| Human Molecular Genetics | Pages |
©1999 Oxford University Press |
A neurological disease caused by an expanded CAG trinucleotide repeat in the TATA-binding protein gene: a new polyglutamine disease?
Introduction
Results
Case record
Discussion
Materials And Methods
Subjects
Analysis of the size of the CAG repeats of TBP gene by PCR
Nucleotide sequence analysis
Haplotype analysis
Physical maps of the PAC contigs and YAC clones containing the TBP gene and flanking microsatellite markers
Western blot analysis
Immunocytochemistry
Acknowledgements
References
A neurological disease caused by an expanded CAG trinucleotide repeat in the TATA-binding protein gene: a new polyglutamine disease?
Received May 10, 1999; Revised and Accepted July 14, 1999
To investigate whether the expansion of CAG repeats of the TATA-binding protein (TBP) gene is involved in the pathogenesis of neurodegenerative diseases, we have screened 118 patients with various forms of neurological disease and identified a sporadic-onset patient with unique neurologic symptoms consisting of ataxia and intellectual deterioration associated with de novo expansion of the CAG repeat of the TBP gene. The mutant TBP with an expanded polyglutamine stretch (63 glutamines) was demonstrated to be expressed in lymphoblastoid cell lines at a level comparable with that of wild-type TBP. The CAG repeat of the TBP gene consists of impure CAG repeat and the de novo expansion involves partial duplication of the CAG repeat. The present study provides new insights into sporadic-onset trinucleotide repeat diseases that involve de novo CAG repeat expansion.
INTRODUCTION
Expansions of CAG trinucleotide repeats have been identified as the causative mutations in at least eight hereditary neurodegenerative disorders (1-11). Although the genes causing these disorders do not share homology except for the CAG repeats, there are several striking similarities among these disorders: (i) the CAG repeats code for polyglutamine stretches; (ii) the mode of inheritance is autosomal dominant, except for spinobulbar muscular atrophy (SBMA) which is inherited as an X-linked recessive trait; (iii) the CAG repeats larger than ~35-40 repeats lead to diseases, except for spinocerebellar ataxia type 6 (SCA6) (10) which is caused by mildly expanded CAG repeats ranging from 21 to 27; (iv) the size of the expanded CAG repeats inversely correlates with the age at onset; and (v) neurologic symptoms are the major presentations of these disorders. Several genes for transcription factors such as TATA-binding protein (TBP) and POU-domain transcription factor contain CAG trinucleotide repeats encoding polyglutamine stretches (12-14). Since the TBP gene contains particularly long and polymorphic CAG repeats ranging from 25 to 42, the TBP gene has been investigated intensively as a candidate for psychiatric disorders (15-17). Expansion of the CAG repeat of the TBP gene, however, has not been identified. In this study, we found a patient with unique neurologic symptoms associated with de novo expansion of the CAG repeat of the TBP gene.
RESULTS
Case record
The patient was a 14-year-old Japanese female. She was the third offspring born to non-consanguineous parents. Her two elder siblings and her parents are healthy. Her birth and development were normal. At the age of 6 years, she was noted to show gait disturbance and intellectual deterioration. At age 9, she showed obvious gait unsteadiness due to truncal ataxia, spasticity and muscle weakness. Furthermore, she had a few episodes of atypical absence at age 9. The symptoms were slowly progressive, and she became confined to a wheelchair at age 13. At age 14, she was thin and short-statured (height: 125 cm; body weight: 25 kg) [mean values of height and body weight of 14-year-old Japanese females are 156.8 cm and 50.4 kg, respectively (18)]. On neurological examination, she showed marked cerebellar ataxia of the limbs and the trunk, hyperreflexia, extensor plantar responses, cerebellar dysarthria, difficulty in swallowing and severely impaired intellectual performance. Examination of the optic nerve (visual acuities, visual fields and optic fundi), oculomotor nerves and other cranial nerves was normal. There were no sensory disturbances, autonomic dysfunction, involuntary movements or minor congenital anomalies such as high arched palate or polydactylia. Atypical absence was not found after the age of 10 years.
