SCA17 gene mapped to chromosome 6q27 are associated with schizophrenia

Schizophrenia Research 78 (2005) 131 – 136 www.elsevier.com/locate/schres

Expanded trinucleotide repeats in the TBP/SCA17 gene mapped to chromosome 6q27 are associated with schizophrenia Chiung-Mei Chen a, Hsien-Yuan Lane b,*, Yih-Ru Wu a, Long-Sun Ro a, Fen-Lin Chen c, Wei-Ling Hung c, Yi-Ting Hou c, Cheng-Yueh Lin c, Shu-Yi Huang c, I-Cheng Chen a, Bing-Wen Soong d, Ming-Liang Li c, Hsiu-Mei Hsieh-Li c, Ming-Tsan Su c, Guey-Jen Lee-Chen c,* a

Department of Neurology, Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Taipei 105, Taiwan b Department of Psychiatry, China Medical University Hospital, No. 2, Yuh-Der Road, Taichung 404, Taiwan c Department of Life Science, National Taiwan Normal University, 88 Ting-Chou Road, Section 4, Taipei 116, Taiwan d Neurological Institute, Taipei Veterans General Hospital and School of Medicine, National Yang-Ming University, Taipei 112, Taiwan Received 13 April 2005; received in revised form 21 June 2005; accepted 21 June 2005 Available online 1 August 2005

Abstract Schizophrenia has a complex and non-Mendelian mode of inheritance. Recently, trinucleotide repeat (TNR)-containing genes have been considered as the candidate genes predisposing to schizophrenia. The purpose of this study was to determine whether a genetic association could be observed between schizophrenia and the TNR polymorphisms within the KLHL1AS/ SCA8, PPP2R2B/SCA12, and TBP/SCA17 genes. We studied 100 unrelated schizophrenia patients and 124 controls without evident neurodegenerative or psychiatric disorders. The overall allele frequency distributions of the KLHL1AS/SCA8 and PPP2R2B/SCA12 genes were not significantly different between the schizophrenic patients and the control subjects ( P N 0.05). The allele frequency distribution in the schizophrenic patients was significantly different from that in the controls at the TBP/ SCA17 gene ( P = 0.0149), with an increased frequency of 36 repeats in the patients and two patients carrying 45 TNR expansions were identified. TBP/SCA17 is the TATA box binding protein gene mapped to chromosome 6q27. The study suggests that TNR expansions of the TBP/SCA17 gene may contribute to the genetic risk of schizophrenia in rare cases. D 2005 Elsevier B.V. All rights reserved. Keywords: Schizophrenia; KLHL1AS/SCA8; PPP2R2B/SCA12; TBP/SCA17; Trinucleotide repeats

* Corresponding authors. G.-J. Lee-Chen is to be contacted at Tel.: +886 2 29336875; fax: +886 2 29312904. H.-Y. Lane is to be contacted at Tel.: +886 4 22052121; fax: +886 4 22361042. E-mail addresses: [email protected] (H.-Y. Lane), [email protected] (G.-J. Lee-Chen). 0920-9964/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2005.06.018

132

C.-M. Chen et al. / Schizophrenia Research 78 (2005) 131–136

1. Introduction Schizophrenia is a debilitating psychiatric disorder that is believed to result from the interaction of environmental factors and a complex mode of inheritance. Several lines of evidence suggested that expansion of unstable trinucleotide repeats (TNR) may be associated with schizophrenia (Morris et al., 1995; O’Donovan et al., 1996). TNR expansion is known to cause a number of human diseases, including Huntington’s disease (HD) and spinocerebellar atrophy types 1, 2, 3, 6, 7, 8, 12, 17 (SCAs) (Cummings and Zoghbi, 2000). The SCAs are autosomal-dominant, progressive neurodegenerative disorders displaying clinical and genetic heterogeneity. In addition to progressive cerebellar ataxia, the SCAs may also exhibit dementia, psychiatric symptoms, pyramidal, parkinsonism, and other extrapyramidal features (Margolis et al., 1999; Stevanin et al., 2000). In fact, psychiatric symptoms are not rare in SCA12 (O’Hearn et al., 2001) and SCA17 (Fujigasaki et al., 2001a; De Michele et al., 2003; Maltecca et al., 2003; Rolfs et al., 2003; Bauer et al., 2004), and SCA8 expanded alleles can be found in psychiatric patients (Pato et al., 2000; Vincent et al., 2000). Furthermore, KLHL1AS/SCA8 (Koob et al., 1999), PPP2R2B/SCA12 (Holmes et al., 1999) and TBP/SCA17 (Koide et al., 1999) are ubiquitously expressed in the brain, making them excellent candidates for genes involved in schizophrenia. In order to examine the possibility that CAG/CTG repeats may contribute to the genetic etiology of schizophrenia, we analyzed TNR length in the KLHL1AS/SCA8, PPP2R2B/SCA12, and TBP/SCA17 genes of schizophrenia patients from the Taiwanese population.

