Brain Advance Access originally published online on April 2, 2007
Brain 2007 130(9):2302-2309; doi:10.1093/brain/awm036
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Novel locus for benign hereditary chorea with adult onset maps to chromosome 8q21.3–q23.3
1Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan, 2Department of Neurology, Sado General Hospital, 3Department of Neurology, Kuroishi Municipal Hospital, 4Department of Neurology, Research Institute for Brain and Blood Vessels, Akita, 5Genome Science Branch, Center for Bioresource-Based Research, Niigata University Brain Research Institute, 6Akita Red Cross Blood Center, 7Department of Neurology, University of Tokyo, Graduate School of Medicine, 8Department of Molecular Neuroscience, Resource Branch for Brain Disease Research, Center for Bioresource-Based Researches, Brain Research Institute, Niigata University, Niigata and 9Geriatric Heath Services Facilities "Sado", Japan
Correspondence to: Masatoyo Nishizawa, MD, PhD, Department of Neurology, Brain Research Institute, Niigata University, 1-757 Asahi-machi-dori Niigata, Niigata 951-8585, Japan E-mail: nishi{at}bri.niigata-u.ac.jp
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Summary |
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Autosomal dominant choreas are genetically heterogeneous disorders including Huntington disease (HD), Huntington disease like 1 (HDL1), Huntington disease like 2 (HDL2), dentatorubro-pallidoluysian atrophy (DRPLA), spinocerebellar ataxia type 17 (SCA17) and benign hereditary chorea (BHC). We identified two Japanese families with adult-onset benign chorea without dementia inherited in an autosomal dominant pattern. All affected individuals presented slowly progressive choreic movements in their upper and lower extremities, trunk and head with an age of onset ranging from 40 to 66 (average 54.3), which were markedly improved by haloperidol. The affected individuals also developed reduced muscle tones in their extremities. The findings obtained in the brain CT or MRI studies of nine affected individuals were normal. These clinical features resemble those of the so-called ‘senile chorea’. HD, HDL1, HDL2, DRPLA, SCA17 and BHC caused by mutations in the TITF-1 gene were excluded by mutational and linkage analyses. A genome-wide linkage analysis revealed linkage to chromosome 8q21.3–q23.3 with a maximum cumulative two-point log of the odds (LOD) score of 4.74 at D8S1784 (
= 0.00). Haplotype analysis of both the families defined the candidate region as 21.5 Mb interval flanked by M9267 and D8S1139. We named this adult-onset dominant inherited chorea ‘benign hereditary chorea type 2 (BHC2)’.
Key Words: benign hereditary chorea; autosomal dominant inheritance; adult-onset; linkage analysis; chromosome 8q21.3–23.3
Abbreviations: BHC, benign hereditary chorea; HD, Huntington disease; HDL1, Huntington disease like 1; HDL2, Huntington disease like 2; DRPLA, dentatorubral pallidoluysian atrophy; SCA, spinocerebellar ataxia; SPECT, single-photon emission computed tomography
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Received October 28, 2006. Revised February 6, 2007. Accepted February 12, 2007.
