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Human Molecular Genetics Pages 1253-1257
Founder effect in spinal and bulbar muscular atrophy (SBMA)
Introduction
Results
Discussion
Materials And Methods
Acknowledgements
References

Founder effect in spinal and bulbar muscular atrophy (SBMA)

Founder effect in spinal and bulbar muscular atrophy (SBMA) Fumiaki Tanaka1, Manabu Doyu1, Yasuhiro Ito1, Michiyo Matsumoto1,2, Terunori Mitsuma2, Koji Abe3, Masashi Aoki3, Yasuto Itoyama3, Kenneth H. Fischbeck4 and Gen Sobue1,*

1Department of Neurology, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466, Japan, 2Division of Neurology, Fourth Department of Internal Medicine, Aichi Medical University, Aichi 480-11, Japan, 3Department of Neurology, Tohoku University School of Medicine, Sendai 980, Japan and 4Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6146, USA

Received April 4, 1996; Revised and Accepted June 24, 1996

We analyzed the polymorphic (CAG)n and (GGC)n repeats of the androgen receptor gene in 113 unrelated X-linked spinal and bulbar muscular atrophy (SBMA) X chromosomes and 173 control X chromosomes in Japanese males. The control chromosomes had an average CAG repeat number of 21 +- 3 with a range from 14-32 repeat units, and SBMA chromosomes had a range from 40-55 with a median of 47 +- 3 copies. The control chromosomes had seven different alleles of the (GGC)n repeat with the range of 11 to 17; the most frequent size of (GGC)n was 16 (79%), while (GGC)17 was very rare (1%). However, in SBMA chromosomes only two alleles were seen; the most frequent size of (GGC)n was 16 (61%) followed by 17 (39%). (GGC)n size distribution was significantly different between SBMA and control chromosomes (P <0.0001), indicating the presence of linkage disequilibrium. There was no allelic association between the (CAG)n and (GGC)n microsatellites among control subjects as well as SBMA patients, which suggests that a founder effect makes a more significant contribution to generation of Japanese SBMA chromosomes than new mutations.

INTRODUCTION

Several neurogenetic diseases caused by triplet repeat mutations including myotonic dystrophy (DM) (1 ), fragile X syndrome (Fra X) (2 ,3 ), spinocerebellar ataxia type 1 (SCA1) (4 ), Machado-Joseph disease (MJD) (5 ) and Huntington's disease (HD) (6 -9 ), dentatorubral and pallidoluysian atrophy (DRPLA) (10 ) have been reported to be associated with founder chromosomes, based on linkage disequilibrium to flanking polymorphic markers. A recent study has suggested that new mutations occur in a subgroup of unstable high-normal triplet repeat alleles with a particular founder chromosomal haplotype (7 -10 ).

The molecular abnormality of X-linked spinal and bulbar muscular atrophy (SBMA) is expansion of a triplet repeat, (CAG)n, located in the first exon of the androgen receptor (AR) gene (11 ). Another triplet repeat, (GGC)n is located approximately 1.2 kb downstream from (CAG)n in the first exon of the AR gene (12 ).

In order to investigate the origin of the SBMA mutations in the Japanese population, we performed (CAG)n and (GGC)n analysis of the AR gene locus in unrelated SBMA and normal X chromosomes in Japanese males, and found linkage disequilibrium between (GGC)n haplotype and (CAG)n mutation. We further investigated the distribution of (CAG)n repeat sizes in a large cohort of Japanese SBMA patients and controls and analyzed the association between the two microsatellites on the normal and SBMA chromosomes separately.

RESULTS

One hundred and fifty-three Japanese control chromosomes displayed an average CAG repeat number of 21 +- 3 with a range from 14-32 repeat units, 20 repeat units being the most common (Table 1 , Fig. 1 ). The analysis of 113 SBMA chromosomes revealed 15 alleles ranging in size from 40-55 with a median of 47 +- 3 (CAG)n copies (Table 2 , Fig. 1 ).