Routine laboratory investigations including tests for liver and renal functions were normal. The result of the antibody titer against measles was negative. Examination of the cerebrospinal fluid (CSF) was normal. Results of nerve conduction velocities (NCVs), somatosensory-evoked potentials (SEPs) and auditory brainstem responses (ABRs) were normal. Magnetic resonance imaging (MRI) showed prominent cerebellar atrophy accompanied by dilatation of the fourth ventricle (Fig. 1), and mild cerebral atrophy as well as dilatation of the lateral ventricles.
Figure 1. MRI findings. T1-weighted midsagittal image showed marked cerebellar atrophy accompanied by dilatation of the fourth ventricle.
Identification of the expanded CAG repeat of the TBP.
We analyzed the size of the CAG repeats of the TBP gene of 52 patients with autosomal dominant SCAs and eight patients with autosomal dominant epilepsies, for whom expansions of the CAG repeats of previously identified genes (1-11) had already been excluded. Furthermore, we also screened 37 patients with sporadic SCAs and 21 patients with sporadic epilepsies. As a result of the screening of the 118 patients, we identified a patient with ataxia, short stature, atypical absence, pyramidal sign and mental deterioration, but without a family history of neurological diseases, who had an expanded CAG repeat coding for 63 glutamines, exceeding the range of CAG repeats in normal individuals (31-42 repeats, 238 chromosomes). The expanded CAG repeat in the TBP gene was observed only in the patient, but not in her parents or her healthy siblings (Fig. 2).
Figure 2. (A) The pedigree of the patient carrying a de novo expansion of the CAG repeat in the TBP gene. The genomic segment of the CAG repeat and the flanking regions were amplified by PCR using the primer pair, 5[prime]-GACCCCACAGCCTATTCAGA-3[prime] and 5[prime]-TTGACTGCTGAACGGCTGCA-3[prime], and subjected to 2% agarose gel electrophoresis. The expanded allele was observed in the patient but not in her parents or healthy siblings. (B) Distribution of the number of the CAG repeats in the TBP genes. The patient had an expanded CAG repeat coding for 63 glutamines (arrow), which exceeds the range of CAG repeats in normal individuals (31-42 repeats, 238 chromosomes).
As shown in Figure 3, the patient had a partially duplicated genomic segment involving the CAG repeat, which encodes 63 glutamines, in addition to the normal allele encoding 36 glutamines. Her father and mother had alleles encoding 35/39 and 36/37 glutamines, respectively (Fig. 3). Paternity and maternity were tested using 10 microsatellite markers on six chromosomes, which yielded a P-value of >99.999% (data not shown), confirming that the expanded CAG repeat in the TBP gene is a de novo mutation.
Figure 3. Nucleotide sequences of the CAG repeats in the TBP gene of the patient and her parents. The PCR products containing the CAG repeats and the flanking sequences were subcloned into the pGEM-T Easy vector. Nucleotide sequence analysis of multiple clones demonstrated that the patient has a partially duplicated segment involving the CAG repeats, which encodes 63 glutamines, in addition to the normal allele encoding 36 glutamines. The father and mother have alleles encoding 35/39 and 36/37 glutamines, respectively.
Haplotype analysis.
Haplotype analysis of the patient, the siblings and the parents using eight microsatellite markers flanking the TBP gene on chromosome 6q27 revealed that the haplotypes of the patient were clearly inherited from the parents with no evidence of recombination events involving the flanking markers (Fig. 4).