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Introduction |
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TopSummaryIntroductionMaterial and methodsResultsDiscussionSupplementary materialReferences |
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Chorea is a well-recognized movement disorder that can be either acquired or inherited. Among the inherited forms of chorea, Huntington disease (HD) [Mendelian Inheritance in Man (MIM) 143100 [OMIM] ], which is characterized by progressive chorea, cognitive impairment and psychiatric symptoms, is the most common. The unstable expansion of a CAG repeat coding for a polyglutamine stretch in the huntingtin gene was identified to be the causative mutation in HD (The Huntington's Disease Collaborative Research Group, 1993
). Recent advancements in molecular genetics have revealed the causative genes of other inherited choreic disorders. In one Swedish family showing an HD-like phenotype, a 192-nt insertion in a region of the prion protein (PRNP) gene was found to be responsible for Huntington disease like 1 (HDL1) (MIM 603218
[OMIM]
) (Moore et al., 2001). In other HD phenocopies, a CTG/CAG trinucleotide expansion mutation has been identified in the junctophilin-3 (JPH3) gene in patients with Huntington disease like 2 (HDL2), which is prevalent in Black South Africans (Holmes et al., 2001). In addition, dentatorubral pallidoluysian atrophy (DRPLA) (MIM 607462
[OMIM]
) (Koide et al., 1994; Nagafuchi et al., 1994) and spinocerebellar ataxia type 17 (SCA17) (MIM 607136
[OMIM]
) (Koide et al., 1999; Zuhlke et al., 2001; Toyoshima et al., 2004) show HD-like phenotypes. In families with recessive inheritance, the causative genes of diseases exhibiting HD-like phenotypes, which include chorea-acanthocytosis (MIM 200150
[OMIM]
) (Rampoldi et al., 2001; Ueno et al., 2001), pantothenate kinase-associated neurodegeneration (MIM 234200
[OMIM]
) (Zhou et al., 2001) and aceruloplasminaemia (MIM 604290
[OMIM]
) (Yoshida et al., 1995) have been identified. In these disorders, chorea is progressive and accompanied by other neurological symptoms including dementia and psychiatric symptoms.
Benign hereditary chorea (BHC) (MIM 118700
[OMIM]
) (de Vries et al., 2000) and ‘senile chorea’ (Critchley, 1931; Alcock, 1936) have been reported as choreic disorders without other neurological symptoms. However, the entity of these disorders is still controversial. BHC is an autosomal dominant choreic disorder with an onset in childhood. Choreic movements tend to attenuate in adolescence or early adulthood (Harper, 1978). In some families, a mutation in the TITF-1 gene, a homeodomain-containing transcription factor essential for the organogenesis of the basal ganglia, is associated with BHC (Breedveld et al., 2002). On the other hand, senile chorea is a slowly progressive chorea without other neurological symptoms in the elderly (Critchley, 1931; Alcock, 1936). Although it has been demonstrated that about 10% of patients with senile chorea have late-onset HD (Piccolo et al., 2003), the cause of the disease in the other patients remains undetermined.
We have recently identified two Japanese families exhibiting adult-onset chorea without dementia inherited in an autosomal dominant pattern. A genome-wide linkage analysis revealed that the causative gene of this disease is located on chromosome 8q21.3–q23.3, indicating a novel locus for hereditary chorea. We named this disease ‘benign hereditary chorea type 2 (BHC2)’.
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Material and methods |
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Clinical studies
This study was approved by the ethical committees of Niigata University. In pedigree 1522, 21 members of a five-generation Japanese family with adult-onset hereditary chorea without dementia were enrolled in the study (Fig. 1A). The clinical information of nine affected individuals was obtained. The subjects were examined by neurologists and blood samples were obtained from 21 family members, including seven affected individuals (three males and four females) and 14 unaffected individuals, after obtaining informed consent. In pedigree 269, five members of a five-generation Japanese family with adult-onset hereditary chorea without dementia were enrolled (Fig. 1B). The clinical information of three affected individuals was obtained. The subjects were examined by neurologists and blood samples were obtained from five family members, including three affected individuals (two males and one female) and two unaffected individuals, after obtaining informed consent. The age at onset was defined as the age when choreic movements were first noted by the patients or the age when the presence of chorea was diagnosed by neurologists. In the two families, nine affected individuals were examined by brain CT or MRI, and two affected individuals (IV : 26 in pedigree 1522 and III : 2 in pedigree 269) were examined by brain 99mTc-ethylcysteinate dimer (99mTc-ECD) single-photon emission computed tomography (SPECT).