The range of GGC repeat sizes was from 11-17 repeats in 173 controls, while restricted to 16 and 17 repeats in 92 SBMA chromosomes (Table 1 , 2 ; Figs 2 , 3 ). In both control and SBMA samples, the most frequent allele size of the (GGC)n repeat was 16; 137 (79%) of 173 control chromosomes and 56 (61%) of 92 SBMA chromosomes (Table 1 , 2 ; Fig. 3 ). Although there were (GGC)17 in over one third of SBMA chromosomes (39%), only 1% of control chromosomes exhibited (GGC)17 (Fig. 3 ). Comparing SBMA to all controls, the repeat length distributions were significantly different for GGC ([chi]2 = 81.2, P <0.0001 with d.f. = 6), consistent with linkage disequilibrium (Fig. 3 ).

There was no allelic association between the (CAG)n and (GGC)n microsatellites among control subjects (Kruskal-Wallis test: 6 d.f., P = 0.18) (Table 1 ), although the distribution variance of CAG repeat size with an allele of (GGC)16 was significantly wider than that with (GGC)11-15,17 (F test, F = 0.57, P <0.05) (Table 1 ). There was also no allelic association among SBMA subjects (Mann-Whitney U test: U = 790.5, P = 0.45) (Table 2 ).

Table 1 Distribution of (CAG)n and (GGC)n in control subjects
(CAG)n/(GGC)n

 11

 12

 13

 14

 15

 16

 17

 *

 Total
14

  

  

  

  

  

 1

  

  

 1
15

  

  

  

  

  

 1

  

  

 1
16

  

  

  

  

  

 2

  

  

 2
17

  

  

  

  

 1

 8

  

  

 9
18

  

  

  

  

  

 5

  

  

 5
19

  

 3

  

  

  

 12

 1

 1

 17
20

 5

 1

 1

  

  

 18

 1

 1

 27
21

 3

 2

  

  

  

 17

  

  

 22
22

 2

 2

 1

  

 1

 16

  

  

 22
23

  

 1

  

 2

  

 10

  

 2

 15
24

 1

  

  

  

 2

 11

  

  

 14
25

  

  

  

  

 3

 8

  

  

 11
26

  

  

  

  

  

 2

  

  

 2
27

  

  

 1

  

  

 1

  

  

 2
28

  

  

  

  

  

 1

  

  

 1
29

  

  

  

  

  

 1

  

  

 1
30
31
32

  

  

  

  

  

 1

  

  

 1
**

 1

  

 1

  

  

 22
Total

 12

 9

 4

 2

 7

 137

 2

  

 173/153
Absolute numbers of chromosomes for each genotype are indicated.*no available data for GGC repeat size; **no available data for CAG repeat size.No association between the two microsatellites among 149 control subjects (Kruskal-Wallis test: 6 d.f., P = 0.18).Variance of CAG repeat size with an allele of (GGC)16 is wider than that with (GGC)11-15,17 (F test, F = 0.57, P <0.05).

Table 2 Distribution of (CAG)n and (GGC)n in SBMA subjects
(CAG)n/(GGC)n

 16

 17

 *

 Total
40

  

 2

 1

 3
41

 1

 1

 2

 4
42

 4

 1

  

 5
43

 3

 4

 1

 8
44

 5

 2

  

 7
45

 3

 2

 1

 6
46

 9

 4

 3

 16
47

 12

 3

 5

 20
48

 3

 4

 4

 11
49

 4

 5

 3

 12
50

 2

 1

 3

 6
51

 1

 4

 2

 7
52

 3

  

 2

 5
53
54

  

 2

  

 2
55

  

  

 1

 1
**

 6

 1
Total

 56

 36

  

 92/113
Absolute numbers of chromosomes for each genotype are indicated.*no available data for GGC repeat size; **no available data for CAG repeat size.No association between the two microsatellites among 85 SBMA subjects (Mann-Whitney U test: U = 790.5, P = 0.45).

DISCUSSION

A cohort of 153 Japanese control chromosomes displayed an average CAG repeat number of 21 +- 3 with a range from 14-32 repeat units (Table 1 , Fig. 1 ), which is consistent with a previous report of 39 Asian controls with an average repeat number of 22 +- 3 ranging in size from 15-29 (13 ) and those of 37 Caucasian control population with 16-26 with a median of 22 +- 3 (14 ). The 113 SBMA chromosomes ranging in size from 40-55 with a median of 47 +- 3 (CAG)n copies was also consistent with a previous report of a mixed SBMA population with 47 +- 4 (CAG)n (14 ), although the range of size for Caucasians was somewhat larger (40-62). The expanded CAG repeats of the SBMA AR gene in the present study showed a narrower range of distribution (16 different repeats, 40-55) than the other CAG repeat diseases (35-50 different repeats in HD, SCA1 and DRPLA, except 21-24 repeats in MJD) (15 -17 ). These findings also indicate relative stability of (CAG)n in SBMA, consistent with the relatively narrow meiotic instability (14 ) and relatively narrow instability in somatic tissue mosaicism (18 ) that has been previously reported.


