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Sandra Martins,
Bing-Wen Soong,
Virginia C N Wong,
Paola Giunti,
Giovanni Stevanin,
Laura P W Ranum,
Hidenao Sasaki,
Olaf Riess,
Shoji Tsuji,
Paula Coutinho,
António Amorim,
Jorge Sequeiros,
Garth A Nicholson
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ABSTRACT: To determine whether the presence of Machado-Joseph disease (MJD, also spinocerebellar ataxia type 3 [SCA3]) among Australian aborigines was caused by a new mutational event or by the introduction of expanded alleles from other populations.
We sequenced a region of 4 kilobases (kb), encompassing the CAG repeat within the ATXN3 gene, in 2 affected Australian aboriginal families and compared them with the Joseph and Machado lineages described before. Full-extended haplotypes (including also more distant single-nucleotide polymorphisms and flanking short tandem repeats) were assessed by segregation and allele-specific amplification. A phylogenetic tree was inferred from genetic distances, and age of the Australasian Joseph-derived lineage was estimated.
The aboriginal communities of Groote Eylandt and Yirrkala, in the Northern Territories, Australia (local ethics institutional permission was granted, and both community and individual informed consent was obtained).
A convenience sample of 19 patients and unaffected relatives, from 2 Australian aboriginal families affected with MJD; 40 families with MJD of multiethnic origins and 50 unrelated Asian control subjects.
The 2 aboriginal families shared the same full haplotype, including 20 single-nucleotide polymorphisms:TTGATCGAGC-(CAG)(Exp)-CACCCAGCGC, that is, the Joseph lineage with a G variant in rs56268847.Among 33 families with the Joseph lineage, this derived haplotype was found only in 5 of 16 Taiwanese, all 3 Indian,and 1 of 3 Japanese families analyzed.
A related-extended MJD haplotype shared by Australian aborigines and some Asian families (a Joseph-derived lineage) suggests a common ancestor for all, dating back more than 7000 years.
Archives of neurology 02/2012; 69(6):746-51. · 6.31 Impact Factor
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Hussein Daoud,
Véronique Belzil, Sandra Martins,
Mike Sabbagh,
Pierre Provencher,
Lucette Lacomblez,
Vincent Meininger,
William Camu,
Nicolas Dupré,
Patrick A Dion,
Guy A Rouleau
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ABSTRACT: To analyze the ataxin 2 (ATXN2) CAG repeat size in a cohort of patients with amyotrophic lateral sclerosis (ALS) and healthy controls. Large (CAG)(n) alleles of the ATXN2 gene (27-33 repeats) were recently reported to be associated with an increased risk of ALS.
Case-control study.
France and Quebec, Canada.
A total of 556 case patients with ALS and 471 healthy controls; both groups of participants are of French or French-Canadian origin.
We observed a significant association between ATXN2 high-length alleles (≥29 CAG repeats) and ALS in French and French-Canadian ALS populations. Furthermore, we identified spinocerebellar ataxia type 2-pathogenic polyglutamine expansions (≥32 CAG repeats) in both familial and sporadic ALS cases.
Altogether, our findings support ATXN2 high-length repeats as a risk factor for ALS and further indicate a genetic link between spinocerebellar ataxia type 2 and ALS.
Archives of neurology 06/2011; 68(6):739-42. · 6.31 Impact Factor
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Handbook of Clinical Neurology 01/2011; 103:227-51.