Figure 4. (A) Haplotype analysis. Haplotype analysis was performed using eight microsatellite markers (D6S411, D6S305, D6S264, D6S446, D6S1693, D6S297, D6S1590 and D6S281) flanking the TBP gene and the CAG repeats in the TBP gene on chromosome 6q27. There were no recombination events involving D6S281, located telomeric to the TBP gene, or D6S1590, located centromeric to the TBP gene. (B) Physical map of the TBP gene and the microsatellite markers (D6S446, D6S1590, TBP and D6S281) based on PAC contigs and YAC clones. The PAC contigs (6ctg169 and 6ctg170) were obtained from the Sanger Centre (http://www.sanger.ac.uk ). The locations of the microsatellite markers (D6S446, D6S1590 and D6S281) and the two sequence-tagged sites (STS-1 and STS-2) were confirmed by PCR analysis of the YAC clones. Although the TBP gene seems to be deleted from YAC clone 933F7, the location of the TBP gene in this physical map was confirmed by the PAC contigs (dJ1086L22-dJ894D12-dJ140C12-dJ191N21).
Western blot analysis.
To examine whether the gene products of the mutant allele were expressed as a mutant TBP, we performed western blot analysis on the lymphoblastoid cell lines. Using an anti-human TBP antibody, we found a 40 kDa band in addition to the 37 kDa band corresponding to the wild-type TBP. The signal intensity of the 40 kDa band was comparable with that for the 37 kDa band, suggesting that the mutant TBP is expressed at the level comparable with that of the wild-type TBP (Fig. 5). Furthermore, using the 1C2 antibody (19), which preferentially recognizes large polyglutamine stretches exceeding 40 glutamines, the band corresponding to the 40 kDa mutant protein was more intensely stained compared with that of the 37 kDa protein.
Figure 5. Western blot analysis of lymphoblastoid cell lines of the patient and the parents. (A) In the patient's lymphoblastoid cell lines, an additional band with an apparent molecular mass (Mr) of 40 kDa was identified by anti-human TBP antibody, in addition to a 37 kDa band corresponding to wild-type. The 40 kDa band was absent in the lymphoblastoid cell lines from the parents. (B) The band with Mr of 40 kDa was preferentially stained by the 1C2 monoclonal antibody compared with the 37 kDa protein.
Immunocytochemistry.
To investigate the subcellular localiza- tion of the mutant TBP, we performed immunocytochemical analysis of lymphoblastoid cell lines established from the patient and the mother using an anti-TBP polyclonal antibody. Strong TBP-immunoreactivity was observed predominantly in the nuclei of the patient's lymphoblastoid cell lines, and similarly in those from her mother, with faint cytoplasmic staining in some cells. No obvious intranuclear inclusions were observed in the patient's lymphoblastoid cell lines.
DISCUSSION
We identified a patient with ataxia, short stature, atypical absence, pyramidal sign and mental deterioration, but without a family history of neurological diseases, who had an expanded CAG repeat in the TBP gene. The present case with the de novo expansion of the CAG repeat in the TBP gene is the first that involves an impure repeat. The nucleotide sequence and haplotype analyses demonstrated that the mutant TBP gene encoding 63 glutamines derived from a normal paternal allele encoding 39 glutamines. Since the mutation was observed in a non-familial case, the following question would be raised: is the neurological phenotype of the patient caused by the expanded CAG repeat in the TBP gene? First, the patient had a CAG repeat encoding 63 glutamines, far exceeding the range in normal individuals [25-42 in Caucasians (2003 chromosomes) (20) and 31-42 in Japanese (238 chromosomes) (Fig. 2B)]. Second, CAG repeats greater than ~35-40 repeat units have been found to cause various hereditary CAG repeat diseases (21), and proteins with expanded polyglutamine stretches have been shown to be toxic to cells associated with aggregate formation (22). Third, TBP is an important general transcription initiation factor with ubiquitous expression, including in the central nervous system, and the mutant TBP is expressed at levels comparable with those of wild-type TBP and localized in the nuclei of lymphoblastoid cell lines similarly to wild-type TBP. Fourth, from haplotype and nucleotide sequence analysis, it is obvious that the expansion of the CAG repeat in the TBP gene arose as a de novo mutation. Taken together, we concluded that the de novo expansion of the CAG repeat in the TBP gene is most likely to cause the neurological phenotype in the present case. The pathophysiology in this case, however, remains unclear, and may involve toxicity caused by the expanded polyglutamine stretch, as in the other CAG repeat diseases, or impaired transcription function of the mutant TBP.
