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
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 repeatsPornprot Limprasert1, Nassim Nouri1, Rock A. Heyman5, Chamnong Nopparatana6, Mahatana Kamonsilp7, Prescott L. Deininger2-4 and Bronya J. B. Keats1,3,4,*
1Department of Biometry and Genetics, 2Department of Biochemistry and Molecular Biology, 3Center for Molecular and Human Genetics, 4Stanley S. Scott Cancer Center, Louisiana State University Medical Center, 1901 Perdido Street, New Orleans, Louisiana 70112, USA, 5Department of Neurology, Pittsburgh University School of Medicine, 325 Scaife Hall, Pittsburgh, PA 15261, USA, 6Department of Pathology, Faculty of Medicine, Prince of Songkla University, Had Yai, Songkla 90112, Thailand and7Department of Pathology, Phamongkutklao Hospital, Bangkok 10400, Thailand
Received September 12, 1995;Revised and Accepted November 8, 1995
Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder associated with an unstable and expanded CAG repeat. We analyzed this locus from various sources including MJD families, Acadian, African American, Caucasian, Greenland Inuit and Thai populations. The range of the CAG repeat size was 14-40 in the normal alleles while the MJD alleles contained 73-78 repeats in our studies. We found 25 different alleles on normal chromosomes with a heterozygosity of 0.86 in combined populations. The most common alleles were 23 (22.9%) and 14 (25.5%) repeats. We also examined 16 chimpanzees and various Old World monkeys: a pigtail macaque, a mangabey and 12 rhesus macaques. The DNA sequences surrounding the CAG repeat did not vary among species. The range of the number of the CAG repeats is 13-14 in macaques, 16 in mangabey and 14-20 in chimpanzees. Variant CAA or AAG triplets in the CAG repeat tracts were found in all 268 human, 28 monkey and 32 chimpanzee chromosomes. As reported in a previous study [Kawaguchi et al. (1994) Nature Genet. 8, 221-228] the common variant positions were the third (CAA), fourth (AAG) and sixth (CAA) positions. However, we found three human chromosomes containing CAG at the sixth position and the mangabey had AAG at the ninth position. In addition, we found CAG at the fourth position and AAG at the sixth position in all macaque chromosomes. The nucleotide following the CAG repeat tract was usually G in all species studied. However, we sometimes found C at this position in human and chimpanzee chromosomes. Interestingly, this variant C was found in all expanded chromosomes and in 54.5% of chromosomes with 27-40 CAG repeats but it was not found in any chromosomes with less than 20 CAG repeats. We hypothesize that the variant C may be associated with CAG repeat instability.
Machado-Joseph disease (MJD) is one of the late-onset auto- somal dominant spinocerebellar ataxias. It was first described in Azorean-Portuguese families (1 -5 ) but many patients from different ethnic backgrounds have now been reported (6 -11 ). The MJD clinical features include: cerebellar ataxia, spasticity, dystonia, ophthalmoplegia, sensory loss, muscle atrophy and faciolingual fasciculation. These clinical features present with variable degrees of severity in members of the same family and at different times during the illness (12 ,13 ).
The MJD locus (MJD1) was mapped to 14q24.3-q32 (14 ), which is the same region that contains the spinocerebellar ataxia type 3 locus, SCA3 (15 ). Kawaguchi et al. (16 ) identified a novel gene that contains CAG repeats and maps to the MJD region. The range for normal chromosomes was 13-36 repeats while MJD chromosomes contained 68-79 repeats. Likewise, Maciel et al. (17 ) reported that normal chromosomes contain 12-37 repeats, whereas MJD chromosomes contain 62-84 repeats. Recently, CAG repeat expansion in the MJD1 gene was reported in German SCA3 patients demonstrating identical mutations in SCA3 and MJD (18 ). The expansion contains variations in the CAG repeat tracts at three positions: CAA and AAG are found at the third and fourth positions, respectively and another CAA variant is present at the sixth position. Furthermore, either cytosine or guanine is found at the end of the CAG repeat tracts (16 ). An inverse correlation between age of onset and CAG repeat numbers has been reported (16 -20 ). Also, male MJD patients tend to develop symptoms earlier than their affected sisters even though they have the same number of CAG repeats (21 ) and the increase in the size of the MJD alleles tends to be greater between affected fathers and affected offspring than between affected mothers and affected offspring (17 ,19 ,20 ).
