DM55-5) containing the myotonic dystrophy protein kinase gene (DMPK) with (CTG)₅₅ and the flanking DMR-N9 and DMAHP genes (37 ). Intergenerational instability was observed in both of these cases. The DM55-5 transgenes showed intergenerational instability in 6.8% of transmissions, the changes generally being expansions of one repeat unit. A higher frequency of unstable transmissions was observed in the Dmt lines (as in the R6 lines), most likely as a consequence of the larger size of the repeat tracts.

Table 1 Summary of CAG/polyglutamine transgenic mouse lines in which a progressive neurological phenotype has been observed

Disease	Construct	Promoter	(CAG)n	Expression		Phenotype	Freq. of lines
				RNA	Protein		showing phenotype
HD	exon 1 (genomic)	HD	18	+	+	none	0/2
HD	exon 1 (genomic)	HD	142	-	-	none	0/1
HD	exon 1 (genomic)	HD	115-156	+	+	+	3/3
SCA1	cDNA (full length)	pcp2a	30b	+	+	none	0/7
SCA1	cDNA (full length)	pcp2a	82	+	+	+	5/6
MJD	cDNA (full length)	L7a	79	NR	NR	none	0/4
MJD	cDNA (C-terminus)	L7a	35	NR	NR	none	0/10
MJD	cDNA (C-terminus)	L7a	79	NR	NR	+	3/3
MJD	polyglutamine tract	L7a	79	NR	NR	+	2/6

NR, not reported. ^aPurkinje cell-specific promoter.
^bInterrupted repeat: (CAG)₁₂CATCAGCAT(CAG)₁₅.

Figure 1. Illustration of the CAG repeat somatic instability seen in the R6 lines. The repeats were amplified by PCR using a fluorescent primer and sized on an ABI sequencer using the Genescan and Genotyper software packages (37). In each case the genescan trace arising from a range of tissues at the age at which the mouse was culled is compared with the trace obtained from tail DNA taken at 3 weeks (top row). The size of the major peaks in the tail traces are: R6/1, 115; R6/2, 145; R6/0, 142; R6/5, range from 123 to 156. The R6/5 line contains four copies of the CAG repeat and the difference in the tail trace between the two R6/5 mice has arisen from germ line instability. It is clear that even after 38 weeks there is no evidence for somatic instability in line R6/0.

The Dmt lines [(CTG)_143-162], like the R6 lines [(CAG)_115-155], showed a tendency to repeat expansion on male, and contraction on female, transmission. It would appear that the instability seen in the Dmt lines parallels that seen in the R6 lines and represents more closely instability seen in some of the CAG/polygln neurodegenerative disorders rather than that seen in DM. Myotonic dystrophy is caused by a CTG expansion which expands to between (CTG)₂₀₀ and (CTG)₄₀₀₀ in the adult and congenital forms of the disease with a maternal bias to the anticipation (40 ). Somatic instability was described in one of the DM55-5 transgenes which had additional repeat bands in brain, liver, kidney and eye. A similar pattern of instability was also seen in one of the progeny of this mouse, with most instability apparent in sperm (38 ).

Comparison of the R6, Dmt and DM55-5 lines with the transgenic lines that do not exhibit CAG/CTG repeat instability does not lead to an understanding of the molecular basis of instability. The absence of instability observed in the first four reports could not simply be due to a size threshold effect. It is not clear whether the size threshold in the mouse is larger than that seen in humans; however, it must be below 55 repeats as a moderate amount of instability was seen in the DM55-5 transgenes. Similarly, the absence of instability in the first four lines cannot be due to differences in trans-acting factors which are likely to be invariant. If cis-acting sequences are important, the analysis of four series of lines (30 ,34 -36 ) which do not show instability and three series (37 -39 ) which fairly consistently do would suggest that these sequences are likely to be present on the transgenes themselves rather than at the integration sites. The absence of instability in the R6/0 line as compared with the other R6 lines could have mechanistic implications. The R6/0 line only differs from the other three at the site of integration which is probably acting to silence the expression of the transgene. This argues against a model in which contractions and expansions of the repeat occur through a mechanism linked to DNA replication. It raises the possibility that the instability is linked to expression which may be a consequence of the open configuration of chromatin leading to DNA damage rather than being directly linked to transcription.