De novo expansions of CAG repeats in Huntington's disease and SCA7 have been reported to occur from large normal alleles (intermediate alleles), which contain uninterrupted pure CAG repeats (23,24). Since the CAG repeat in the TBP gene is interrupted by many CAAs, it is expected to be much more stable than pure CAG repeats and the multistep gradual expansion is unlikely to be observed for the TBP gene. The de novo expansion of the CAG repeat in the TBP gene occurred from the paternal large normal allele, which consists of interrupted CAG repeats, raising the possibility that plural mechanisms exist in the de novo CAG repeat expansion.
On the basis of the haplotype analysis (Fig. 4), meiotic unequal crossing-over, which has been described in CMT1A and hereditary neuropathy with liability to pressure palsies (25), appears excluded as the cause of this expansion. An interesting mechanism can be proposed, based on recent studies in yeast, which showed that mutants lacking the flap endonuclease (FEN1) activity demonstrated marked destabilization of CAG repeats that can lead to expansion (26). Such mutants are incapable of removing the 5[prime]-flap generated by displacement synthesis, when DNA polymerase encounters the 5[prime]-end of a downstream Okazaki fragment. It has been proposed that a CTG/CAG repeat in a 5[prime]-flap may form stable FEN1-resistant hairpin structures (27). The duplicated segment in the TBP gene is indeed predicted to form such an intramolecular hairpin structure, which may become FEN-1-resistant and result in de novo expansion of the CAG repeat of the TBP gene (Fig. 6). On the other hand, unequal sister chromatid exchange remains another possibility. Unequal sister chromatid exchange between the sister chromatids of the single paternal X chromosome has been suggested to underlie the de novo partial duplication of the Duchenne/Becker muscular dystrophy (DMD/BMD) gene (28). These mechanisms may also be involved in the large expansions occasionally observed on paternal transmissions in the other CAG repeat diseases.
Figure 6. A hypothetical model of repeat expansion in TBP gene. Synthesis of the upstream Okazaki fragment (1) results in the displacement of the 5[prime]-end of the downstream Okazaki fragment (2) to generate a single-stranded 5[prime]-flap. The 5[prime]-flap of Okazaki fragment may form a stable intramolecular hairpin structure involving part of the CAG repeat of the TBP gene, which may become FEN-1 resistant and lead to expansion mutations of the segment engaged in the hairpin structure.
In conclusion, the present case provides new insight into sporadic-onset trinucleotide repeat diseases that involve de novo CAG repeat expansion. We suggest that patients with cerebellar ataxia and mental deterioration, but without a family history, should be intensively screened for CAG repeat expansions in the TBP gene. A similar phenomenon may underlie many other sporadic neurological disorders. Neuronal intranuclear inclusion disease (29), which in most cases has a sporadic onset and for which expansions of the CAG repeats have been implicated as the pathogenic mechanism, is also a good candidate for this class of disease.
MATERIALS AND METHODS
Subjects
We analyzed the size of the CAG repeats in the TBP gene in 52 patients with autosomal dominant SCAs and eight patients with autosomal dominant epilepsies (benign adult familial myoclonus epilepsy, also called familial essential myoclonus epilepsy), for whom expansions of the CAG repeats of previously identified genes (1-11) had been excluded. Furthermore, we also screened 37 patients with sporadic SCAs as well as 21 patients with sporadic epilepsies. As controls, 119 healthy Japanese individuals were analyzed. Genomic DNAs were extracted from peripheral blood leukocytes, which were obtained with informed consent.
Analysis of the size of the CAG repeats of TBP gene by PCR
The number of CAG repeat units in the TBP gene was determined by PCR as previously described.