MJD is one of the eight disorders known to be caused by expansion of a trinucleotide repeat. The other disorders include fragile X syndrome (FRAXA and FRAXE), myotonic dystrophy (DM), spinal bulbar muscular atrophy (SBMA), Huntington disease (HD), spinocerebellar ataxia type 1 (SCA1) and dentatorubral pallidoluysian atrophy (DRPLA) (22 ). The MJD mutation is a polymorphic CAG repeat in the 5' end of the coding region. Studies have been performed in Japanese (16 ,19 ,20 ), Portuguese Azorean and their descendants (17 ,20 ), Brazilian (17 ), German (18 ,23 ), French (23 ,24 ) and African American (23 ) families since thegene has been cloned. In this paper, we report results on patients from one Caucasian and two Thai families and unaffected members of five populations comprising African American, Caucasian, French-Acadian, Greenland Inuit and Thai. We also present the results of our investigations of the CAG repeat region in mangabey and macaque monkeys and chimpanzees.
We performed PCR to determine if the CAG repeat expansion occurred at the MJD1 locus in 40 patients from 12 families. All patients had been clinically diagnosed with autosomal dominant spinocerebellar ataxia (SCA). Nine patients in three of these families (one Caucasian and two Thai families) were found to contain the CAG repeat expansion at the MJD1 locus with a CAG repeat range of 73-78 (Fig. 1 ). Based on available clinical records, several of the Caucasian patients had prominent eyes and faciolingual fasiculations suggesting MJD. In contrast, the Thai patients did not have these clinical features. The age of onset of ataxia varied from 32 years (78 repeats, not shown in Fig. 1 ) to 45 years (74 repeats, No. 8 Fig. 1 ). A 23 year old Caucasian patient (76 repeats, No. 6 Fig. 1 ) does not yet have ataxia but she has nystagmus and hyperreflexia in her lower extremities.
Seven hundred and forty-two unrelated chromosomes from five populations were analyzed. These populations were Caucasian, French-Acadian, African American, Greenland Inuit and Thai. For estimation of the CAG repeat size, we included all variant triplets in our studies. We found 25 different alleles ranging from 14 to 40 CAG repeats. The heterozygosity was 0.86 in the combined population. Not surprisingly, the CAG repeat distributions showed no statistically significant difference between the Acadian and Caucasian populations ([chi]2 = 3.13, degree of freedom = 4, P value = 0.54). However, the distributions in the African Americans, Greenland Inuits and Thais were significantly different from the Caucasians and also from one another (P value < 0.05). The two most common alleles were 14 and 23 repeats with frequencies of 25.5% and 22.9%, respectively. The CAG repeat distributions showed three distinct peaks at 14, 23 and around 27-28 repeats (Table 1 ). The numbers of alleles varied from population to population ranging from 10 alleles with heterozygosity of 0.86 in the Greenland Inuit population to 21 alleles with heterozygosity of 0.91 in the African American population. Only 6.5% of the chromosomes had more than 30 repeats. The allelic frequencies, numbers of alleles and hetero- zygosities in the human populations are shown in Table 1 .
To determine if the normal chromosome is susceptible to intergenerational instability, we examined 60 families. Normal sized CAG repeats were faithfully transmitted from parents to offspring without any alteration in CAG repeat number in 390 meioses. However, transmission of the CAG repeat from affected parent to offspring was associated with some degree of instability (Fig. 1 ).