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Exclusion of known dominant choreas and genome-wide linkage analysis
High-molecular-weight genomic DNA was extracted from the peripheral white blood cells of the subjects according to standard protocols. The mutational analyses of CAG or CTG repeat expansions in the huntingtin, JPH3, DRPLA protein and TATA-binding protein (TBP) genes were performed by previously described methods (The Huntington's Disease Collaborative Research Group, 1993
; Koide et al., 1994; Nagafuchi et al., 1994; Koide et al., 1999; Holmes et al., 2001; Zuhlke et al., 2001; Toyoshima et al., 2004). The mutational analyses of the octapeptide-coding region of the PRNP gene were performed as described previously (Moore et al., 2001). We performed both sequence analysis of the TITF-1 gene in the patients in each family and linkage analysis for the BHC locus in pedigree 1522 to exclude BHC. All three coding exons and exon–intronic junctions of the TITF-1 gene were amplified according to a previously published method (Breedveld et al., 2002). Two flanking markers, D14S1017 and D14S69, were chosen for linkage analysis for BHC locus at 14q13.
After excluding the known dominant choreas, we performed a genome-wide linkage analysis in the 21 family members of pedigree 1522 using 763 microsatellite markers from the ABI PRISM Linkage Mapping Set HD-5 (Applied Biosystems) to cover the entire autosome with an average interval of 4.6 cM. We carried out PCR using various MapPair microsatellite markers and analysed PCR products on an ABI Prism 3100 Genetic Analyzer (Applied Biosystems). We determined all allele sizes using the GeneScan (version 3.1.2 ABI) and GENEMAPPER programs (Applied Biosystems). Two-point LOD scores were calculated using the MLINK program of LINKAGE (version 5.2) and the FASTLINK 4.1P package (Lathrop et al., 1985; Cottingham et al., 1993) for all loci under the assumption of autosomal dominant inheritance and a disease frequency of 0.00001. Four liability classes were set on the basis of the results of the analysis of the cumulative age at onset: 0.0 for ages 0 to 39, 0.33 for ages 40 to 49, 0.66 for ages 50 to 59, and 1.00 for ages over 60. The allele frequency of the markers was determined by analysing at least 95 Japanese control subjects. The genetic distance between adjacent markers was determined using the Marshfield sex-averaged linkage map. Haplotypes were constructed manually to minimize the number of recombination events. We developed an original dinucleotide polymorphic marker (M9267) between GATA8B01 and D8S270 on the basis of simple repeat information obtained from the UCSC Genome Browser on Human May 2004 (http://genome.ucsc.edu/index.html). Primer sequences were 5'-CAACCATATATGTGTGGGTGTG-3' for the forward primer and 5'-GTTCACTGAAGGAGAGTAGAG-3' for the reverse primer. This marker is located at chromosomal position 92786662-92786798 bp on 8q21.3. After obtaining convincing linkage for the disease locus and haplotype analysis for pedigree 1522, we conducted a linkage analysis and a haplotype analysis for pedigree 269 using flanking markers. We referred to the UCSC Genome Browser on Human May 2004 to obtain the physical map and candidate gene information.
Candidate gene analysis
The direct sequencing of all three coding exons of KCNV1 gene including exon–intronic junctions was performed using six appropriate primer pairs. PCR products were purified with ExoSAP-IT (Amersham Biosciences) for cycle sequence reactions using BigDye Terminator (ABI). The reaction products were purified using a DyeEx Spin kit (Qiagen) and analysed using an ABI 3100 DNA sequencer (ABI). PCR primers and annealing conditions are available upon request.
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Results |
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Clinical summary of 12 patients in pedigrees 1522 and 269 (Table 1)
The clinical features of the affected individuals are summarized in Table 1. The inheritance is consistent with an autosomal dominant pattern because of equal male : female ratio of the affected individuals (15 : 18) who were ascertained in successive generations (Fig. 1). The mean age at onset was 54.3 (range 40 to 66).