Figure 1.Frequency distribution of (CAG)n repeat sizes observed in controls and SBMA subjects. Shaded bars indicate SBMA chromosomes and open bars indicate control chromosomes. One hundred and fifty-three control chromosomes displayed an average CAG repeat number of 21 +- 3 with a range from 14-32 repeat units; 20 repeat units were the most common. One hundred and thirteen SBMA chromosomes revealed 15 alleles ranging in size from 40-55 with a median of 47 +- 3 (CAG)n copies.


Figure 2. Representative measurements of triplet repeat lengths of (GGC)n using fluorescein-labeled PCR products analyzed on the autoread sequencer (ALFred, Pharmacia). The top 12 traces show SBMA chromosomes and the bottom 12 traces show control chromosomes. The distribution of (GGC)n in SBMA chromosomes is restricted on GGC16 and GGC17, while that in control chromosomes is on wide-range of size.The size-frequency distribution of the GGC repeats significantly differs among the various racial-ethnic control subjects (13 ). In one series, 70% of Asian controls had (GGC)16 compared to 57% Caucasian and 20% African-American controls, and very few Asians (3%) had alleles longer than 16 which otherwise were common [32% (13 ) or 42% (11 )] in Caucasians. The remaining 27% had (GGC)n ranging from 10-15 (13 ). The distribution of GGC repeat sizes in our Japanese control subjects (Table 1 , Fig. 3 ) is consistent with reported Asian controls (13 ).

We observed no association between the two microsatellites among control subjects (Kruskal-Wallis test: 6 d.f., P = 0.18) (Table 1 ). These findings are consistent with the previously reported results of lack of allelic association between (CAG)n and (GGC)n microsatellites among normal subjects in any of the racial groups (13 ,19 ), which indicate that either one or both of the repeats mutate occasionally. The rate of mutation at the CAG site was measured using single-cell assays of sperm and a rate of 1-4% was obtained (20 ). Such mutations would lead to lack of allelic association between (CAG)n and (GGC)n microsatellites among normal subjects despite the close proximity of the two microsatellites.


Figure 3. Frequency distribution of (GGC)n repeat sizes observed in control and SBMA subjects. Shaded bars indicate SBMA chromosomes and open bars indicate control chromosomes. The most frequent allele size of the (GGC)n repeat was 16; 137 (79%) of 173 control chromosomes versus 56 (61%) of 92 SBMA chromosomes. Although there was an additional allele of 17 repeats in over one third of SBMA chromosomes (39%), very few of control chromosomes exhibited 17 copies (1%). Control chromosomes showed seven different haplotypes (11-17) while the SBMA chromosomes showed less heterogeneous distribution of only two types (16 and 17). The distribution of (GGC)n repeat size differs between control and SBMA chromosomes ([chi]2 = 81.2, P <0.0001 with d.f. = 6), providing the evidence for linkage disequilibrium in (CAG)n-(GGC)n haplotypes.

Furthermore, we observed no association between the two microsatellites among SBMA patients (Table 2 ). The mutation rate at the expanded (CAG)n allele in sperm is more than that of control; the average expansion was 2.7 repeats (21 ), and average gain of (CAG)n repeat units in paternal transmission was 1.4 in SBMA (22 ), which would account for the lack of allelic association between the two microsatellites among SBMA patients (Table 2 ).