made based on DSM-IV criteria (American Psychiatric Association, 1994). In addition, 124 unrelated subjects (69 males and 55 females, mean age: 36.4 F 10.0 years) from the health evaluation clinics, Chang Gung Memorial Hospital, Taiwan, were recruited as normal controls. The controls were interviewed by two neurologists (C.-M. Chen and Y.-R. Wu) to exclude any history of neurodegenerative or psychiatric disorders. Some of the controls had been used in the earlier published studies (Wu et al., 2004, 2005). The family members of the two patients with expanded CAG repeat alleles were interviewed by the psychiatrist, H.-Y. Lane. All examinations were performed after obtaining informed consent. 2.2. Genetic analysis DNA was extracted from peripheral blood leukocytes using a DNA extraction kit (Stratagene). Molecular analysis of the CAG/CTG repeats in the KLHL1AS/SCA8, PPP2R2B/SCA12 and TBP/SCA17 genes were performed by polymerase chain reaction (PCR) as previously described (Wu et al., 2004). 2.3. Statistical analysis Possible differences between the normal and patient groups in normal repeat frequency distributions were assessed using a non-parametric Mann–Whitney U-test. Allele frequencies at each locus were estimated by the gene count method. The statistical value of P b 0.0167 was considered significant after a Bonferroni correction.

3. Results

2. Materials and methods

3.1. Frequency distributions of the TNR repeat length

2.1. Subjects

Fig. 1 shows the allele frequency distributions of the CAG/CTG repeat lengths at the SCA8, 12 and 17 loci in 100 schizophrenia patients and 124 controls. The summary of heterozygosity, allele ranges and most common allele sizes can be found in Table 1. The overall allele frequency distributions of SCA8 and SCA12 loci in the patients were not significantly different from those in the controls ( P = 0.0636 and 0.2328, respectively) and no SCA8 and SCA12 TNR expansion was found in either group. Two TBP/SCA17

A hundred unrelated schizophrenia patients (56 males and 44 females, mean age: 34.6 F 9.9 years, age at onset: 24.6 F 7.4 years), all ethnic Chinese, were recruited from the psychiatry clinics, China Medical University Hospital, Taiwan for investigation. The clinical diagnosis of schizophrenia was

C.-M. Chen et al. / Schizophrenia Research 78 (2005) 131–136 0.3 SCA8

0.7 SCA17

0.2

0.6

Frequency

0.1

0.5

16

0.3

133

24

26

34

0.4

36

0.3

SCA12

0.2

0.2

0.1

0.1

schizophrenia (2)

4

14

22

24

26

28

28

No. of repeat units

30 32

34

36 38

40 42

44

46

No of repeat units

Fig. 1. Distribution of CAG/CTG repeat lengths in the schizophrenia patients (closed bars) and controls (open bars) at the SCA8, 12 and 17 loci. The expanded alleles in SCA17 are shown in the enlarged closed bars with the number indicated below in parenthesis.

CAG repeat expansions (45 repeats) were detected in two patients. The TBP/SCA17 allele frequency distribution in the schizophrenia patients with or without the inclusion of two expanded alleles was significantly different from that in the controls ( P = 0.0149 and 0.0078, respectively). It appears that the frequency of 36 repeats is increased in patients (65.2% vs. 50.0%, P = 0.0398). 3.2. TBP allele with 45 TNR expansions in two schizophrenia patients 3.2.1. Patient 1 Mr. A, a 27-year-old Han Chinese, was physically and mentally healthy until 7 years prior to admission when he began to suffer an insidious loss of drive. Affective flattening, alogia, social withdrawal, auditory hallucinations and persecutory delusions also gradually emerged. Due to the deteriorated major areas of functioning, e.g., interpersonal relations, occupational performance, and self-care, he was admitted. All