CONCLUSION

It is clear that a polygln expansion can give rise to a progressive neurological phenotype in the mouse. The analysis of existing and further transgenic models of CAG/polygln repeat disease will be informative with respect to uncovering the molecular basis of these disorders. Comparison of transgenes arising from full length and truncated constructs may resolve the speculation that the toxic agent is a truncated version of the proteins in question. The models will be useful in allowing the study of the early disease stages for which patient material is rarely available. Comparison of future models in which the transgenes are under the control of endogenous or ubiquitous promoters may shed light on the factors which determine the differing patterns of neurodegeneration.

REFERENCES

1 HDCRG (1993) A novel gene containing a trinucleotide repeat that is unstable on Huntington's disease chromosomes. Cell 72, 971-983.

2 La Spada, A.R. et al. (1991) Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 352, 77-79. MEDLINE Abstract

3 Koide, R. et al. (1994) Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA). Nature Genet. 6, 9-13.

4 Nagafuchi, S. et al. (1994) Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p. Nature Genet. 6, 14-18. MEDLINE Abstract

5 Orr, H.T. et al. (1993) Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nature Genet. 4, 221-226. MEDLINE Abstract

6 Imbert, G. et al. (1996) Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats. Nature Genet. 14, 285-291. MEDLINE Abstract

7 Sampei, K. et al. (1996) Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT. Nature Genet. 14, 277-284.

8 Pulst, S.-M. et al. (1996) Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2. Nature Genet. 14, 269-276. MEDLINE Abstract

9 Kawaguchi, Y. et al. (1994) CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nature Genet. 8, 221-228. MEDLINE Abstract

10 Zhuchenko, O. et al. (1997) Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage dependent calcium channel. Nature Genet. 15, 62-69.

11 Ross, C.A. (1995) When more is less: pathogenesis of glutamine repeat neurodegenerative diseases. Neuron 15, 493-496. MEDLINE Abstract

12 Perutz, M.F. (1996) Glutamine repeats and inherited neurodegenerative diseases: molecular aspects. Curr. Opin. Struct. Biol 6, 848-858. MEDLINE Abstract

13 Trottier, Y. et al. (1995) Polyglutamine expansion as a pathological epitope in Huntington's disease and four dominant cerebellar ataxias. Nature 378, 403-406. MEDLINE Abstract

14 Li, X.-J. et al. (1995) A huntingtin-associated protein enriched in brain with implications for pathology. Nature 378, 398-402. MEDLINE Abstract

15 Wanker, E.E. et al. (1997) HIP-1: A huntingtin interacting protein isolated by the yeast two-hybrid system. Hum. Mol. Genet. 6, 487-495. MEDLINE Abstract

16 Kalchman, M.A. et al. (1996) Huntingtin is ubiquinated and interacts with a specific ubiquitin-conjugating enzyme. J. Biol. Chem. 271, 19385-19394. MEDLINE Abstract

17 Burke, J.R. et al. (1996) Huntingtin and DRPLA proteins selectively interact with the enzyme GAPDH. Nature Med. 2, 347-350.

18 Goldberg, Y.P. et al. (1996) Cleavage of huntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tract. Nature Genet. 13, 442-449. MEDLINE Abstract

19 Duyao, M. et al. (1993) Trinucleotide repeat length instability and age of onset in Huntington's disease. Nature Genet. 4, 387-392. MEDLINE Abstract

20 Chung, M. et al. (1993) Evidence for a mechanism predisposing to intergenerational CAG repeat instability in spinocerebellar ataxia type 1. Nature Genet. 5, 254-258. MEDLINE Abstract

21 Telenius, H. et al. (1994) Somatic and gonadal mosaicism of the Huntington disease gene CAG repeat in brain and sperm. Nature Genet. 6, 409-413. MEDLINE Abstract

22 Aronin, N. et al. (1995) CAG expansion affects the expression of mutant huntingtin in the Huntington's disease brain. Neuron 15, 1193-1201. MEDLINE Abstract

23 Chong, S.S. et al. (1995) Gametic and somatic tissue-specific heterogeneity of the expanded SCA1 CAG repeat in spinocerebellar ataxia type 1. Nature Genet. 10, 344-350. MEDLINE Abstract

24 Ueno, S. et al. (1995) Somatic mosaicism of CAG repeat in dentatorubral-pallidoluysian atrophy (DRPLA). Hum. Mol. Genet. 4, 663-666.