Our results demonstrate that the distribution of (GGC)n repeat size differs between control and SBMA chromosomes ([chi]2 = 81.2, P <0.0001 with d.f. = 6) (Fig. 3 ), providing evidence for linkage disequilibrium in SBMA. The linkage disequilibrium has three possible explanations. First is the presence of a founder effect in the SBMA mutation; second is the generation of new (GGC)n microsatellite mutations with expansion of the (CAG)n repeat; third is susceptibility to pathologic expansion of the (CAG)n repeat associated with the (GGC)n alleles with 16 and 17 repeats. The second explanation has been suggested for fragile X syndrome (3 ). Large FMR-1 CGG repeats may be associated with new adjacent microsatellite mutations, which lead to microsatellite heterogeneity in patients and a different distribution in controls and patients (3 ). In the present study, control chromosomes showed seven different (GGC)n haplotypes while SBMA chromosomes showed less heterogeneous distribution of only two (GGC)n types (Fig. 3 ), which could not be explained by this hypothesis. The third explanation has been suggested for HD and DRPLA especially as a multi-step model (7 -10 ). In this model the expanded triplet repeats evolves from a founder chromosomal haplotype with long-normal repeats and repeat number further increases occasionally. In HD, a block of CCG repeats lies immediately adjacent to the block of CAG repeats which is responsible for the disease and a significant inverse relationship between CCG and CAG repeat size on normal chromosomes has been demonstrated (9 ). A CCG of 7 repeats is overrepresented on HD chromosomes and associated with long-normal (CAG)n alleles; new mutations for HD likely arise from these long-normal alleles (9 ). In the present study, however, we could not observe allelic association between the (CAG)n and (GGC)n microsatellites among control subjects (Kruskal-Wallis test: 6 d.f., P = 0.18) (Table 1 ), this being consistent with the previous reports (13 ,19 ). Single sperm data also show that expansion is less common than contraction in long-normal CAG alleles in the AR gene (20 ), which is markedly different from that at the HD locus; expansion is more frequent in the long-normal allele (30 repeats) and in the intermediate allele (36 repeats) (23 ). These findings suggest that new mutations for SBMA are more unlikely to arise from long-normal CAG alleles than for HD. However, since divergence of CAG repeat distribution with (GGC)16 in the control chromosomes was significantly wider than that with other GGC haplotypes (F test, F = 0.57, P <0.05) (Table 1 ), it is possible that Japanese SBMA mutation could have arisen more than once on (GGC)16 background. The (GGC)17 allele is common in control Caucasian subjects [32% (13 ) or 42% (12 )], whereas it was rare (1%) in Japanese control subjects. Nonetheless there is no evidence that SBMA is more prevalent in the Caucasian than in the Japanese population. Japanese SBMA with (GGC)17 could have been introduced from Caucasian ancestry, although there is no evidence to support such a view.

Based on this evidence, a founder effect may make a more significant contribution to linkage disequilibrium in (CAG)n-(GGC)n haplotypes in Japanese SBMA subjects than new mutations.

In the original report of (CAG)n expansion in SBMA, there was no evidence of allelic association with a nearby restriction endonuclease polymorphism in an ethnically diverse population (11 ). Later, an absence of linkage disequilibrium between SBMA and the (GGC)n repeat was reported in ethnically mixed subjects (24 ). In ethnically mixed control chromosomes, in contrast to Japanese ones, there are two main alleles at 16 and 17 copies of GGC, which amount to about 90% of all control chromosomes (24 ). Similar results in Caucasian normal subjects were obtained (12 ,13 ). This (GGC)n size distribution in normal Caucasian subjects could have masked linkage disequilibrium between SBMA and (GGC)n and account for the different results.

Our results, demonstrating a founder effect for SBMA in a Japanese population, indicates that de novo pathological expansion is probably rarer than in other triplet repeat diseases, despite instability in normal and mutant chromosomes.

MATERIALS AND METHODS

The Japanese control and SBMA subjects were drawn from widely dispersed geographical areas of Japan.

For determining the GGC repeat sizes by polymerase chain reaction (PCR), we used previously described methods (12 ,13 ) with some modifications: the reaction volumes were 10 [mu]l containing ~150 ng of purified genomic DNA, 0.4 [mu]M of each fluorescein-labeled primer flanking the GGC repeat in exon 1 of the AR gene (5'-ACACTCTCTTCACAGCCGA-3') and ( 5'-ACTGGGATAGGGCACT CTGCT-3'), 1 * PCR buffer (50 mM KCl, 10 mM Tris-HCl (pH 8.3), 1.5 mM MgCl2), 200 [mu]M dATP, dCTP and dTTP, 50 [mu]M dGTP, 150 [mu]M 7-deaza dGTP and 0.1 U of Taq polymerase (Takara, Japan). The Taq polymerase was added to the PCR reactions after the genomic DNA had denatured at 95oC for 5 min; PCR conditions were 35 cycles of denaturation at 95oC for 1 min, annealing at 60oC for 1 min, and elongation at 72oC for 1 min, with a final extension of 7 min. The PCR products were analyzed by electrophoresis in 6% HydroLink LongRanger gels (AT Biochem, PA, USA) with an autoread sequencer (ALFred, Pharmacia, Sweden). Their sizes were determined by comparison to M13 DNA dideoxy sequencing ladders. The size of (CAG)n was determined in SBMA subjects and controls as previously described (25 ).

