SCA17 caused by homozygous repeat expansion in TBP due to partial isodisomy 6

Zühlke, Christine; Spranger, Matthias; Spranger, Stefanie; Voigt, Robert L.; Lanz, Michael; Gehlken, Ulrike; Hinrichs, Frauke; Schwinger, E.

doi:10.1038/sj.ejhg.5201018

Cited by 42 publications

(41 citation statements)

References 19 publications

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“…The majority of the pedigrees have been identified in patients from Germany-Austria (approx 20 families) [2,16,31,[42][43][44][45], and from Japan (13 families) [19,27,28,38]. Additional SCA17 families were identified in Taiwan [23,41], USA [34], and Europe (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…A subsequent study of Nakamura et al in eight novel Japanese patients described the complexity of the phenotype characterized by a variable combination of ataxia, dementia, parkinsonism, chorea, dystonia, and epilepsy [27]. Further cases of SCA17 have been reported in families from Germany, Belgium, France, and Japan [2,12,16,28,32,36,38,[42][43][44][45]. Currently, repeat expansions in the TBP gene have been identified in approximately 50 pedigrees worldwide.…”

Section: Introductionmentioning

confidence: 99%

“…As far as genotype-phenotype correlations, incomplete penetrance in subjects carrying expansions in the range of 44-48 repeats was demonstrated in a limited number of SCA17 families in which mutation-transmitting parents with no signs of disease have been reported [28,43,45].…”

Section: Introductionmentioning

confidence: 99%

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Spinocerebellar ataxia type 17 (SCA17): Oculomotor phenotype and clinical characterization of 15 Italian patients

et al. 2007

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SCA17 is a rare type of autosomal dominant spinocerebellar ataxia caused by a CAG/CAA expansion in the gene encoding the TATA-binding protein (TBP). We screened for triplet expansion in the TBP gene 110 subjects with progressive cerebellar ataxia and 94 subjects with Huntington-like phenotype negative at specific molecular tests. SCA17 mutation-positive subjects were found in both groups of patients. Expanded alleles with > or = 44 CAG/CAA repeats were identified in 11 individuals and in 4 non-symptomatic relatives. Eleven de novo diagnosed patients and four patients previously reported underwent extensive clinical, neuroradiological and oculographic examination. Cerebellar signs and symptoms were present in all cases; 80% of the patients had mild to severe cognitive deficits; 66% of patients showed choreic movements; pyramidal signs, bradykinesia and dystonia were observed in approx 50% of the cases. MRI demonstrated cortical and cerebellar atrophy in all patients, whereas neurophysiological examination excluded signs of peripheral nervous system involvement. Oculographic examinations were performed in 9 out of 15 patients and showed a distinct pattern of oculomotor abnormalities, characterized by impairment of smooth pursuit, defects in the saccade accuracy, normal saccade velocity, hyperreflexia of vestibuloocular reflexes, and absence of nystagmus. In summary, this study presents one of the largest series of SCA17 patients in Europe. In our group of patients, SCA17 represents the third most frequent SCA genotype. Our clinical data confirm the large variability in SCA17 phenotypic presentation, and indicate that a peculiar combination of neuroradiological, electrophysiological and oculomotor findings is recognizable in SCA17.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Spinocerebellar ataxia type 17 (SCA17): Oculomotor phenotype and clinical characterization of 15 Italian patients

et al. 2007

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“…The threshold for pathological expansions varies according to the study from 43 to 45 repeats (36,38,(46)(47)(48). Sporadic patients carrying from 43 to 63 repeats have been identified, while affected members of families with dominant transmission of the disease carry between 45 and 66 CAG/CAA repeats (34)(35)(36)(37)(38)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57).…”

Section: Tata-box Binding Proteinmentioning

confidence: 99%

“…Elongation of repeated CAG elements, alone or as the result of the loss of CAA interruptions, is the major mechanism leading to abnormally elongated SCA17 repeats (11,15,(33)(34)(35)(36)38,47,(50)(51)(52)(54)(55)(56)(57)(58). In three cases, including two de novo expansions, the expanded repeat is the result of partial duplication or insertion of repeats into the CAG/CAA stretch (11,57).…”

Section: Instability and Origin Of The Expansions In The Tbp Genementioning

confidence: 99%

Spinocerebellar ataxia 17 (SCA17) and Huntington’s disease-like 4 (HDL4)

2008

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Spinocerebellar ataxia 17 (SCA17) or Huntington's disease-like-4 is a neurodegenerative disease caused by the expansion above 44 units of a CAG/CAA repeat in the coding region of the TATA box binding protein (TBP) gene leading to an abnormal expansion of a polyglutamine stretch in the corresponding protein. Alleles with 43 and 44 repeats have been identified in sporadic cases and their pathogenicity remains uncertain. Furthermore, incomplete penetrance of pathological alleles with up to 49 repeats has been suggested. The imperfect nature of the repeat makes intergenerational instability extremely rare and de novo mutations are most likely the result of partial duplications. This is one of the rarer forms of autosomal dominant cerebellar ataxia but the associated phenotype is often severe, involving various systems (cerebral cortex, striatum, and cerebellum), with extremely variable age at onset (range: 3-75 years) and clinical presentation. This gene is thought to account for a small proportion of patients with a Huntington's disease-like phenotype and cerebellar signs. Parkinson's disease-like, Creutzfeldt-Jakob disease-like and Alzheimer disease-like phenotypes have also been described with small SCA17 expansions. The abnormal protein is expressed at the same level as its normal counterpart and forms neuronal intranuclear inclusions containing other proteins involved in protein folding or degradation. The increase in the size of the glutamine stretch enhances transcription in vitro, probably leading to transcription deregulation. Interestingly, the TBP protein mutated in SCA17 is recruited in the inclusions of other polyglutaminopathies, suggesting its involvement in the transcription down-regulation observed in these diseases.

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