We used the same primers from the human studies to amplify DNA from various Old World monkeys (a pigtail macaque, a mangabey, 12 rhesus macaques) and 16 chimpanzees. DNA sequences surrounding CAG repeats were highly conserved between human and other species. The numbers of CAG repeats were 13 and 14 in macaques, 16 in mangabey and 14-20 in chimpanzees. The percentages of each CAG repeat size in macaque and chimpanzee chromosomes are compared with those in Caucasian chromosomes in Figure 2 . To identify CAG repeat variation, we sequenced 268 human (259 unrelated and nine expanded chromosomes), 32 chimpanzee and 28 monkey chromosomes. We found CAA or AAG variant triplets in the CAG repeat tracts in all species including the human expanded chromosomes. The common pattern was CAA at the third and sixth position and AAG at the fourth position in mangabey, chimpanzee and human chromosomes. However, we found two Thai (19 repeats) and one Caucasian (22 repeats) chromosomes containing a CAG repeat at the sixth position and we found AAG at the ninth position in the mangabey. In addition we found CAA at the third position, CAG at the fourth and AAG at the sixth position in all macaque chromosomes. Figure 3 shows the observed DNA sequences in human, chimpanzee, mangabey and macaque chromosomes.
The nucleotide following the CAG repeat tract is usually guanine in all species. However, cytosine is sometimes found at this position in human chromosomes and we found cytosine in at least two of the chimpanzee chromosomes with 20 repeats. The presence of a cytosine at this position is associated with the numbers of CAG repeats (Table 2 ). For the two common allele sizes, 14 and 23, we found no cytosine of 61 chromosomes and 1 (Thai) of 66 chromosomes, respectively. In addition, all chromosomes with 15-19 and 24-26 repeats contained guanine, as did 13 of 14 chromosomes with 22 repeats (the one chromosome with cytosine was Caucasian). In contrast, cytosine was found in 20 of 22 chromosomes with 20 and 21 repeats. All such Acadian and Caucasian chromosomes had cytosine; the two chromosomes with guanine were both Thai chromosomes. Cytosine was found on all expanded chromosomes and 42 of 77 (54.5%) chromosomes with 27-40 repeats contained cytosine. Of these, 18 of 19 were Thai, seven of seven were Inuit, seven of 14 were Caucasian, four of 17 were African American and six of 20 were Acadian chromosomes. Interestingly, only one of the African American alleles had 20 or 21 repeats and the percentage of 27-40 repeat alleles with cytosine was lowest in this population.
Numbers of chromosomes (frequencies) of each CAG repeat size at the MJD1 locus in human populations
CAG
Acadian
Black
Caucasian
Inuit
Thai
Combined
14
62 (0.261)
14 (0.135)
46 (0.235)
10 (0.192)
57 (0.375)
189 (0.255)
15
0
0
1 (0.005)
0
0
1 (0.001)
16
0
0
0
0
0
0
17
0
0
0
0
0
0
18
1 (0.004)
1 (0.010)
0
0
2 (0.013)
4 (0.005)
19
0
4 (0.038)
1 (0.005)
0
7 (0.046)
12 (0.016)