laboratory and imaging examinations revealed negative findings. Neurological and physical examinations revealed no ataxic gait, involuntary movements or other abnormalities. Mr. A was diagnosed with schizophrenia, paranoid type, and he received risperidone at a dose of 2 mg per day. After 2 weeks of therapy, he gradually regained social interests to some degree. The number of expanded TNR at the SCA17 locus was 45 and the sequence was (CAG)3(CAA)3(CAG)14 CAACAGCAA(CAG)20CAACAG. Both parents (father, aged 50; mother, aged 48) and the two younger brothers (aged 24 and 22) revealed no psychiatric or neurodegenerative diseases. 3.2.2. Patient 2 Mr. B, a 21-year-old Han Chinese, was also physically and mentally healthy until 3 years prior to admission when he began suffering from persecutory delusions, disorganized speech, and social withdrawal. He was admitted due to an acute exacerbation of queer behaviors. Thorough laboratory

Table 1 Distribution of CAG/CTG repeat lengths in 200 schizophrenia and 248 control alleles Gene

KLHL1AS/SCA8 PPP2R2B/SCA12 TBP/SCA17

Allele range (in repeats)

Observed heterozygosity

The most common alleles (in repeats)

Patients

Controls

Patients

Controls

Patients

Controls

17–40 9–26 32–45

18–41 7–27 32–42

0.83 0.73 0.52

0.90 0.85 0.68

18 13 36

18 10 36

134

C.-M. Chen et al. / Schizophrenia Research 78 (2005) 131–136

examinations demonstrated normal findings. Neurological and physical examination revealed no ataxic gait, or any movement abnormality. He was diagnosed with schizophrenia, paranoid type. After 6 weeks of risperidone therapy, his symptoms subsided moderately. The number of expanded TNR at the SCA17 locus was 45 and the sequence was (CAG)3(CAA)3(CAG)11CAACAGCAA(CAG)23yyCAACAG. Both parents (father aged 51; mother aged 45) and the younger sister (aged 19) of the patient all revealed no history of psychiatric or neurodegenerative diseases.

4. Discussion The study examined the TNR in the KLHL1AS/ SCA8, PPP2R2B/SCA12, and TBP/SCA17 genes in a normal Taiwanese population and in patients with schizophrenia. Our results showed that the PPP2R2B/ SCA12 unstable CAG repeats did not contribute to genetic risk factors of schizophrenia, which is similar to the previously reported study (Laurent et al., 2003). However, the proportion of large alleles (N15) was greater in our population than that found in the French, Indian, and Italian control populations (Fujigasaki et al., 2001b; Brusco et al., 2002). This finding was also seen in another Taiwanese population (Tsai et al., 2004). For KLHL1AS/SCA8 locus, the distribution of TNR alleles in this study was similar to that previously reported in Taiwanese and other ethnic groups (Koob et al., 1999; Tsai et al., 2004). We did not find expanded KLHL1AS/SCA8 CTG repeats in the patients. This is in contrast to the previous reports (Pato et al., 2000; Vincent et al., 2000). Interestingly, two patients carrying 45 TNR expansions in the TBP/ SCA17 gene were identified. Also the allele frequency distribution of the TBP/SCA17 TNR in the schizophrenia patients with or without inclusion of the two expanded alleles was significantly different from that in the controls. The increased frequency of 36 repeats in patients may implicate that the 36 repeats-allele itself could possibly contribute to schizophrenia risk, or could be in linkage disequilibrium with a nearby, causative mutation. The SCA17 was reported to be caused by an expansion of CAG repeats encoding a polyglutamine tract in the TATA binding protein, TBP (Koide et al., 1999; Nakamura et al., 2001). TBP is the subunit of RNA polymerase II transcription factor D, which is crucial for the expression of most genes and is ubiquitously