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The initial symptom of all the affected individuals was the choreic movements of the distal parts of their upper or lower extremities. These choreic movements progressed slowly and extended to limbs, shoulders and head. All the affected individuals developed chorea and showed reduced muscle tones in their extremities. Five of the 12 patients (41.7%) developed dysarthria owing to the choreic movements of the face and tongue. These choreic movements were observed at rest and exacerbated by mental strain and exercises, including walking, writing, speaking and eating. No obvious cognitive impairment, psychiatric symptoms, parkinsonism or ataxia were observed. The brain CT and MRI findings of nine affected individuals were normal. However, 99mTc-ECD SPECT showed reductions in tracer uptake level in the bilateral basal ganglia in two patients (IV : 26 in pedigree 1522 and III : 2 in pedigree 269), suggesting a functional disturbance in the basal ganglia. Haloperidol treatment (0.75–6 mg/day) was highly effective for chorea.
Case report: pedigree 1522
The proband (IV : 17) had chorea in his bilateral legs while walking at age 49 years. The choreic movements in his lower extremities gradually worsened. At age 69 years, he had sudden, small-amplitude jerky movements in the distal parts of his upper and lower extremities and trunk. No choreic movements were observed in his face or tongue. A surface electromyogram (EMG) of his biceps brachii, triceps brachii, wrist extensor and flexor muscles at rest showed frequent grouped discharges varying in duration. Brain CT findings were normal (Fig. 2B and F). The choreic movements were markedly suppressed by haloperidol treatment (3 mg/day). He did not show any signs of mental deterioration until his death from subarachnoid haemorrhage at age 78 years. No autopsy was performed.
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Patient IV : 10, a woman with a normal intellect, had jerky movements in her upper extremities and head at age 65 years. On neurological examination at age 68 years, she showed choreic movements in the distal parts of her upper and lower extremities, trunk, face and head. Brisk tendon reflexes with Babinski signs and mild spastic paraparesis, presumably caused by cervical spondylotic myelopathy, were also observed. Brain CT findings were normal (Fig. 2A and E). Her choreic movements were markedly suppressed by haloperidol treatment (6 mg/day). At age 88 years, she was living in a nursing home and had mild memory loss beginning in her early 80s. Reduced muscle tones in her extremities were observed. Her choreic movements were still suppressed by haloperidol treatment.
Patient IV : 26, a man with a normal intellect, had jerky movements in his hands at age 48 years. On neurological examination at age 53 years, he showed mild choreic movements in his extremities with reduced muscle tones and head. At age 70 years, he had dysarthria as well as choreic movements in his extremities, trunk, head and face. He was still ambulatory even 22 years after the onset of the disease. Brain MRI findings were normal (Fig. 2C and G). 99mTc-ECD SPECT showed reductions in tracer-uptake level in the bilateral basal ganglia. His choreic movements were suppressed by haloperidol treatment (2 mg/day).
Case report: pedigree 269
The proband (III : 2), a woman with a normal intellect, had jerky movements in her bilateral upper extremities at age 40 years. These choreic movements slowly worsened and extended to her trunk and lower extremities. At age 65 years, she was hospitalized because of suicidal ideation and depression. At age 80 years, she had jerky movements in the distal parts of her upper and lower extremities, trunk, neck and tongue. Brain MRI findings were normal for her age. She did not show apparent signs of mental deterioration until her death from choking caused by sputum at age 83 years.
Patient IV : 1, a man with a normal intellect, had jerky movements in his upper extremities at age 52 years. On neurological examination at age 64 years, he showed mild choreic movements in the distal parts of his extremities. Brain MRI findings were also normal (Fig. 2D and H). His choreic movements were markedly suppressed by haloperidol treatment (0.75 mg/day).
Exclusion of known dominant choreas and linkage to chromosome 8q21.3–23.3
Testing for the trinucleotide repeat expansions in the causative gene for HD in patients IV : 10, IV : 26 in pedigree 1522, and patient III : 2 in pedigree 269, gave normal results (17/18, 18/20 and 17/21 repeats, respectively), and those for SCA17 also gave normal results (35/37, 31/35 and 35/36 repeats, respectively).
No mutations in the causative gene for HDL1, HDL2 and DRPLA were found in patients in both families.