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ABSTRACT: The spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease characterized by gait and limb ataxia. This disease is caused by the expansion of a (CAG)n located in the ATXN2, that encodes a polyglutamine tract of more than 34 repeats. Lately, alleles with 32–33 CAGs have been associated to late-onset disease cases. Repeat interruptions by CAA triplets are common in normal alleles, while expanded alleles usually contain a pure repeat tract. To investigate the mutational origin and the instability associated to the ATXN2 repeat, we performed an extensive haplotype study and sequencing of the CAG/CAA repeat, in a cohort of families of different geographic origins and phenotypes. Our results showed (1) CAA interruptions also in expanded ATXN2 alleles; (2) that pathological CAA interrupted alleles shared an ancestral haplotype with pure expanded alleles; and (3) higher genetic diversity in European SCA2 families, suggesting an older European ancestry of SCA2. In conclusion, we found instability towards expansion in interrupted ATXN2 alleles and a shared ancestral ATXN2 haplotype for pure and interrupted expanded alleles; this finding has strong implications in mutation diagnosis and counseling. Our results indicate that interrupted alleles, below the pathological threshold, may be a reservoir of mutable alleles, prone to expansion in subsequent generations, leading to full disease mutation. © 2009 Wiley-Liss, Inc.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 08/2009; 153B(2):524 - 531. · 3.70 Impact Factor
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Teresa Almeida,
Isabel Alonso, Sandra Martins,
Eliana Marisa Ramos,
Luísa Azevedo,
Kinji Ohno,
António Amorim,
Maria Luiza Saraiva-Pereira,
Laura Bannach Jardim,
Tohru Matsuura,
Jorge Sequeiros,
Isabel Silveira
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ABSTRACT: Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant neurodegenerative disease characterized by cerebellar ataxia and seizures. The disease is caused by a large ATTCT repeat expansion in the ATXN10 gene. The first families reported with SCA10 were of Mexican origin, but the disease was soon after described in Brazilian families of mixed Portuguese and Amerindian ancestry. The origin of the SCA10 expansion and a possible founder effect that would account for its geographical distribution have been the source of speculation over the last years. To unravel the mutational origin and spread of the SCA10 expansion, we performed an extensive haplotype study, using closely linked STR markers and intragenic SNPs, in families from Brazil and Mexico. Our results showed (1) a shared disease haplotype for all Brazilian and one of the Mexican families, and (2) closely-related haplotypes for the additional SCA10 Mexican families; (3) little or null genetic distance in small normal alleles of different repeat sizes, from the same SNP lineage, indicating that they are being originated by a single step mechanism; and (4) a shared haplotype for pure and interrupted expanded alleles, pointing to a gene conversion model for its generation. In conclusion, we show evidence for an ancestral common origin for SCA10 in Latin America, which might have arisen in an ancestral Amerindian population and later have been spread into the mixed populations of Mexico and Brazil.
PLoS ONE 02/2009; 4(2):e4553. · 4.09 Impact Factor
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ABSTRACT: In repeat expansion disorders, the size of pathological alleles is the most relevant factor accounting for the disease severity and age-at-onset, emphasizing the clinical significance of their underlying intergenerational instability. In one of these diseases, Machado-Joseph disease (MJD), the sex of transmitting progenitor and the C(987)GG/G(987)GG polymorphism are the best studied factors acting on intergenerational instability of expanded alleles. Here, we assessed the influence of other cis and inter-allelic acting factors, at the ATXN3 locus, through the analysis of MJD lineages, flanking STR-based haplotypes, the initial repeat size and parental age. A total of 100 transmissions of the expanded MJD allele were analyzed according to the sex of the transmitting parent. We have shown that independent origin mutations (identified by intragenic SNP-based haplotypes) behave differently, as the status of instability (contraction, no change or further expansion) is concerned. Indeed, 72% of expansions were associated to the worldwide spread TTACAC lineage, whereas the GTGGCA displayed 75% of all contractions observed. The analysis of flanking recombinant haplotypes did not suggest any further distant cis elements acting up- or downstream the ATXN3 locus. Considering the increased amplitude of expansions seen in older transmitting fathers, a repair-based mechanism may be suggested for the meiotic instability at this locus; furthermore, the lack of correlation between the initial repeat size and degree of instability did not support a replication-based mechanism. In summary, our findings point to different mechanisms of instability underlying male and female meioses, as well as contraction and expansion processes in MJD.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 07/2008; 147B(4):439-46. · 3.70 Impact Factor
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Sandra Martins,
Francesc Calafell,
Claudia Gaspar,
Virginia C N Wong,
Isabel Silveira,
Garth A Nicholson,
Ewout R Brunt,
Lisbeth Tranebjaerg,
Giovanni Stevanin,
Mingli Hsieh, [......],
Mitsunori Watanabe,
Laura B Jardim,
Paola Giunti,
Olaf Riess,
Laura P W Ranum,
Alexis Brice,
Guy A Rouleau,
Paula Coutinho,
António Amorim,
Jorge Sequeiros
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ABSTRACT: Machado-Joseph disease is the most frequent dominant ataxia worldwide. Despite its frequency and presence in many populations, only 2 founder mutations have been suggested to explain its current geographic distribution.
To trace back in history the main mutational events in Machado-Joseph disease, we aimed to assess ancestral haplotypes and population backgrounds, to date the mutations, and to trace the routes and time of introduction of the founder haplotypes in different populations. Design, Setting, and
We studied 264 families with Machado-Joseph disease from 20 different populations. Six intragenic single-nucleotide polymorphisms were used to determine ancestral mutational events; 4 flanking short tandem repeats were used to construct extended haplotypes and measure accumulation of genetic diversity over time within each lineage.