expressed (Kao et al., 1990). The normal range of TBP/ SCA17 CAG/CAA repeat numbers varies between 25 and 43 (Rolfs et al., 2003; Wu et al., 2005). An intermediate range with reduced penetrance is assumed to be 44–47 CAA/CAG repeats (Oda et al., 2004). Phenotypically, beside cerebellar ataxia, psychiatric features such as psychosis, depression, and dementia are common and may be the first symptoms (Fujigasaki et al., 2001a; De Michele et al., 2003; Maltecca et al., 2003; Rolfs et al., 2003; Bauer et al., 2004). Intranuclear inclusions and neuronal loss were found diffusely throughout the brain of SCA17 patients (Fujigasaki et al., 2001a), which may reflect the clinical variability. Three possible explanations for our finding of expanded CAG/CAA alleles in two patients with idiopathic schizophrenia are discussed as the following. i) The finding is coincidental, and the SCA17 expansions bear no relation to the schizophrenia phenotype in these patients. This is not unlikely, given the high prevalence of schizophrenia and negative family history of our two patients. ii) The patients are earlyonset SCA17, with an onset of psychiatric symptoms initially, which may or may not be followed by neurodegenerative symptoms. These patients fall within the range of reduced penetrance (44–47 repeats) for SCA17, which may explain the negative family history. It is noted that these two patients are below the usual age of onset for SCA17 with expansions in this size range. This may be unusual, but still likely, if the age at onset of SCA17 is influenced by modifying genetic or environmental factors. It is also noted that within SCA17 families, affected members may have psychiatric symptoms only, whereas others show cerebellar symptoms or dementia (Rolfs et al., 2003). Our two patients could fall into this category. iii) The schizophrenia seen in these patients is distinct from the psychiatric symptoms normally associated with SCA17, and TBP expansions in this size range may be a cause of idiopathic schizophrenia. Without DNA from family members, it is difficult to distinguish between options 1 and 3, but the finding is worth reporting so that other groups may screen additional sets of schizophrenia patients for TBP/SCA17 expansions. Previously it was reported that no expanded TBP/ SCA17 or novel unstable TNR was found in patients with schizophrenia (Rubinsztein et al., 1996; Bowen et al., 1996; Tsutsumi et al., 2004). This is in contrast to our finding of expanded CAG/CAA alleles in two

C.-M. Chen et al. / Schizophrenia Research 78 (2005) 131–136

schizophrenia patients. The differential results may be explained by the genetic background differences, the small sample sizes, the possibility that our finding is coincidental, and the possibility that the repeat expansion detection assay used may have missed expansions as small as 45. In conclusion, our data suggest that expansions of TNR in the KLHL1AS/SCA8, PPP2R2B/SCA12, and TBP/SCA17 genes are not responsible for the majority of schizophrenia cases. Nevertheless, we demonstrated two patients with schizophrenia associated with a 45 CAG expansion at the TBP gene, which suggests that CAG repeat expansions of the TBP/SCA17 gene may be a rare cause of schizophrenic-like disorders. However, our sample size was small and the results need replication.

Acknowledgements We thank the schizophrenia patients and the normal controls for participating in this study. This work was supported by grants NSC-93-3112-B-003-002 and NSC93-2314-B-182A-171 from the National Science Council, Executive Yuan, Taiwan, ORD93-2 from National Taiwan Normal University, Taipei, Taiwan, CMRPG 33108 from Chang Gung Memorial Hospital, Taipei, Taiwan, NHRI-EX-94-9405PI from the National Health Research Institutes and 94DOH004 from the National Research Program for Genomic Medicine, Taiwan.

References American Psychiatric Association, 1994. Structured Clinical Interview for DSM-IV. American Psychiatric Press, Washington, DC. Bauer, P., Laccone, F., Rolfs, A., Wullner, U., Bosch, S., Peters, H., Liebscher, S., Scheible, M., Epplen, J.T., Weber, B.H., HolinskiFeder, E., Weirich-Schwaiger, H., Morris-Rosendahl, D.J., Andrich, J., Riess, O., 2004. Trinucleotide repeat expansion in SCA17/TBP in white patients with Huntington’s disease-like phenotype. J. Med. Genet. 41, 230 – 232. Bowen, T., Guy, C., Speight, G., Jones, L., Cardno, A., Murphy, K., McGuffin, P., Owen, M.J., O’Donovan, M.C., 1996. Expansion of 50 CAG/CTG repeats excluded in schizophrenia by application of a highly efficient approach using repeat expansion detection and a PCR screening set. Am. J. Hum. Genet. 59, 912 – 917. Brusco, A., Cagnoli, C., Franco, A., Dragone, E., Nardacchione, A., Grosso, E., Mortara, P., Mutani, R., Migone, N., Orsi, L., 2002.