25 Takano, H. et al. (1996) Somatic mosaicism of expanded CAG repeats in brains of patients with dentatorubral-pallidoluysian atrophy: cellular population-dependent dynamics of mitotic instability. Am. J. Hum. Genet. 58, 1212-1222. MEDLINE Abstract

26 Tanaka, F. et al. (1996) Differential pattern of tissue-specific somatic mosaicism of expanded CAG trinucleotide repeat in dentatorubral-pallidoluysian atrophy, Machado-Joseph disease, and X-linked recessive spinal and bulbar muscular atrophy. J. Neurol. Sci. 135, 43-50. MEDLINE Abstract

27 Nasir, J. et al. (1995) Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes. Cell 81, 811-823. MEDLINE Abstract

28 Duyao, M.P. et al. (1995) Inactivation of the mouse Huntington's disease gene homolog Hdh. Science 269, 407-410.

29 Zeitlin, S. et al. (1995) Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington's disease gene homologue. Nature Genet. 11, 155-163. MEDLINE Abstract

30 Goldberg, Y.P. et al. (1996) Absence of the disease phenotype and intergenerational stability of the CAG repeat in transgenic mice expressing the human Huntington's disease transcript. Hum. Mol. Genet. 5, 177-185. MEDLINE Abstract

31 Hodgson, J.G. et al. (1996) Human huntingtin derived from YAC transgenes compensates for loss of murine huntingtin by rescue of the embryonic lethal phenotype. Hum. Mol. Genet. 5, 1875-1885. MEDLINE Abstract

32 Mangiarini, L. et al. (1996) Exon 1 of the Huntington's disease gene containing a highly expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87, 493-506. MEDLINE Abstract

33 Davies, S.W. et al. (1997) Formation of neuronal intranuclear inclusions (NII) underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell, in press.

34 Burright, E.N. et al. (1995) SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat. Cell 82, 937-948. MEDLINE Abstract

35 Ikeda, H. et al. (1996) Expanded polyglutamine in the Machado-Joseph disease protein induces cell death in vitro and in vivo. Nature Genet. 13, 196-202. MEDLINE Abstract

36 Bingham, P.M. et al. (1995) Stability of an expanded trinucleotide repeat in the androgen receptor gene in transgenic mice. Nature Genet. 9, 191-196. MEDLINE Abstract

37 Mangiarini, L. et al. (1997) Instability of highly expanded CAG repeats in transgenic mice is related to expression of the transgene. Nature Genet. 15, 197-200. MEDLINE Abstract

38 Gourdon, G. et al. (1997) Moderate intergenerational and somatic instability of a 55-CTG repeat in transgenic mice. Nature Genet. 15, 190-192. MEDLINE Abstract

39 Monckton, D.G. et al. (1997) Hypermutable myotonic dystrophy CTG repeats in transgenic mice. Nature Genet. 15, 193-196. MEDLINE Abstract

40 Wieringa, B. (1994) Commentary: Myotonic dystrophy reviewed: back to the future? Hum. Mol. Genet. 3, 1-7. MEDLINE Abstract

---

*To whom correspondence should be addressed. Tel: +44 171 955 4485; Fax: +44 171 95 4444; Email: g.bates@umds.ac.uk

-->

---

This page is maintained by OUP admin. Last updated Fri Sep 12 18:09:23 BST 1997. Part of the OUP Journals World Wide Web service. Copyright Oxford University Press, 1997

CiteULike    Connotea    Del.icio.us    What's this?

This article has been cited by other articles:

				H. Seo, W. Kim, and O. Isacson Compensatory changes in the ubiquitin-proteasome system, brain-derived neurotrophic factor and mitochondrial complex II/III in YAC72 and R6/2 transgenic mice partially model Huntington's disease patients Hum. Mol. Genet., October 15, 2008; 17(20): 3144 - 3153. [Abstract] [Full Text] [PDF]

				R. Gonitel, H. Moffitt, K. Sathasivam, B. Woodman, P. J. Detloff, R. L. M. Faull, and G. P. Bates DNA instability in postmitotic neurons PNAS, March 4, 2008; 105(9): 3467 - 3472. [Abstract] [Full Text] [PDF]