The worldwide-spread lineage, TTACAC, had its highest diversity in the Japanese population, where we identified the ancestral short tandem repeat-based haplotype. Accumulated variability suggested a postneolithic mutation, about 5774 +/- 1116 years old, with more recent introductions in North America, Germany, France, Portugal, and Brazil. As to the second mutational event, in the GTGGCA lineage, only 7 families (of 71 families) did not have Portuguese ancestry, although gene diversity was again smaller in Portuguese families (0.44) than in non-Portuguese families (0.93).
The worldwide-spread mutation may have first occurred in Asia and later been diffused throughout Europe, with a founder effect accounting for its high prevalence in Portugal; the other Machado-Joseph disease lineage is more recent, about 1416 +/- 434 years old, and its dispersion may be explained mainly by recent Portuguese emigration.
Archives of Neurology 11/2007; 64(10):1502-8. · 7.58 Impact Factor
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ABSTRACT: Despite the intense debate around the repeat instability reported on the large group of neurological disorders caused by trinucleotide repeat expansions, little is known about the mutation process underlying alleles in the normal range that, ultimately, expand to pathological size. In this study, we assessed the mutation mechanisms by which wild-type Machado-Joseph disease (MJD) alleles have been generated throughout human evolution. Haplotypes including the CAG repeat, six intragenic SNPs and four flanking microsatellites were analysed in 431 normal chromosomes of European, Asian and African origin. A bimodal CAG repeat length frequency distribution was found in the four most frequent wild-type lineages (H1-GCGGCA; H2-GTGGCA; H3-TTAGAC and H4-TTACAC). Based on flanking microsatellite haplotypes, the variance calculated by analysis of molecular variance between modal (CAG)n alleles was little or null in lineages H1, H2 and H4, as were the pairwise differences. Moreover, genetic distances among all the alleles from each lineage did not reflect the allele sizes differences, as expected if a stepwise mutation model was the main process of evolution. On the contrary, when exposed in maximum parsimonious phylogenetic trees, a large number of mutation steps separated same-size alleles, whereas several microsatellite haplotypes were shared by modal CAGs. In conclusion, our results suggest that the main mutation mechanism occurring in the evolution of the polymorphic CAG region at MJD/SCA3 locus is a multistep one, either by gene conversion or DNA slippage; repeats with 14, 21, 23 and 27 CAGs are the main alleles involved in this process.
European Journal of HumanGenetics 09/2006; 14(8):932-40. · 4.40 Impact Factor
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ABSTRACT: Spinocerebellar ataxia type 8 (SCA8) is an autosomal dominant late-onset neurodegenerative disorder, belonging to the group of diseases caused by trinucleotide repeat expansions. SCA8 remains one of the most intriguing SCAs, regarding the reduced disease penetrance, and the high instability and poorly understood functional meaning of the (CTA)n(CTG)n expansion. We performed haplotype and sequencing analysis in a large region, encompassing the repeat, in four SCA8 and 20 control Portuguese families. The results from the haplotype study including the combined repeat and six SNP markers showed two different haplotypes, AG-Exp-GTTG and AG-Exp-CTTG, in the SCA8 families. Among the control population, these were also the most frequent, in a total of five haplotypes found unequally distributed throughout repeat sizes. From cloning fragments of control, unstable normal and expanded chromosomes, eleven different base substitutions were identified in exon A of the SCA8 gene. In some instances, somatic variability in repeat size or base composition was found for a same chromosome, regardless of its normal or expanded nature. In conclusion, our results in Portuguese families with ataxia show that SCA8 expansions arose in common backgrounds; in addition, this region seems to be unstable beyond the repeat. © 2005 Wiley-Liss, Inc.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 09/2005; 139B(1):109 - 114. · 3.70 Impact Factor
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ABSTRACT: Dentatorubropallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder characterized by a variable combination of progressive ataxia, epilepsy, myoclonus, choreoathetosis and dementia. This disease is caused by a (CAG)(n) expansion in the DRPLA gene, on chromosome 12p13. DRPLA is prevalent in Japan, but several families of non-Japanese ancestry have already been published. To identify the origin of expanded alleles in Portuguese families with DRPLA, we studied two previously reported intragenic SNPs in introns 1 and 3, in addition to the CAG repeat of the DRPLA gene. The results showed that all four Portuguese DRPLA families shared the same haplotype, which is also common to that reported for Japanese DRPLA chromosomes. This haplotype is also the most frequent in Japanese normal alleles, whereas it was rare in Portuguese control chromosomes. Thus, our findings support that a founder DRPLA haplotype of Asian origin was introduced in Portugal, being responsible for the frequency of the disease in this country.
European Journal of HumanGenetics 11/2003; 11(10):808-11. · 4.40 Impact Factor