Nucleotide sequence analysis
To determine the nucleotide sequence of the mutant TBP gene with the expansion of the CAG repeat, the PCR products containing the CAG repeats in the TBP gene were subcloned into pGEM-T Easy Vector by TA cloning (Promega, Madison, WI), and subjected to nucleotide sequence analysis using automated DNA sequencers (PE Applied Biosystems, Foster City, CA).
Haplotype analysis
Haplotype analysis was performed using eight microsatellite markers (D6S411, D6S305, D6S264, D6S446, D6S1693, D6S297, D6S1590 and D6S281) flanking the TBP gene, and the CAG repeats of the TBP gene on chromosome 6q27. Primer sequences were obtained from the Genome Data Base (GDB).
Physical maps of the PAC contigs and YAC clones containing the TBP gene and flanking microsatellite markers
PAC contigs (6ctg169 and 6ctg170) were obtained from the Sanger Centre (http://www.sanger.ac.uk ). CEPH YAC clones were kindly provided by Prof. Yusuke Nakamura (Human Genome Center, Institute of Medical Science, University of Tokyo, Japan). Localizations of D6S446, D6S1590, STS-1, TBP (CAG repeats of the TBP gene), STS-2 and D6S281 were determined by PCR analysis using genomic DNAs of YAC clones. STS-1 and STS-2 were generated by the following primer pairs, respectively: STS-1F, 5[prime]-AATCTCTTGACCTCGTGATC-3[prime]; STS-1R, 5[prime]-GAGAATGGTATTTGCAAGGC-3[prime]; STS-2F, 5[prime]-TCCAAATGTGGGAATACTGG-3[prime]; STS-2R, 5[prime]-ATATAGAGACACGGCAGAGG-3[prime].
Western blot analysis
Lymphoblastoid cell lines were established from the patient and her parents. Expression of wild-type and mutant TBP in the lymphoblastoid cell lines was analyzed by western blot analysis. Fifty micrograms of total protein from the lymphoblastoid cell lines dissolved in a solution containing 1% SDS, 10% sucrose, 1 mM Tris-HCl pH 7.4, 0.5 mM EDTA and 0.4 mM DL-dithiothreitol were fractionated through a 12% SDS-polyacrylamide gel (with 0.32% N,N[prime]-methylene-bis-acrylamide), and transferred to a polyvinyldifluoride membrane (PVDF; Bio-Rad, Hercules, CA). The blot was incubated with monoclonal anti-human TBP antibody (1:1000 dilution; QED Bioscience, CA) or 1C2 monoclonal antibody (1:5000 dilution) against human TBP, which recognizes preferentially expanded polyglutamine stretches (kindly provided by Dr J.L. Mandel, Institute de Génétique et de Biologie Moléculaire, CNRS/INSERM/ULP, France), followed by visualization by enhanced chemilumin- escence (Amersham, Cheshire, UK).
Immunocytochemistry
Smears of lymphoblastoid cell lines established from the patient and her mother were fixed with 4% paraformaldehyde in 0.1 M sodium phosphate buffer pH 7.4, for 15 min, and immunostained with a rabbit polyclonal antibody against TBP (SI-1; Santa Cruz Biotechnology, Santa Cruz, CA) by the avidin-biotin-peroxidase complex (ABC) method using a Vectastain ABC kit (Vector Laboratories, CA) and diaminobenzidine as the chromogen.
ACKNOWLEDGEMENTS
We are especially grateful to the members of the family for their cooperation. We thank Saori Maruyama for her excellent technical assistance, and Dr Yusuke Nakamura for kindly providing the YAC clones. We also thank Dr Jean-Louis Mandel for critical reading of the manuscript and for kindly providing the 1C2 antibody. This study was supported in part by a grant for Research for the Future Program from the Japan Society for the Promotion of Science (JSPS-RFTF96L00103); a grant for Research Fellowship from the Japan Society for the Promotion of Science for Young; a Grant-in-Aid for Scientific Research on Priority Areas (Human Genome Program) from the Ministry of Education, Science and Culture, Japan; a grant from the Research Committee for Ataxic Diseases, the Ministry of Health and Welfare, Japan; grants for Research on Brain Science and for Surveys and Research on Specific Diseases, the Ministry of Health and Welfare, Japan; and special coordination funds from the Japanese Science and Technology Agency.