135

Analysis of SCA8 and SCA12 loci in 134 Italian ataxic patients negative for SCA1–3, 6 and 7 CAG expansions. J. Neurol. 249, 923 – 929. Cummings, C.J., Zoghbi, H.Y., 2000. Fourteen and counting: unraveling trinucleotide repeat diseases. Hum. Mol. Genet. 9, 909 – 916. De Michele, G., Maltecca, F., Carella, M., Volpe, G., Orio, M., De Falco, A., Gombia, S., Servadio, A., Casari, G., Filla, A., Bruni, A., 2003. Dementia, ataxia, extrapyramidal features, and epilepsy: phenotype spectrum in two Italian families with spinocerebellar ataxia type 17. Neurol. Sci. 24, 166 – 167. Fujigasaki, H., Martin, J.J., De Deyn, P.P., Camuzat, A., Deffond, D., Stevanin, G., Dermaut, B., Van Broeckhoven, C., Durr, A., Brice, A., 2001a. CAG repeat expansion in the TATA boxbinding protein gene causes autosomal dominant cerebellar ataxia. Brain 124, 1939 – 1947. Fujigasaki, H., Verma, I.C., Camuzat, A., Margolis, R.L., Zander, C., Lebre, A.S., Jamot, L., Saxena, R., Anand, I., Holmes, S.E., Ross, C.A., Durr, A., Brice, A., 2001b. SCA12 is a rare locus for autosomal dominant cerebellar ataxia: a study of an Indian family. Ann. Neurol. 49, 117 – 121. Holmes, S.E., O’Hearn, E.E., McInnis, M.G., Gorelick-Feldman, D.A., Kleiderlein, J.J., Callahan, C., Kwak, N.G., IngersollAshworth, R.G., Sherr, M., Sumner, A.J., Sharp, A.H., Ananth, U., Seltzer, W.K., Boss, M.A., Vieria-Saecker, A.M., Epplen, J.T., Riess, O., Ross, C.A., Margolis, R.L., 1999. Expansion of a novel CAG trinucleotide repeat in the 5V region of PPP2R2B is associated with SCA12. Nat. Genet. 23, 391 – 392. Kao, C.C., Lieberman, P.M., Schmidt, M.C., Zhou, Q., Pei, R., Berk, A.J., 1990. Cloning of a transcriptionally active human TATA binding factor. Science 248, 1646 – 1650. Koide, R., Kobayashi, S., Shimohata, T., Ikeuchi, T., Maruyama, M., Saito, M., Yamada, M., Takahashi, H., Tsuji, S., 1999. A neurological disease caused by an expanded CAG trinucleotide repeat in the TATA-binding protein gene: a new polyglutamine disease? Hum. Mol. Genet. 8, 2047 – 2053. Koob, M.D., Moseley, M.L., Schut, L.J., Benzow, K.A., Bird, T.D., Day, J.W., Ranum, L.P., 1999. An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8). Nat. Genet. 21, 379 – 384. Laurent, C., Niehaus, D., Bauche, S., Levinson, D.F., Soubigou, S., Pimstone, S., Hayden, M., Mbanga, I., Emsley, R., Deleuze, J.F., Mallet, J., 2003. CAG repeat polymorphisms in KCNN3 (HSKCa3) and PPP2R2B show no association or linkage to schizophrenia. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 116, 45 – 50. Maltecca, F., Filla, A., Castaldo, I., Coppola, G., Fragassi, N.A., Carella, M., Bruni, A., Cocozza, S., Casari, G., Servadio, A., De Michele, G., 2003. Intergenerational instability and marked anticipation in SCA-17. Neurology 61, 1441 – 1443. Margolis, R.L., McInnis, M.G., Rosenblatt, A., Ross, C.A., 1999. Trinucleotide repeat expansion and neuropsychiatric disease. Arch. Gen. Psychiatry 56, 1019 – 1031. Morris, A.G., Gaitonde, E., McKenna, P.J., Mollon, J.D., Hunt, D.M., 1995. CAG repeat expansions and schizophrenia: association with disease in females and with early age-at-onset. Hum. Mol. Genet. 4, 1957 – 1961.