20
14 (0.059)
0
12 (0.061)
5 (0.096)
1 (0.007)
32 (0.043)
21
21 (0.088)
1 (0.010)
18 (0.092)
1 (0.019)
8 (0.052)
49 (0.066)
22
3 (0.013)
17 (0.164)
11 (0.056)
0
0
31 (0.042)
23
73 (0.307)
13 (0.125)
53 (0.271)
6 (0.116)
25 (0.164)
170 (0.229)
24
12 (0.050)
10 (0.096)
8 (0.041)
0
2 (0.013)
32 (0.043)
25
1 (0.004)
3 (0.029)
0
0
2 (0.013)
6 (0.008)
26
2 (0.008)
1 (0.010)
3 (0.015)
8 (0.154)
1 (0.007)
15 (0.020)
27
19 (0.080)
5 (0.048)
26 (0.133)
9 (0.173)
17 (0.112)
76 (0.103)
28
11 (0.046)
4 (0.038)
9 (0.046)
7 (0.135)
11 (0.072)
42 (0.057)
29
7 (0.030)
4 (0.038)
1 (0.005)
0
9 (0.059)
21 (0.028)
30
3 (0.013)
7 (0.067)
3 (0.015)
1 (0.019)
0
14 (0.019)
31
2 (0.008)
4 (0.038)
2 (0.010)
4 (0.077)
1 (0.007)
13 (0.018)
32
1 (0.004)
2 (0.019)
0
0
1 (0.007)
4 (0.005)
33
4 (0.017)
4 (0.038)
0
1 (0.019)
1 (0.007)
10 (0.014)
34
1 (0.004)
5 (0.048)
1 (0.005)
0
0
7 (0.010)
35
0
1 (0.010)
0
0
4 (0.026)
5 (0.007)
36
1 (0.004)
1 (0.010)
0
0
2 (0.013)
4 (0.005)
37
0
1 (0.010)
0
0
0
1 (0.001)
38
0
2 (0.019)
0
0
0
2 (0.003)
39
0
0
0
0
1 (0.007)
1 (0.001)
40
0
0
1 (0.005)
0
0
1 (0.001)
Total
238
104
196
52
152
742
No. of alleles
18
21
16
10
18
25
Het
0.81
0.91
0.83
0.86
0.80
0.86
There was no statistically significant difference in the distributions of CAG repeat between Acadians and Caucasians ([chi]2 = 3.13, df = 4, p-value = 0.54). All other comparisons were different at the 5% significance level.
CAG repeat numbers and the variant cytosine in 268 human chromosomesa
CAG repeat numbers
Numbers of chromosome studied
TotalPercentage
(numbers of variant cytosine)
(numbers of variant cytosine)of variant cytosine
Acadian
Black
Caucasian
Inuit
Thai
14
25
4
20
0
12
61 (0)
0
15-19
1
2
1
0
3
7 (0)
0
20b
5 (5)
0
4 (4)
1 (1)
1
11 (10)
90.9
21
7 (7)
0
2 (2)
0
2 (1)
11 (10)
90.9
22
0
9
5 (1)
0
0
14 (1)
7.1
23
29
9
16
2
10 (1)
66 (1)
1.5
24-26
5
2
1
3
1
12 (0)
0
27
6
1
3 (3)
3 (3)
1 (1)
14 (7)
50.0
28-30
9 (4)
4 (1)
8 (2)
2 (2)
9 (8)
32 (17)
53.1
31-35
4 (2)
9 (2)
2 (1)
2 (2)
6 (6)
23 (13)
56.5
36-40
1
3 (1)
1 (1)
0
3 (3)
8 (5)
62.5
Total
92 (18)
43 (4)
63 (14)
13 (8)
48 (20)
259 (64)
24.7
Expanded (73-78)
0
0
5 (5)
0
4 (4)
9 (9)
100
a259 unrelated normal chromosomes, nine expanded chromosomes from three families.bWe also found variant cytosine in at least two chimpanzee chromosomes.
This study included 40 SCA patients from 12 families as well as 371 unrelated individuals comprising 119 French-Acadians from south-western Louisiana, 52 African Americans, 93 Caucasians, 26 Greenland Inuits and 76 Thais. Meiotic stability was studied in 37 Acadian and 23 Caucasian families. Genomic DNA from 14 monkeys (a pigtail macaque, a mangabey, 12 rhesus macaque) and 16 chimpanzees were included in our studies. Rhesus macaques were randomly selected from the Delta Regional Primate Center, Covington, Louisiana. Chimpanzee samples were from unrelated or distantly related individuals at the Southwest Foundation for Biomedical Research in San Antonio, Texas.