The size of (GGC)n was analyzed for association with the SBMA mutation using a [chi]2 test. In addition, to examine the association between CAG and GGC size, Kruskal-Wallis test was used among controls and Mann-Whitney U test was used among SBMA subjects. The distribution variance of CAG repeat size among controls was analyzed using an F test.

ACKNOWLEDGEMENTS

Part of this work was supported by grants from the Ministry of Welfare and Health of Japan, the Uehara Memorial Research Foundation, the Muscular Dystrophy Association and the National Institutes of Health.

REFERENCES

1 Yamagata, H., Miki, T., Ogihara, T., Nakagawa, M., Higuchi, I., Osame, M., Shelbourne, P., Davies, J. and Johnson, K. (1992) Expansion of unstable DNA region in Japanese myotonic dystrophy patients. Lancet, 339, 692. MEDLINE Abstract

2 Richards, R.I., Holman, K., Friend, K., Kremer, E., Hillen, D., Staples, A., Brown, W.T., Goonewardena, P., Tarleton, J., Schwartz, C. and Sutherland, G.R. (1992) Evidence of founder chromosomes in fragile X syndrome. Nature Genet., 1, 257-260. MEDLINE Abstract

3 Zhong N, Ye L, Dobkin C, and Brown, W. (1994) Fragile X founder chromosome effects: linkage disequilibrium or microsatellite heterogeneity? Am. J. Med. Genet., 51, 405-411.

4 Lunkes, A., Goldfarb, L.G., Platonov, F.A., Alexeev, V.P., Duenas-Barajas, E., Gajdusek, D.C. and Auburger, G. (1994) Autosomal dominant spinocerebellar ataxia (SCA) in a Siberian founder population: assignment to the SCA1 locus. Exp. Neurol., 126, 310-312. MEDLINE Abstract

5 Takiyama, Y., Igarashi, S., Rogaeva, E.A., Endo, K., Rogaev, E.I., Tanaka, H., Sherrington, R., Sanpei, K., Liang, Y., Saito, M., Tsuda, T., Takano, H., Ikeda, M., Lin, C., Chi, H., Kennedy, J.L., Lang, A.E., Wherrett, J.R., Segawa, M., Nomura, Y., Yuasa, T., Weissenbach, J., Yoshida, M., Nishizawa, M., Kidd, K.K., Tsuji, S. and St George-Hyslop, P.H. (1995) Evidence for inter-generational instability in the CAG repeat in the MJD1 gene and for conserved haplotypes at flanking markers amongst Japanese and Caucasian subjects with Machado-Joseph disease. Hum. Mol. Genet., 4, 1137-1146. MEDLINE Abstract

6 MacDonald, M.E., Novelletto, A., Lin, C., Tagle, D., Barnes, G., Bates, G., Taylor, S., Allitto, B., Altherr, M., Myers, R., Lehrach, H., Collins, F.S., Wasmuth, J.J., Frontali, M. and Gusella, J.F. (1992) The Huntington's disease candidate region exhibits many different haplotypes. Nature Genet., 1, 99-103. MEDLINE Abstract

7 Almqvist, E., Spence, N., Nichol, K., Andrew, S.E., Vesa, J., Peltonen, L., Anvret, M., Goto, J., Kanazawa, I., Goldberg, Y.P. and Hayden, M.R. (1995) Ancestral differences in the distribution of the [Delta] 2642 glutamic acid polymorphism is associated with varying CAG repeat lengths on normal chromosomes: insights into the genetic evolution of Huntington disease. Hum. Mol. Genet., 4, 207-214. MEDLINE Abstract