Sequence analysis of the TITF-1 gene revealed no mutation and linkage to BHC locus was excluded in pedigree 1522 based on two-point LOD scores of negative infinity at both D14S1017 and D14S69 (Supplementary Table).
We first conducted a genome-wide linkage analysis for only pedigree 1522, because pedigree 269 was too small to obtain the evidence of linkage. The first convincing linkage evidence of the disease locus was obtained at D8S1778 and D8S1784, for which MLINK yielded maximum LOD scores of 5.16 and 3.84 at a recombination rate of 0.00, respectively (Table 2A). All the other chromosomes showed consistently negative LOD scores. A haplotype analysis using eight additional markers (D8S273, GATA8B01, M9267, D8S270, D8S1779, D8S1139, D8S555 and D8S547) adjacent to D8S1778 and D8S1784 revealed a disease-associated haplotype shared by the affected individuals in pedigree 1522. The centromeric boundary of the candidate interval was defined by recombination events at M9267 observed in the affected individuals IV : 26 and V : 7, while the telomeric boundary was defined by a recombination event observed at D8S1139 in the affected individual V : 28 (Fig. 1A). Thus, the candidate interval was a 21.5 Mb region defined by M9267 and D8S1139 on chromosome 8q21.3–q23.3 (Fig. 1A). The disease-associated haplotype was cosegregated with seven affected individuals (IV : 10, IV : 22, IV : 26, V : 7, V : 18, V : 24 and V : 28) in pedigree 1522. In pedigree 269, a maximum two-point LOD score of 0.90 at both D8S1784 and D8S1779 ( = 0.0) was obtained on this region (Table 2B). The maximum cumulative two-point LOD score of both families was 4.74 at D8S1784 ( = 0.00). A disease-associated haplotype was cosegregated with three affected individuals (III : 2, IV : 1 and IV : 2) in this family. Thus, linkage to 8q was also supported by analysis of the second family.
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Discussion |
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TopSummaryIntroductionMaterial and methodsResultsDiscussionSupplementary materialReferences |
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In this study, we identified two Japanese families characterized by autosomal dominant inheritance, adult-onset chorea (>40 years old), the absence of dementia and caudate atrophy on brain CT/MRI, a good response to haloperidol treatment and a benign clinical course. After excluding the possibilities of known dominant inherited choreas, such as HD, HDL1, HDL2, DRPLA, SCA17 and BHC, we identified a new locus for this disorder on chromosome 8q21.3–23.3. Fine mapping using eight additional markers and haplotype analysis defined the candidate interval as 21.5 Mb between M9267 and D8S1139.
In the candidate region on chromosome 8q21.3–23.3, over 100 genes have been identified. Among these genes, we have focused on the potassium channel, subfamily V, member 1 gene (KCNV1) expressed in the brain, because episodic ataxia type 1 (EA1) caused by point mutations in the human potassium channel gene KCNA1 is known to present with paroxysmal choreoathetosis (MIM 160120
[OMIM]
) (Browne et al., 1994). However, we have failed to find any mutations in the KCNV1 gene by a direct sequencing analysis.
The clinical features and neuroimages of our families resemble those of senile chorea except for the presence of heredity. It has been reported that patients having senile chorea without a family history exhibit mild expansions in the CAG repeat (38–40 repeat expansions) of the HD gene (Garcia et al., 1997). Thus, one form of senile chorea has been found to be late-onset HD with mild expansions in the CAG repeat of the HD gene. However, abnormal expansions in the CAG repeat of the HD gene were not detected in the patients in our families. The clinical presentations of our families also resemble those of BHC except for adult-onset and the absence of spontaneous remission. BHC is an autosomal dominant disorder presenting with childhood-onset chorea, the absence of dementia and caudate atrophy, and negligible progression or its absence. The age at onset of BHC is typically before the age of 5 years, and its choreic movements tend to decrease in adolescence or early adulthood. In certain families, BHC is caused by mutations in the TITF-1 gene on chromosome 14q13.3. However, no mutations in the TITF-1 gene were found in the patients in both families and no evidence for linkage to BHC locus was found in the first large family. Since BHC is a genetically heterogeneous disorder (Breedveld et al., 2002), the causative gene of this disorder in our families might contribute to elucidate the pathogenesis of BHC families without TITF-1 gene mutations.
