Large, expanded repeats in SCA8 are not confined to patients with cerebellar ataxia

Worth, Paul; Houlden, Henry; Giunti, Paola; Davis, Mary B.; Wood, Nicholas W.

doi:10.1038/73411

Cited by 102 publications

(85 citation statements)

References 2 publications

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“…In contrast with previous reports [8][9][10] suggesting that SCA8 expanded CTG repeats could be a nonpathogenic polymorphism in linkage disequilibrium with an ataxia locus, our results support the evidence that SCA8 expansions are rare (3% of all ataxic patients) but may confer a susceptibility predisposing to the ataxic phenotype. These data are confirmed by the virtual absence of pathogenic allele expansions on nonataxic patients' chromosomes (0/572 in our study) and by the low frequency (4.3% = 5/115) of expansions among patients with genetically unidentified forms of hereditary (50 patients) and sporadic (65 patients) ataxia.…”

Section: Commentcontrasting

confidence: 80%

Genetic and Clinical Analysis of Spinocerebellar Ataxia Type 8 Repeat Expansion in Italy

Cellini

Nacmias²,

Forleo³

et al. 2001

Arch Neurol

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Section: Commentcontrasting

confidence: 80%

Genetic and Clinical Analysis of Spinocerebellar Ataxia Type 8 Repeat Expansion in Italy

Cellini

Nacmias²,

Forleo³

et al. 2001

Arch Neurol

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“…Distributions of normal alleles were extracted from the literature when possible [Watkins et al, 1995;Jodice et al, 1997;Leggo et al, 1997;Takano et al, 1998;Antonarakis et al, 1999;Holmes et al, 1999;Tsai et al, 1999;Saleem et al, 2000a;Saleem et al, 2000b;Vincent et al, 2000;Fujigasaki et al, 2001;Jernstrom et al, 2001;Worth et al, 2000]. When no published information could be found, or a small number of chromosomes were available in the literature, for any population and locus (Africans for SCA3, SCA8, SCA12, KCNN3, and NCOA3; and East Asian for SCA12), healthy human individuals were typed with additional Japanese and Tanzanian samples.…”

Section: Materials and Methods Allele Distributionsmentioning

confidence: 99%

Dynamics of CAG repeat loci revealed by the analysis of their variability

et al. 2002

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In order to understand the dynamics of the expressed single tandem repeat trinucleotides (most of them involved in pathological expansion), the diversity in 10 different loci (SCA1, SCA2, SCA3, SCA6, SCA8, SCA12, DRPLA, HD, KCNN3, and NCOA3) was analyzed in four major human groups (Africans, Europeans, Indians, and East Asians). The present analysis intends to disentangle population-based from genetic-based factors having shaped STR (trinucleotide) variation and to recognize, for each locus, the specific rate and pattern of mutation (bias toward expansion or contraction, constraints on allele size), and the footprints of selection. Population differences account for a very small part of the total variation, but a clear footprint appears of population growth after a bottleneck in all non-African populations, giving support to the out-of-Africa model of modern humans. Most of the diversity is found among loci, and different dynamics are inferred for each of them. SCA2 and SCA3 follow an unrestricted stepwise mutation model, while the rest of loci are found under allele size constrictions and a bias to expansion (SCA1, SCA6, HD, and KCNN3), contraction (SCA12, DRPLA, and NCOA3), or unbiased (SCA8).

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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: 97%

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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Large, expanded repeats in SCA8 are not confined to patients with cerebellar ataxia

Cited by 102 publications

References 2 publications

Genetic and Clinical Analysis of Spinocerebellar Ataxia Type 8 Repeat Expansion in Italy

Genetic and Clinical Analysis of Spinocerebellar Ataxia Type 8 Repeat Expansion in Italy

Dynamics of CAG repeat loci revealed by the analysis of their variability

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

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