8 Rubinsztein, D.C., Leggo, J., Goodburn, S., Barton, D.E. and Ferguson-Smith, M.A. (1995) Haplotype analysis of the [Delta] 2642 and (CAG)n polymorphisms in the Huntington's disease (HD) gene provides an explanation for an apparent `founder' HD haplotype. Hum. Mol. Genet., 4, 203-206. MEDLINE Abstract

9 Squitieri, F., Andrew, S.E., Goldberg, Y.P., Kremer, B., Spence, N., Zeisler, J., Nichol, K., Theilmann, J., Greenberg, J., Goto, J., Kanazawa, I., Vesa, J., Peltonen, L., Almqvist, E., Anvret, M., Telenius, H., Lin, B., Napolitano, G., Morgan, K. and Hayden, M.R. (1994) DNA haplotype analysis of Huntington disease reveals clues to the origins and mechanisms of CAG expansion and reasons for geographic variations of prevalence. Hum. Mol. Genet. 3, 2103-2114. MEDLINE Abstract

10 Yanagisawa, H., Fujii, K., Nagafuchi, S., Nakahori, Y., Nakagome, Y., Akane, A., Nakamura, M., Sano, A., Komure, O., Kondo, I., Jin, D.K., Sørensen, S.A., Potter, N.T., Young, S.R., Nakamura, K., Nukina, N., Nagao, Y., Tadokoro, K., Okuyama, T., Miyashita, T., Inoue, T., Kanazawa, I. and Yamada, M. (1996) A unique origin and multistep process for the generation of expanded DRPLA triplet repeats. Hum. Mol. Genet., 5, 373-379. MEDLINE Abstract

11 La Spada, A.R., Wilson, E.M., Lubahn, D.B., Harding, A.E. and Fischbeck, K.H. (1991) Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature, 352, 77-79. MEDLINE Abstract

12 Sleddens H.F., Oostra B.A., Brinkmann A.O. and Trapman, J. (1993) Trinucleotide (GGN) repeat polymorphism in the androgen receptor (AR) gene. Hum. Mol. Genet., 2, 493. MEDLINE Abstract

13 Irvine, R.A., Yu, M.C., Ross, R.K. and Coetzee, G.A. (1995) The CAG and GGC microsatellites of the androgen receptor gene are in linkage disequilibrium in men with prostate cancer. Cancer Res., 55, 1937-1940. MEDLINE Abstract

14 La Spada, A.R., Roling, D.B., Harding, A.E., Warner, C.L., Spiegel, R., Hausmanowa-Petrusewicz, I., Yee W. C and Fischbeck, K.H. (1992) Meiotic stability and genotype-phenotype correlation of trinucleotide repeat in X-linked spinal and bulbar mucular atrophy. Nature Genet., 2, 301-304. MEDLINE Abstract

15 La Spada, A.R., Paulson, H.L. and Fischbeck, K.H. (1994) Trinucleotide repeat expansion in neurological disease. Ann. Neurol., 36, 814-822. MEDLINE Abstract

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

17 Maruyama, H., Nakamura, S., Matsuyama, Z., Sakai, T., Doyu, M., Sobue, G., Seto, M., Tsujihata, M., Ooi, N., Nishio, T., Takahashi, R., Hayashi, M., Nishio, I., Ohtake, T., Oda, T., Nishimura, M., Saida, T., Matsumoto, H., Baba, M., Kawaguchi, Y., Kakizuka, A. and Kawakami, H. (1995) The molecular growth of the CAG trinucleotide repeats and clinical features of Machado-Joseph disease. Hum. Mol. Genet., 4, 807-812. MEDLINE Abstract

18 Tanaka, F., Sobue, G., Doyu, M., Ito, Y., Yamamoto, M., Shimada, N., Yamamoto, K., Riku, S., Hashizume, Y. and Mitsuma, T. (1996) Differential pattern in tissue-specific somatic mosaicism of expanded CAG trinucleotide repeat in dentatorubural-pallidoluysian atrophy (DRPLA), Machado-Joseph disease (MJD) and X-linked recessive spinal and bulbar muscular atrophy (SBMA). J. Neurol. Sci., 135, 43-50. MEDLINE Abstract

19 Macke, J.P., Hu, N., Hu, S., Bailey, M., King, V.L., Brown, T., Hamer, D. and Nathans, J. (1993) Sequence variation in the androgen receptor gene is not a common determinant of male sexual orientation. Am. J. Hum. Genet., 53, 844-852. MEDLINE Abstract