Genomic DNA was isolated from blood leukocytes following a standard phenol/chloroform protocol. To identify CAG repeats, we used MJD52/MJD70 primers described by Kawaguchi et al. (16 ). The 8 µl PCR mixture included 80 ng of genomic DNA, 5 mM MgCl2, 200 µM dNTPs, 13 ng of the MJD70 and 1.3 ng of the MJD52, end labeled with [[gamma]-32P]dATP and 0.25 unit of Taq enzyme. A final concentration of 2% formamide was added to the PCR reaction. Samples were denatured at 94oC for 5 min followed by 30 cycles of denaturation (94oC, 1 min), annealing [(55oC for human; 45oC for monkey), 1 min] extension (72oC, 1 min) and a final extension of 5 min at 72oC in a Perkin-Elmer GeneAmp Thermal Cycler 9600. The PCR product was electrophoresed on a 5% denaturing polyacrylamide sequencing gel for 3 h. The DNA fragments were visualized by autoradiography using X-ray film (Kodak). Allele sizes were estimated relative to a DNA sequencing ladder. We included the AAG and two CAA variant triplets in determining the number of CAG repeats.
The PCR mixture was amplified using the MJD52 and PN2 (5'-ATGTCAGATAAAGTGTGAAG-3') primers under the same conditions as above except that 26 ng of each primer was used and the annealing temperature was 52oC for the human samples. The PCR products were electrophoresed on a 2% low melting temperature agarose gel and bands were excised. The DNA was purified from the gel using the Geneclean Spin (BIO101 Inc.) protocol. The purified PCR products were reamplified using biotinylated MJD52 and normal PN2. The PCR products were bound to 100 µg of streptavidin coated magnetic beads (Dynabeads M280) and processed as described by the Dynal Inc. manual protocol. 10 µl of 0.1 M NaOH was used to denature the DNA and the non-biotinylated single strand DNA was neutralized with HCl and Tris-HCl pH 7.5. We used the sequenase 7-deaza dGTP sequencing kit (USB) protocol. MJD70 and PN3 (5'-ACAATGTATTTTCCTTATGA-3') were used as internal primers for sequencing the biotinylated (solid stage) and non-biotinylated strands (non-solid stage), respectively. The sequencing products were separated on a 5% polyacrylamide gel and exposed to Biomax film (Kodak).
We used the programs PIC (to calculate heterozygosities) and CONTING (to test for significant differences among CAG repeat distributions) in the LINKAGE UTILITY computer package described by Ott (37 ). For the analysis, we divided CAG repeats into five groups: 14-19, 20-21, 22-23, 24-27 and 28-40. We compared each pair of populations and determined whether statistically significant or non-significant differences occurred at a P value of 0.05.
We would like to thank the families participating in this study. We are grateful to Drs James E. Hixson and Shelley A. Cole for providing chimpanzee DNA, Dr Vicki Traina-Dorge for providing monkey DNA and Drs Henning Pedersen, Gert Mulvad, Elisabeth Jul, William D. Scheer, Joan E. Bailey-Wilson and Mary Z. Pelias for providing some of the human samples. Part of this work was supported by grants from the National Ataxia Foundation, Grant No. HL-42082 from the National Heart, Lung and Blood Institute, NIH and the Foundation Fighting Blindness.
1 Nakano, K.K., Dawson, D.M. and Spence, A. (1972) Machado disease: A hereditary ataxia in Portuguese emigrants to Massachusetts. Neurology,22, 49-55.MEDLINE Abstract
2 Woods, B.T. and Schaumburg, H.H. (1972) Nigro-spino-dentatal degeneration with nuclear ophthalmoplegia: A unique and partially treatable clinico-pathological entity. J. Neurol. Sci., 17, 149-166.MEDLINE Abstract
3 Rosenberg, R.N., Nyhan, W.L., Bay, C. and Shore, P. (1976) Autosomal dominant striatonigral degeneration. A clinical, pathologic and biochemical study of a new genetic disorder. Neurology, 26, 703-714.MEDLINE Abstract
4 Romanul, F.C.A., Lowler, H.L., Radvany, J., Feldman, R.G. and Feingold, M. (1977) Azorean disease of the nervous system. N. Engl. J. Med., 296, 1505-1508.