				M. A. Albertelli, A. Scheller, M. Brogley, and D. M. Robins Replacing the Mouse Androgen Receptor with Human Alleles Demonstrates Glutamine Tract Length-Dependent Effects on Physiology and Tumorigenesis in Mice Mol. Endocrinol., June 1, 2006; 20(6): 1248 - 1260. [Abstract] [Full Text] [PDF]

				Q. Wang, D. D. Mosser, and J. Bag Induction of HSP70 expression and recruitment of HSC70 and HSP70 in the nucleus reduce aggregation of a polyalanine expansion mutant of PABPN1 in HeLa cells Hum. Mol. Genet., December 1, 2005; 14(23): 3673 - 3684. [Abstract] [Full Text] [PDF]

				U. Rub, D. Del Turco, K. Del Tredici, R. A. I. de Vos, E. R. Brunt, G. Reifenberger, C. Seifried, C. Schultz, G. Auburger, and H. Braak Thalamic involvement in a spinocerebellar ataxia type 2 (SCA2) and a spinocerebellar ataxia type 3 (SCA3) patient, and its clinical relevance Brain, October 1, 2003; 126(10): 2257 - 2272. [Abstract] [Full Text] [PDF]

				J. C. Dorsman, B. Pepers, D. Langenberg, H. Kerkdijk, M. Ijszenga, J. T. den Dunnen, R.A.C. Roos, and G.-J. B. van Ommen Strong aggregation and increased toxicity of polyleucine over polyglutamine stretches in mammalian cells Hum. Mol. Genet., June 15, 2002; 11(13): 1487 - 1496. [Abstract] [Full Text] [PDF]

				G. B. Panigrahi, J. D. Cleary, and C. E. Pearson In Vitro (CTG){middle dot}(CAG) Expansions and Deletions by Human Cell Extracts J. Biol. Chem., April 12, 2002; 277(16): 13926 - 13934. [Abstract] [Full Text] [PDF]

				P. Popoli, A. Pintor, M. R. Domenici, C. Frank, M. T. Tebano, A. Pezzola, L. Scarchilli, D. Quarta, R. Reggio, F. Malchiodi-Albedi, et al. Blockade of Striatal Adenosine A2A Receptor Reduces, through a Presynaptic Mechanism, Quinolinic Acid-Induced Excitotoxicity: Possible Relevance to Neuroprotective Interventions in Neurodegenerative Diseases of the Striatum J. Neurosci., March 1, 2002; 22(5): 1967 - 1975. [Abstract] [Full Text] [PDF]

				A. L. Peel, R. V. Rao, B. A. Cottrell, M. R. Hayden, L. M. Ellerby, and D. E. Bredesen Double-stranded RNA-dependent protein kinase, PKR, binds preferentially to Huntington's disease (HD) transcripts and is activated in HD tissue Hum. Mol. Genet., July 1, 2001; 10(15): 1531 - 1538. [Abstract] [Full Text] [PDF]

				A. Dodd, P. M. Curtis, L. C. Williams, and D. R. Love Zebrafish: bridging the gap between development and disease Hum. Mol. Genet., October 1, 2000; 9(16): 2443 - 2449. [Abstract] [Full Text] [PDF]

				H. Li, S.-H. Li, A. L. Cheng, L. Mangiarini, G. P. Bates, and X.-J. Li Ultrastructural localization and progressive formation of neuropil aggregates in Huntington's disease transgenic mice Hum. Mol. Genet., July 1, 1999; 8(7): 1227 - 1236. [Abstract] [Full Text] [PDF]

				D. F. Smith, L. Whitesell, and E. Katsanis Molecular Chaperones: Biology and Prospects for Pharmacological Intervention Pharmacol. Rev., December 1, 1998; 50(4): 493 - 514. [Abstract] [Full Text] [PDF]

				L. P. Rowland Molecular Basis of Genetic Heterogeneity: Role of the Clinical Neurologist J Child Neurol, March 1, 1998; 13(3): 122 - 132. [Abstract] [PDF]

This Article Abstract FREE Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Archive Download to citation manager Search for citing articles in: ISI Web of Science (51) Request Permissions Google Scholar Articles by Bates, G. P. Articles by Davies, S. W. Search for Related Content PubMed PubMed Citation Articles by Bates, G. P. Articles by Davies, S. W. Social Bookmarking          What's this?