The anatomical basis of chorea is not yet well understood. In our patients, a functional disturbance in the basal ganglia was suggested from the result of the 99mTc-ECD SPECT image, whereas no significant atrophic changes were detected on brain CT or MRI. In HD, the neurodegeneration of the striatum or caudate nucleus neurons may contribute to the development of chorea. The corpus luysi or its connection and thalamus are also considered as anatomical bases for the acquired chorea. The TITF-1 gene is a homeodomain-containing transcription factor essential for the organogenesis of the basal ganglia (Breedveld et al., 2002). In the post-mortem brain of a patient with BHC carrying a TITF-1 gene mutation, although no significant gross abnormalities were observed, a loss of most TITF-1-mediated striatal interneurons was noted (Kleiner-Fisman et al., 2005).
In conclusion, we reported two Japanese families with adult-onset chorea without dementia and mapped the disease locus to a 21.5 Mb region on chromosome 8q21.3–q23.3. The clinical features of each individual resemble those of senile chorea. To narrow the candidate region and identify the causative gene of BHC2, collection of other families with the same phenotype as BHC2 families is important. The identification of the gene responsible for BHC2 is expected to provide accurate genetic diagnoses of unclassified choreas, including senile chorea and lead to the better understanding of the pathogenesis of chorea.
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Supplementary material |
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Supplementary material is available at Brain Online.
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Footnotes |
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*These authors contributed equally to this work.
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Acknowledgements |
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The authors would like to thank all the family members who participated in this study. They would also like to thank Dr Magoichi Tsuji (Iwakubi Clinic, Sado General Hospital) for medical care of patients, Dr Masahisa Sato (Department of Neurology, Saiseikai Niigata Second Hospital) for his advice on surface EMG and Miyuki Tsuchiya (Department of Neurology, Brain Research Institute, Niigata University) for technical assistance. This study was supported by a grant from the Research for the Future Program of the Japan Society for the Promotion of Science and a grant from the Research Committee for Ataxic Diseases, Ministry of Health and Welfare, and a Grant-in-Aid for Scientific Research on Priority Areas "Applied Genomics", from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and a Grant-in-Aid for "the Research Committee for Ataxic Diseases" of the Research on Measures for Intractable Diseases from the Ministry of Health, Welfare and Labour, Japan.
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References |
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TopSummaryIntroductionMaterial and methodsResultsDiscussionSupplementary materialReferences |
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Alcock NS. A note on the pathology of senile chorea (non-hereditary). Brain (1936) 59:376–87.
Breedveld GJ, van Dongen JW, Danesino C, Guala A, Percy AK, Dure LS, et al. Mutations in TITF-1 are associated with benign hereditary chorea. Hum Mol Genet (2002) 11:971–9.
Browne DL, Gancher ST, Nutt JG, Brunt ER, Smith EA, Kramer P, et al. Episodic ataxia/myokimia syndrome is associated with point mutations in the human potassium channel gene KCNA1. Nat Genet (1994) 8:136–40.[CrossRef][Web of Science][Medline]
Cottingham RW Jr, Idury RM, Schaffer AA. Faster sequential genetic linkage computations. Am J Hum Genet (1993) 53:252–63.[Web of Science][Medline]
Critchley M. The neurology of old age. Lancet (1931) 1:1221–39.