REFERENCES
+To whom correspondence should be addressed. Tel: +81 25 227 0663; Fax: +81 25 227 0820; Email: tsuji{at}cc.niigata-u.ac.jp
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R. J. Sinke, E. F. Ippel, C. M. Diepstraten, F. A. Beemer, J. H. J. Wokke, B. J. van Hilten, N. V. A. M. Knoers, H. K. P. van Amstel, and H. P. H. Kremer Clinical and Molecular Correlations in Spinocerebellar Ataxia Type 6: A Study of 24 Dutch Families Arch Neurol, November 1, 2001; 58(11): 1839 - 1844. [Abstract] [Full Text] [PDF]
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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. [Abstract] [Full Text] [PDF]
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C. Zander, J. Takahashi, K. H. El Hachimi, H. Fujigasaki, V. Albanese, A. S. Lebre, G. Stevanin, C. Duyckaerts, and A. Brice Similarities between spinocerebellar ataxia type 7 (SCA7) cell models and human brain: proteins recruited in inclusions and activation of caspase-3 Hum. Mol. Genet., October 1, 2001; 10(22): 2569 - 2579. [Abstract] [Full Text] [PDF]
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H. Fujigasaki, J.-J. Martin, P. P. De Deyn, A. Camuzat, D. Deffond, G. Stevanin, B. Dermaut, C. Van Broeckhoven, A. Durr, and A. Brice CAG repeat expansion in the TATA box-binding protein gene causes autosomal dominant cerebellar ataxia Brain, October 1, 2001; 124(10): 1939 - 1947. [Abstract] [Full Text] [PDF]
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K. Nakamura, S.-Y. Jeong, T. Uchihara, M. Anno, K. Nagashima, T. Nagashima, S.-i. Ikeda, S. Tsuji, and I. Kanazawa SCA17, a novel autosomal dominant cerebellar ataxia caused by an expanded polyglutamine in TATA-binding protein Hum. Mol. Genet., July 1, 2001; 10(14): 1441 - 1448. [Abstract] [Full Text] [PDF]
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A.-S. Lebre, L. Jamot, J. Takahashi, N. Spassky, C. Leprince, N. Ravise, C. Zander, H. Fujigasaki, P. Kussel-Andermann, C. Duyckaerts, et al. Ataxin-7 interacts with a Cbl-associated protein that it recruits into neuronal intranuclear inclusions Hum. Mol. Genet., May 1, 2001; 10(11): 1201 - 1213. [Abstract] [Full Text] [PDF]
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 M. J. Sobrido and D. H. Geschwind Molecular Genetics and Inherited Ataxias: Redefining Phenotypes and Pathogenesis Neuroscientist, December 1, 2000; 6(6): 465 - 474. [Abstract] [PDF]
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 J. D. Wood, F. C. Nucifora Jr., K. Duan, C. Zhang, J. Wang, Y. Kim, G. Schilling, N. Sacchi, J. M. Liu, and C. A. Ross Atrophin-1, the Dentato-Rubral and Pallido-Luysian Atrophy Gene Product, Interacts with Eto/Mtg8 in the Nuclear Matrix and Represses Transcription J. Cell Biol., September 4, 2000; 150(5): 939 - 948. [Abstract] [Full Text] [PDF]
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C. J. Cummings and H. Y. Zoghbi Fourteen and counting: unraveling trinucleotide repeat diseases Hum. Mol. Genet., April 1, 2000; 9(6): 909 - 916. [Abstract] [Full Text] [PDF]
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