5 Coutinho, P. and Andrade, C. (1978) Autosomal dominant system degeneration in Portuguese families of the Azores islands. Neurology, 28, 703-709.MEDLINE Abstract
6 Lima, L. and Coutinho, C. (1980) Clinical criteria for diagnosis of Machado-Joseph disease: Report of a non-Azorean Portuguese family. Neurology, 30, 319-322.MEDLINE Abstract
7 Healton, E.B., Burst, J.C.M., Kerr, D.L. Resor, S. and Penn, A. (1980) Presumably Azorean disease in a presumably non-Portuguese family. Neurology, 30, 1084-1089.MEDLINE Abstract
8 Sakai, T., Ohta, M. and Ishino, H. (1983) Joseph disease in a non-Portuguese family. Neurology, 33, 74-80.MEDLINE Abstract
9 Livingstone, I.R. and Sequeiros, J. (1984) Machado-Joseph disease in an American-Italian family. J. Neurogenet.,1, 185-188.MEDLINE Abstract
10 Twist, F.C., Casaubon, L.K., Ruttledge, M.H., Rao, V.S., MacLeod, M., Radvany, J. Zhao, Z., Rosenberg, R.N., Ferrer, L.A. and Rouleau, G.A. (1995). Machado Joseph disease maps to the same region of chromosome 14 as the spinocerebellar ataxia type 3 locus. J. Med. Genet., 32, 25-31.
11 Burt, T., Blumbergo, P. and Currie, B. (1993) A dominant hereditary ataxia resembling Machado-Joseph disease in Arnhem Land Australia. Neurology,43, 1750-1752.MEDLINE Abstract
12 Barbeau, A., Roy, M., Cunha., L., de Vincete, A.N., Rosenberg, R.N., Nyhan, W.L., MacLeod, P.L., Chazot, G., Langston, L.B., Dawson., D.W. and Coutinho, P. (1984) The natural history of Machado-Joseph disease: An analysis of 138 personally examined cases. Can. J. Neurol. Sci., 11, 510-525.MEDLINE Abstract
13 Rosenberg, R.N. (1992) Machado-Joseph disease: An autosomal dominant motor system degeneration. Movement Dis., 7, 193-203.
14 Takiyama, Y., Nishizawa, M., Tanaka, H., Kawashima, S., Sakamoto, H., Karube, Y., Shimazaki, H., Soutome, M., Endo, K., Ohta, S., Kagawa, Y., Kanazawa, I., Mizuno, Y., Yoshioda, M., Yuasa, T., Horikawa, Y., Oyanagi, I., Nagai, H., Kondo, T., Inuzuka, T., Onodera, O. and Tsuji, S. (1993) The gene for Machado-Joseph disease maps to human chromosome 14q. Nature Genet., 4, 300-304.MEDLINE Abstract
15 Stevanin, G., Guern, E.L., Ravisé, N., Chneiweiss, H., Dürr, A., Cancel, G., Vignal, A., Boch, A.L., Ruberg, M., Penet, C., Pothin, Y., Lagroua, I., Haguenau, M., Raneurel, G., Weissenbach, J., Agid, Y. and Brice A. (1994) A third locus for autosomal dominant cerebellar ataxia type I maps to chromosome 14q24.3-qter: Evidence for the fourth locus. Am. J. Hum. Genet., 54, 11-20.MEDLINE Abstract
16 Kawaguchi, Y., Okamoto, T, Taniwaki, M., Aizawa, M., Inoue, M., Katayama, S., Kawakami, H., Nakamura, S., Nishimura, M., Akiguchi, I., Kimura, J., Narumiya, S. and Kakizuka, A. (1994) CAG repeat expansions in a novel gene for Machado-Joseeph disease at chromosome 14q32.1. Nature Genet., 8, 221-228.MEDLINE Abstract
17 Maciel, P., Gaspar, C., DeStefano, A.L., Silverira, I., Coutinho, P., Radvany, J., Dawson, D.M., Sudaraky, L., Guimaraes, J. Loureiro, J.E.L., Nezarati, M.M., Corwin, L.I., Lopes-Cendes, I., Rooke, K., Rosenberg, R., MacLeod, P., Farrer, L.A., Sequeiros, J. and Rouleau, G. A. (1995) Correlation between CAG repeat length and clinical features in Machado-Joseph disease. Am. J. Hum. Genet.57, 54-61.MEDLINE Abstract
