SCA8 Repeat Expansion: Large CTA/CTG Repeat Alleles Are More Common in Ataxic Patients, Including Those with SCA6

Izumi, Yuishin; Makino, Hírofumi; Oda, Masaya; Morino, Hiroyuki; Okada, Takayuki; Ito, Hidefumi; Sasaki, Iwao; Tanaka, Hiroyasu; Komure, Osamu; Udaka, Fukashi; Nakamura, Shotaro; Kawakami, Hideshi

doi:10.1086/367775

Cited by 62 publications

(57 citation statements)

References 20 publications

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“…[19][20][21][22][23][24] Conversely, homozygotes of SCA3, SCA6, SCA8 and SCA12 did not have severe clinical phenotypes compared with heterozygotes. 19,[25][26][27][28] On the basis of our results, there does not seem to be a strong gene dosage effect in 16q-ADCA. As some homozygotes with SCAs caused by gain-of-function mutations did not always show as severe a phenotype as the heterozygote, it is reasonable to suggest that 16q-ADCA operates through a gain-of-function mechanism.…”

Section: Discussionmentioning

confidence: 42%

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: 42%

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

et al. 2009

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“…27 There is a danger of assigning too much relevance to an expansion, given its high prevalence and when it is still disputed by some in which size range SCA8 expansions are pathogenic. [28][29][30][31] Families in which affected individuals have another SCA, in addition to an SCA8 expansion, are known. 30,32 Ceasing to test other loci, if a SCA8 expansion is found, could lead to missing the causative mutation.…”

Section: Methodologiesmentioning

confidence: 99%

“…[28][29][30][31] Families in which affected individuals have another SCA, in addition to an SCA8 expansion, are known. 30,32 Ceasing to test other loci, if a SCA8 expansion is found, could lead to missing the causative mutation. There is a thought that PST or PND should not be offered for SCA8; however, some consider that genetic linkage testing could be offered, if the expansion segregates with the disease and penetrance can be confirmed in the family.…”

Section: Methodologiesmentioning

confidence: 99%

Consensus and controversies in best practices for molecular genetic testing of spinocerebellar ataxias

Sequeiros

Seneca²,

Martindale

2010

Eur J Hum Genet

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Many laboratories worldwide are offering molecular genetic testing for spinocerebellar ataxias (SCAs). This is essential for differential diagnosis and adequate genetic counselling. The European Molecular Genetics Quality Network (EMQN) started an SCA external quality assessment scheme in 2004. There was a clear need for updated laboratory guidelines. EMQN and EuroGentest organized a Best Practice (BP) meeting to discuss current practices and achieve consensus. A pre-meeting survey showed that 36 laboratories (20 countries) conducted nearly 18 000 SCA tests the year before, and identified issues to discuss. Draft guidelines were produced immediately after the meeting and discussed online for several months. The final version was endorsed by EMQN, and harmonized with guidelines from other oligonucleotide repeat disorders. We present the procedures taken to organize the survey, BP meeting, as well as drafting and approval of BP guidelines. We emphasize the most important recommendations on (1) pre-test requirements, (2) appropriate methodologies and (3) interpretation and reporting, and focus on the discussion of controversial issues not included in the final document. In addition, after an extensive review of scientific literature, and responding to recommendations made, we now produce information that we hope will facilitate the activities of diagnostic laboratories and foster quality SCA testing. For the main loci, this includes (1) a list of repeat sequences, as originally published; (2) primers in use; and (3) an evidence-based description of the normal and pathogenic repeat-size ranges, including those of reduced penetrance and those in which there is still some uncertainty. This information will be maintained and updated in http://www.scabase.eu.

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“…Although these Parkinson-like symptoms are most intriguing in view of the association of Klhl1 with mdDA neuronal pathology, they have been mainly attributed to Klhl1-related deficits in Purkinje cells of the cerebellum (He et al, 2006). However, in humans, a direct link between abnormal expansions of trinucleotide repeats within the SCA8 locus, where KLHL1 is located, and cases of Parkinson's disease have been reported (Worth et al, 2000;Izumi et al, 2003;Wu et al, 2004). The expression of Klhl1 in mdDA neurons of the SNc and VTA and the notion that Klhl1 is linked to mdDA pathology in Nurr1-and Pitx3-deficient embryos provide a new basis for studying the role of Klhl1 in the mdDA system.…”

Section: Research Articlementioning

confidence: 99%

Identification ofDlk1, PtpruandKlhl1as novel Nurr1 target genes in meso-diencephalic dopamine neurons

et al. 2009

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The orphan nuclear receptor Nurr1 is essential for the development of meso-diencephalic dopamine (mdDA) neurons and is required, together with the homeobox transcription factor Pitx3, for the expression of genes involved in dopamine metabolism. In order to elucidate the molecular mechanisms that underlie the neuronal deficits in Nurr1 -/-mice, we performed combined gene expression microarrays and ChIP-on-chip analysis and thereby identified Dlk1, Ptpru and Klhl1 as novel Nurr1 target genes in vivo. In line with the previously described cooperativity between Nurr1 and Pitx3, we show that the expression of Ptpru and Klhl1 in mdDA neurons is also dependent on Pitx3. Furthermore, we demonstrate that Nurr1 interacts with the Ptpru promoter directly and requires Pitx3 for full expression of Ptpru in mdDA neurons. By contrast, the expression of Dlk1 is maintained in Pitx3 -/-embryos and is even expanded into the rostral part of the mdDA area, suggesting a unique position of Dlk1 in the Nurr1 and Pitx3 transcriptional cascades. Expression analysis in Dlk1 -/-embryos reveals that Dlk1 is required to prevent premature expression of Dat in mdDA neuronal precursors as part of the multifaceted process of mdDA neuronal differentiation driven by Nurr1 and Pitx3. Taken together, the involvement of Nurr1 and Pitx3 in the expression of novel target genes involved in important neuronal processes such as neuronal patterning, axon outgrowth and terminal differentiation, opens up new avenues to study the properties of mdDA neurons during development and in neuronal pathology as observed in Parkinson's disease.

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SCA8 Repeat Expansion: Large CTA/CTG Repeat Alleles Are More Common in Ataxic Patients, Including Those with SCA6

Cited by 62 publications

References 20 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

Consensus and controversies in best practices for molecular genetic testing of spinocerebellar ataxias

Identification ofDlk1, PtpruandKlhl1as novel Nurr1 target genes in meso-diencephalic dopamine neurons

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