de Vries BB, Arts WF, Breedveld GJ, Hoogeboom JJ, Niermeijer MF, Heutink P. Benign hereditary chorea of early onset maps to chromosome 14q. Am J Hum Genet (2000) 66:136–42.[CrossRef][Web of Science][Medline]
Garcia Ruiz PJ, Gomez-Tortosa E, del Barrio A, Benitez J, Morales B, Vela L, et al. Senile chorea: a multicenter prospective study. Acta Neurol Scand (1997) 95:180–3.[Web of Science][Medline]
Harper PS. Benign hereditary chorea. Clinical and genetic aspects. Clin Genet (1978) 13:85–95.[Web of Science][Medline]
Holmes SE, O'Hearn E, Rosenblatt A, Callahan C, Hwang HS, Ingersoll-Ashworth RG, et al. A repeat expansion in the gene encoding junctophilin-3 is associated with Huntington disease-like 2. Nat Genet (2001) 29:377–8.[CrossRef][Web of Science][Medline]
Kleiner-Fisman G, Calingasan NY, Putt M, Chen J, Beal MF, Lang AE. Alterations of striatal neurons in benign hereditary chorea. Mov Disord (2005) 20:1353–7.[CrossRef][Web of Science][Medline]
Koide R, Ikeuchi T, Onodera O, Tanaka H, Igarashi S, Endo K, et al. Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA). Nat Genet (1994) 6:9–13.[CrossRef][Web of Science][Medline]
Koide R, Kobayashi S, Shimohata T, Ikeuchi T, Maruyama M, Saito M, et al. A neurological disease caused by an expanded CAG trinucleotide repeat in the TATA-binding protein gene: a new polyglutamine disease? Hum Mol Genet (1999) 8:2047–53.
Lathrop GM, Lalouel JM, Julier C, Ott J. Multilocus linkage analysis in humans: detection of linkage and estimation of recombination. Am J Hum Genet (1985) 37:482–98.[Web of Science][Medline]
Moore RC, Xiang F, Monaghan J, Han D, Zhang Z, Edstrom L, et al. Huntington disease phenocopy is a familial prion disease. Am J Hum Genet (2001) 69:1385–8.[CrossRef][Web of Science][Medline]
Nagafuchi S, Yanagisawa H, Sato K, Shirayama T, Ohsaki E, Bundo M, et al. Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p. Nat Genet (1994) 6:14–8.[CrossRef][Web of Science][Medline]
Piccolo I, Defanti CA, Soliveri P, Volonte MA, Cislaghi G, Girotti F. Cause and course in a series of patients with sporadic chorea. J Neurol (2003) 250:429–35.[CrossRef][Web of Science][Medline]
Rampoldi L, Dobson-Stone C, Rubio JP, Danek A, Chalmers RM, Wood NW, et al. A conserved sorting-associated protein is mutant in chorea-acanthocytosis. Nat Genet (2001) 28:119–20.[CrossRef][Web of Science][Medline]
The Huntington's Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell (1993) 72:971–83.[CrossRef][Web of Science][Medline]
Toyoshima Y, Yamada M, Onodera O, Shimohata M, Inenaga C, Fujita N, et al. SCA17 homozygote showing Huntington's disease-like phenotype. Ann Neurol (2004) 55:281–6.[CrossRef][Web of Science][Medline]
Ueno S, Maruki Y, Nakamura M, Tomemori Y, Kamae K, Tanabe H, et al. The gene encoding a newly discovered protein, chorein, is mutated in chorea-acanthocytosis. Nat Genet (2001) 28:121–2.[CrossRef][Web of Science][Medline]
Yoshida K, Furihata K, Takeda S, Nakamura A, Yamamoto K, Morita H, et al. A mutation in the ceruloplasmin gene is associated with systemic hemosiderosis in humans. Nat Genet (1995) 9:267–72.[CrossRef][Web of Science][Medline]
Zhou B, Westaway SK, Levinson B, Johnson MA, Gitschier J, Hayflick SJ. A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. Nat Genet (2001) 28:345–9.[CrossRef][Web of Science][Medline]
Zuhlke C, Hellenbroich Y, Dalski A, Kononowa N, Hagenah J, Vieregge P, et al. Different types of repeat expansion in the TATA-binding protein gene are associated with a new form of inherited ataxia. Eur J Hum Genet (2001) 9:160–4.[CrossRef][Web of Science][Medline]
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