18 Schöls, L., Vieira-Saecker, A.M.M., Schöls, S., Przuntek, H., Epplen, J. and Riess, O. (1995) Trinucleotide expansion within the MJD1 gene presents clinically as spinocerebellar ataxia and occurs most frequently in German SCA patients. Hum. Mol. Genet. 4, 1001-1005.MEDLINE Abstract
19 Maruyama, H., Nakamura, S., Matsuyama, Z., Sakai, T., Doyu, M., Sobue, G., Seto, M., Tsujihata, M., Oh-i, T., Nishio, T., Sunohara, N., Takahashi, R., Hayashi, M., Nishino, I., Ohtake, T., Oda, T., Nishimura, M., Saida, T., Matsumoto, H., Baba, M., Kawaguchi, Y., Kakizuka A. and Kawakami, H. (1995) Molecular features of the CAG repeats and clinical manifestation of Machado-Joseph disease. Hum. Mol. Genet., 4, 807-812.MEDLINE Abstract
20 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
21 Kawakami, H., Maruyama, H., Nakamura, S., Kawaguchi, Y., Kakizuka, A., Doyu, M. and Sobue, G. (1995) Unique features of the CAG repeats in Machado-Joseph disease. Nature Genet., 9, 344-345. MEDLINE Abstract
23 Ranum, L.P.W., Lundgren, J.K., Schut, L.J., Ahrens, M.J., Perlman, S., Aita J., Bird, T.D., Gomez, C., Orr, H.T. (1995) Spinocerebellar ataxia type I and Machado-Joseph disease: Incidence of CAG expansions among adult-onset ataxia patients from 311 families with dominant, recessive, or sporadic ataxia. Am. J. Hum. Genet.57, 603-608.
24 Cancel, G., Abbas, N., Stevanin, G., Dürr, A., Chneiweiss, H., Neri, C., Duychaerts, C., et al. (1995) Marked phenotypic heterogeneity associated with expansion of a CAG repeat sequence at the spinocerebellar ataxia 3/Machado-Joseph disease locus. Am. J. Hum. Genet., 57, 808-816.
25 Twells, R., Yenchitsomanus, P., Sirinavin, C., Allotey, R., Poungvarin, N., Viriyavejakul, A., Cemal, C., Weber, J., Farrall, M., Rodprasert, P., Prayoonwiwat, N., Williamson, R. and Chamberlain, S. (1994) Autosomal dominant cerebellar ataxia with dementia: Evidence for a fourth disease locus. Hum. Mol. Genet., 3, 177-180.MEDLINE Abstract
26 La Spada, A.R., Roling D.B., Harding, A.E., Warner, C.L., Spiegel, R., Hausmanowa-Petrusewicz, I., Yee, W. and Fischbeck, K.H. (1992) Meiotic stability and genotype-phenotype correlation of the trinucleotide repeat in X-linked spinal and bulbar muscular atrophy. Nature Genet., 2, 301-304.MEDLINE Abstract
27 Orr, H.T., Chung, M.Y., Banfi, S., Kwiatkowski Jr., T.J., Servadio, A., Beaudet, A. L., MacCall, A.E., Duvick, L.A., Ranum, L.P.W. and Zoghbi, H.Y. (1993) Expansion of an unstable trinucleotide repeat in spinocerebellar ataxia type 1. Nature Genet., 4, 221-226.MEDLINE Abstract
28 Goldfarb, L.G., Lunkes, A., Vasconcelos, O., Platonov, F.A., Nagle, J., Cervenakova, S.K., Kononwa, S.K., Penn, M., Aliprandis, E., Higgins, J.J., Vlsdimirtsev, V.A., Dubnick, M., Alexeev, V.P., Gajdusek, D.C. (1994) Mutation analysis of spinocerebellar ataxia type 1 (SCA1) in a large Iakut kinship of Eastern Siberia. Am. J. Hum. Genet., 55 (Suppl.), A221.