20 Zhang, L., Leeflang, E.P., Yu, J. and Arnheim, N. (1994) Studying human mutations by sperm typing: instability of CAG trinucleotide repeats in the human androgen receptor gene. Nature Genet. 7, 531-535. MEDLINE Abstract

21 Zhang, L., Fischbeck, K.H. and Arnheim, N. (1995) CAG repeat length variation in sperm from a patient with Kennedy's disease. Hum. Mol. Genet. 4, 303-305. MEDLINE Abstract

22 Shimada, N., Sobue, G., Doyu, M., Yamamoto, K., Yasuda, T., Mukai, E., Kachi, T. and Mitsuma, T. (1995) X-linked recessive bulbospinal neuropathy: clinical phenotypes and CAG repeat size in androgen receptor gene analysis of 95 Japanese patients. Muscle & Nerve, 18, 1378-1384. MEDLINE Abstract

23 Leeflang, E.P., Zhang, L., Tavaré, S., Hubert, R., Srinidhi, J., MacDonald, M.E., Myers, R.H., Young, M., Wexler, N.S., Gusella, J.F. and Arnheim, N. (1995) Single sperm analysis of the trinucleotide repeats in the Huntington's disease gene: quantification of the mutation frequency spectrum. Hum. Mol. Genet., 4, 1519-1526. MEDLINE Abstract

24 La Spada, A.R., Fischbeck, K.H. and Richards, R.I. (1993) Absence of allelic association in X-linked spinal and bulbar muscular atrophy (abstract). Am. J. Hum. Genet., 53 (suppl), 823.

25 Doyu, M., Sobue, G., Mukai, E., Kachi, T., Yasuda, T., Mitsuma, T. and Takahashi, A. (1992) Severity of X-linked recessive bulbospinal neuronopathy correlates with size of tandem CAG repeat in androgen receptor gene. Ann. Neurol., 32, 707-710. MEDLINE Abstract

*To whom correspondence should be addressed

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H. Adachi, M. Katsuno, M. Minamiyama, M. Waza, C. Sang, Y. Nakagomi, Y. Kobayashi, F. Tanaka, M. Doyu, A. Inukai, et al.
Widespread nuclear and cytoplasmic accumulation of mutant androgen receptor in SBMA patients
Brain, March 1, 2005; 128(3): 659 - 670.
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 Hum Mol GenetHome page
M. Minamiyama, M. Katsuno, H. Adachi, M. Waza, C. Sang, Y. Kobayashi, F. Tanaka, M. Doyu, A. Inukai, and G. Sobue
Sodium butyrate ameliorates phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy
Hum. Mol. Genet., June 1, 2004; 13(11): 1183 - 1192.
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H. Adachi, M. Katsuno, M. Minamiyama, C. Sang, G. Pagoulatos, C. Angelidis, M. Kusakabe, A. Yoshiki, Y. Kobayashi, M. Doyu, et al.
Heat Shock Protein 70 Chaperone Overexpression Ameliorates Phenotypes of the Spinal and Bulbar Muscular Atrophy Transgenic Mouse Model by Reducing Nuclear-Localized Mutant Androgen Receptor Protein
J. Neurosci., March 15, 2003; 23(6): 2203 - 2211.
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 Hum Mol GenetHome page
R. I. Richards
Dynamic mutations: a decade of unstable expanded repeats in human genetic disease
Hum. Mol. Genet., October 1, 2001; 10(20): 2187 - 2194.
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 Am. J. Pathol.Home page
M. Li, Y. Nakagomi, Y. Kobayashi, D. E. Merry, F. Tanaka, M. Doyu, T. Mitsuma, Y. Hashizume, K. H. Fischbeck, and G. Sobue
Nonneural Nuclear Inclusions of Androgen Receptor Protein in Spinal and Bulbar Muscular Atrophy
Am. J. Pathol., September 1, 1998; 153(3): 695 - 701.
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 GeneticsHome page
A. Di Rienzo, P. Donnelly, C. Toomajian, B. Sisk, A. Hill, M. L. Petzl-Erler, G. K. Haines, and D. H. Barch
Heterogeneity of Microsatellite Mutations Within and Between Loci, and Implications for Human Demographic Histories
Genetics, March 1, 1998; 148(3): 1269 - 1284.
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