136

C.-M. Chen et al. / Schizophrenia Research 78 (2005) 131–136

Nakamura, K., Jeong, S.Y., Uchihara, T., Anno, M., Nagashima, K., Nagashima, T., Ikeda, S., Tsuji, S., Kanazawa, I., 2001. SCA17, a novel autosomal dominant cerebellar ataxia caused by an expanded polyglutamine in TATA-binding protein. Hum. Mol. Genet. 10, 1441 – 1448. Oda, M., Maruyama, H., Komure, O., Morino, H., Terasawa, H., Izumi, Y., Imamura, T., Yasuda, M., Ichikawa, K., Ogawa, M., Matsumoto, M., Kawakami, H., 2004. Possible reduced penetrance of expansion of 44 to 47 CAG/CAA repeats in the TATAbinding protein gene in spinocerebellar ataxia type 17. Arch. Neurol. 61, 209 – 212. O’Donovan, M.C., Guy, C., Craddock, N., Bowen, T., McKeon, P., Macedo, A., Maier, W., Wildenauer, D., Aschauer, H.N., Sorbi, S., Feldman, E., Mynett-Johnson, L., Claffey, E., Nacmias, B., Valente, J., Dourado, A., Grassi, E., Lenzinger, E., Heiden, A.M., Moorhead, S., Harrison, D., Williams, J., McGuffin, P., Owen, M.J., 1996. Confirmation of association between expanded CAG/CTG repeats and both schizophrenia and bipolar disorder. Psychol. Med. 26, 1145 – 1153. O’Hearn, E., Holmes, S.E., Calvert, P.C., Ross, C.A., Margolis, R.L., 2001. SCA-12: tremor with cerebellar and cortical atrophy is associated with a CAG repeat expansion. Neurology 56, 299 – 303. Pato, C.N., Macedo, A., Ambrosio, A., Vincent, J.B., Bauer, A., Schindler, K., Xu, J., Coelho, I., Dourado, A., Valente, J., Azevedo, M.H., Kennedy, J.L., Pato, M.T., 2000. Detection of expansion regions in Portuguese bipolar families. Am. J. Med. Genet. 96, 854 – 857. Rolfs, A., Koeppen, A.H., Bauer, I., Bauer, P., Buhlmann, S., Topka, H., Schols, L., Riess, O., 2003. Clinical features and neuropathology of autosomal dominant spinocerebellar ataxia (SCA17). Ann. Neurol. 54, 367 – 375. Rubinsztein, D.C., Leggo, J., Crow, T.J., DeLisi, L.E., Walsh, C., Jain, S., Paykel, E.S., 1996. Analysis of polyglutamine-coding repeats in the TATA-binding protein in different human popula-

tions and in patients with schizophrenia and bipolar affective disorder. Am. J. Med. Genet. 67, 495 – 498. Stevanin, G., Durr, A., Brice, A., 2000. Clinical and molecular advances in autosomal dominant cerebellar ataxias: from genotype to phenotype and physiopathology. Eur. J. Hum. Genet. 8, 4 – 18. Tsai, H.F., Liu, C.S., Leu, T.M., Wen, F.C., Lin, S.J., Liu, C.C., Yang, D.K., Li, C., Hsieh, M., 2004. Analysis of trinucleotide repeats in different SCA loci in spinocerebellar ataxia patients and in normal population of Taiwan. Acta Neurol. Scand. 109, 355 – 360. Tsutsumi, T., Holmes, S.E., McInnis, M.G., Sawa, A., Callahan, C., DePaulo, J.R., Ross, C.A., DeLisi, L.E., Margolis, R.L., 2004. Novel CAG/CTG repeat expansion mutations do not contribute to the genetic risk for most cases of bipolar disorder or schizophrenia. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 124, 15 – 19. Vincent, J.B., Yuan, Q.P., Schalling, M., Adolfsson, R., Azevedo, M.H., Macedo, A., Bauer, A., DallaTorre, C., Medeiros, H.M., Pato, M.T., Pato, C.N., Bowen, T., Guy, C.A., Owen, M.J., O’Donovan, M.C., Paterson, A.D., Petronis, A., Kennedy, J.L., 2000. Long repeat tracts at SCA8 in major psychosis. Am. J. Med. Genet. 96, 873 – 876. Wu, Y.R., Lin, H.Y., Chen, C.M., Gwinn-Hardy, K., Ro, L.S., Wang, Y.C., Li, S.H., Hwang, J.C., Fang, K., Hsieh-Li, H.M., Li, M.L., Tung, L.C., Su, M.T., Lu, K.T., Lee-Chen, G.J., 2004. Genetic testing in spinocerebellar ataxia in Taiwan: expansions of trinucleotide repeats in SCA8 and SCA17 are associated with typical Parkinson’s disease. Clin. Genet. 65, 209 – 214. Wu, Y.R., Fung, H.C., Lee-Chen, G.J., Gwinn-Hardy, K., Ro, L.S., Chen, S.T., Hsieh-Li, H.M., Lin, H.Y., Lin, C.Y., Li, S.N., Chen, C.M., 2005. Analysis of polyglutamine-coding repeats in the TATA-binding protein in different neurodegenerative diseases. J. Neural Transm. 112, 539 – 546.