29 Duyao, M., Ambrose, C., Myers, R., Novelletto, A, Persichetti, F., Frontali, M., Folstein, S., Ross, C., Franz, M., Abbott, M, Gray, J., Conneally, P., Young, A., Penny, J, Hollingsworth, Z., Shoulson, I., Lazzarini, A., Falek, A., Koroshetz, W., Sax, D., Bird, E., Vonsattel, J., Romos, M., Scanchez-Ramos, J., Snodgrass, S., de Young, M., Wexler, N., Moscowitz, G., Penchaszadeh, G., MacFarlane, G., Anderson, M., Jenkins, B., Srinidni J., Barnes, G., Gusella, J. and MacDonald, M. (1993). Trinucleotide repeat length instability and age of onset in Huntington's disease. Nature Genet., 4, 387-392.MEDLINE Abstract
30 Koide, R., Ikeuchi, T., Onodera, O., Tanaka, H., Igarashi., S., Endo, K., Takahashi, H., Kondo, R., Ishikawa, A., Hayashi, T., Saito, M., Tomoda, A., Miike, T., Naita, H., Ikuta, F. and Tsuji, S. (1994) Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA). Nature Genet., 6, 9-13.MEDLINE Abstract
31 Nagafuchi, S., Yanagisawa, H., Sato, K., Shirayama, T., Ohsaki, E., Bundo, M., Takeda, T., Tadokoro, K., Kondo, I., Murayama, N., Tanaka, Y., Kikushima, H., Umino, K., Kurosawa, H., Furukawa, T., Nihei, K., Inoue, T., Sano, A., Komure, O., Tahahashi, M., Yoshizawa, T., Kanazawa, I. and Yamada, M. (1994) Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p. Nature Genet., 6, 14-18.MEDLINE Abstract
32 Limprasert, P., Nouri, N. and Keats, B.J.B. (1994) Meiotic stability and polymorphism of CAG repeat in normal chromosome at SCA1 locus. Am. J. Hum. Genet., 55 (Suppl.), A193.
33 Rubinsztein, D.C., Leggo, J., Coetzee, G.A., Irvine, R.A., Buckley, M., Ferguson-Smith, M.A. (1995) Sequence variation and size ranges of CAG repeats in the Machado-Joseph, spinocerebellar ataxia type1 and androgen receptor genes. Hum. Mol. Genet., 4, 1585-1590.MEDLINE Abstract
34 Kunst, C.B. and Warren, S.T. (1994) Cryptic and polar variation of the fragile X repeat could result in predisposing normal alleles. Cell, 77, 853-861.MEDLINE Abstract
35 Chung, M.Y., Ranum, L.P.W., Duvick, L.A. Servadio, A., Zoghbi, H.Y. and Orr, H.T. (1993) Evidence for a mechanism predisposing to intergenerational CAG repeat instability in spinocerebellar ataxia type 1. Nature Genet., 5, 254-258.MEDLINE Abstract
36 Gacy, M.A, Goellner, G., Juranic, N., Macura, S., McMurray, C.T. (1995) Trinucleotide repeats that expand in human disease form hairpin structures in vitro. Cell, 81, 533-540.
37 Ott, J. (1991) Analysis of human genetic linkage, revised edition. Baltimore: Johns Hopkins University Press.
*To whom correspondence should be addressed
This page is maintained by OUP admin. Last updated Thu Oct 31 15:21:55 GMT 1996. Part of the OUP Journals World Wide Web service.Copyright Oxford University Press, 1996
