Redefining the disease locus of 16q22.1-linked autosomal dominant cerebellar ataxia

Amino, Takeshi; Ishikawa, Kinya; Toru, Shuta; Ishiguro, Taro; Sato, Nozomu; Tsunemi, Taiji; Murata, Miho; Kobayashi, Kenzo; Inazawa, Johji; Toda, Tatsushi; Mizusawa, Hidehiro

doi:10.1007/s10038-007-0154-1

Cited by 27 publications

(32 citation statements)

References 24 publications

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“…10,11,[14][15][16][17] Although the pathogenicity of the À16C4T substitution is controversial because of the discovery of two patients from families having 16q-ADCA, who did not have the À16C4T substitution, 10,11 it remains useful for the screening of 16q-ADCA in Japanese patients, as the À16C4T substitution has never been seen in Japanese controls thus far. 12 We found 32 pedigrees within 62 affected individuals who carried the À16C4T substitution of puratrophin-1. Nineteen patients were believed to be recessive for SCA or sporadic LCCA, but we revealed that all 19 had the haplotype block (SNP05-SNP06-À16C4T substitution of puratrophin-1), which is highly specific to 16q-ADCA.…”

Section: Discussionmentioning

confidence: 93%

“…We examined all the patients with puratrophin-1 alteration to determine whether they had a haplotype block (SNP05 and SNP06, highly specific to the 16q-ADCA allele), but neither of the SNPs was identified in 200 control chromosomes. 12 All patients had changes in SNP05 (G-A) and SNP06 (A-G), whereas none of the 96 controls had the haplotype block ( Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…8 Using PCR-direct sequencing, we typed SNP02, -04, -05 and -06, which are highly specific to the diseased chromosome. 12 The SCA5, SCA10, SCA14 and FGF mutations were not analyzed in this study. Expert neurologists provided information on the clinical features of the 16q-ADCA patients.…”

Section: Methodsmentioning

confidence: 99%

“…9 However, three patients from families having 16q-ADCA (À16C4T) did not have the substitution. [10][11][12] Haplotype analysis suggested that the mutation was in a region centromeric to the À16C4T substitution. [10][11][12] We had reported that this disease locus was telomeric to the puratrophin-1 gene.…”

Section: Introductionmentioning

confidence: 99%

“…[10][11][12] Haplotype analysis suggested that the mutation was in a region centromeric to the À16C4T substitution. [10][11][12] We had reported that this disease locus was telomeric to the puratrophin-1 gene. 8 To clarify the disease locus in these patients, we reexamined the disease haplotype using microsatellite markers and a series of single-nucleotide polymorphisms (SNPs) specific to 16q-ADCA.…”

Section: Introductionmentioning

confidence: 99%

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Clinical and genetic characterization of 16q-linked autosomal dominant spinocerebellar ataxia in South Kyushu, Japan

et al. 2009

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16q-ADCA (OMIM no. 117210) is an autosomal dominant spinocerebellar ataxia (AD-SCA) characterized by late-onset pure cerebellar ataxia and À16C4T substitution of the puratrophin-1 gene. Recently, a series of single-nucleotide polymorphisms (haplotype block) were found to be specific to 16q-ADCA. We screened patients with ataxia and found 62 patients, including four homozygotes who carry the C-T substitution of the puratrophin-1 gene. By further analysis of the patients with the haplotype block, we observed a single-founder effect for 16q-ADCA, even in patients who are supposed to be sporadic late cortical cerebellar atrophy (LCCA). We also observed slippage mutations of microsatellite markers, GATA01 and 17msm, in the pedigrees. We compared the clinical course of 16q-ADCA in heterozygotes and homozygotes with the haplotype block and observed no apparent gene dosage effect. 16q-ADCA accounts for 27% of AD-SCAs and is the most frequent AD-SCA in South Kyushu, Japan.

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Section: Discussionmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Clinical and genetic characterization of 16q-linked autosomal dominant spinocerebellar ataxia in South Kyushu, Japan

et al. 2009

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CAG Repeat Expansion in THAP11 Is Associated with a Novel Spinocerebellar Ataxia

et al. 2023

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Background More than 50 loci are associated with spinocerebellar ataxia (SCA), and the most frequent subtypes share nucleotide repeats expansion, especially CAG expansion. Objective The objective of this study was to confirm a novel SCA subtype caused by CAG expansion. Methods We performed long‐read whole‐genome sequencing combined with linkage analysis in a five‐generation Chinese family, and the finding was validated in another pedigree. The three‐dimensional structure and function of THAP11 mutant protein were predicted. Polyglutamine (polyQ) toxicity of THAP11 gene with CAG expansion was assessed in skin fibroblasts of patients, human embryonic kidney 293 and Neuro‐2a cells. Results We identified THAP11 as the novel causative SCA gene with CAG repeats ranging from 45 to 100 in patients with ataxia and from 20 to 38 in healthy control subjects. Among the patients, the number of CAA interruptions within CAG repeats was decreased to 3 (up to 5–6 in controls), whereas the number of 3′ pure CAG repeats was up to 32 to 87 (4–16 in controls), suggesting that the toxicity of polyQ protein was length dependent on the pure CAG repeats. Intracellular aggregates were observed in cultured skin fibroblasts from patients. THAP11 polyQ protein was more intensely distributed in the cytoplasm of cultured skin fibroblasts from patients, which was replicated with in vitro cultured neuro‐2a transfected with 54 or 100 CAG repeats. Conclusions This study identified a novel SCA subtype caused by intragenic CAG repeat expansion in THAP11 with intracellular aggregation of THAP11 polyQ protein. Our findings extended the spectrum of polyQ diseases and offered a new perspective in understanding polyQ‐mediated toxic aggregation. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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Autosomal Dominant Spinocerebellar Ataxias and Episodic Ataxias

Taroni

Chiapparini

Mariotti

2021

Handbook of the Cerebellum and Cerebellar Disorders

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Redefining the disease locus of 16q22.1-linked autosomal dominant cerebellar ataxia

Abstract: The 16q22

Cited by 27 publications

References 24 publications

Clinical and genetic characterization of 16q-linked autosomal dominant spinocerebellar ataxia in South Kyushu, Japan

Clinical and genetic characterization of 16q-linked autosomal dominant spinocerebellar ataxia in South Kyushu, Japan

CAG Repeat Expansion in THAP11 Is Associated with a Novel Spinocerebellar Ataxia

Autosomal Dominant Spinocerebellar Ataxias and Episodic Ataxias

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