Journal ArticleDOI
High frequency of intermediate alleles on huntington disease‐associated haplotypes in British Columbia's general population
TLDR
It is suggested that IAs are relatively frequent in the general population and are often found on haplotypes associated with expanded CAG lengths, given that they are both found on disease‐associated haplotypes.Abstract:
Intermediate alleles (27–35 CAG, IAs) for Huntington disease (HD) usually do not confer the disease phenotype but are prone to CAG repeat instability. Consequently, offspring are at-risk of inheriting an expanded allele in the HD range (≥36 CAG). IAs that expand into a new mutation have been hypothesized to be more susceptible to instability compared to IAs identified on the non-HD side of a family from the general population. Frequency estimates for IAs are limited and have largely been determined using clinical samples of HD or related disorders, which may result in an ascertainment bias. This study aimed to establish the frequency of IAs in a sample of a British Columbia's (B.C.) general population with no known association to HD and examine the haplotype of new mutation and general population IAs. CAG sizing was performed on 1,600 DNA samples from B.C.'s general population. Haplotypes were determined using 22 tagging SNPs across the HTT gene. 5.8% of individuals were found to have an IA, of which 60% were on HD-associated haplotypes. There was no difference in the haplotype distribution of new mutation and general population IAs. These findings suggest that IAs are relatively frequent in the general population and are often found on haplotypes associated with expanded CAG lengths. There is likely no difference in the propensity of new mutation and general population IAs to expand into the disease range given that they are both found on disease-associated haplotypes. These findings have important implications for clinical practice. © 2013 Wiley Periodicals, Inc.read more
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Journal ArticleDOI
Polyglutamine Repeats in Neurodegenerative Diseases.
TL;DR: It has become apparent that CAG/polyQ repeat expansions produce neurodegeneration via multiple downstream mechanisms, involving both gain- and loss-of-function effects, and the likelihood of developing effective therapies targeting single nodes is reduced.
Journal ArticleDOI
Length of Uninterrupted CAG, Independent of Polyglutamine Size, Results in Increased Somatic Instability, Hastening Onset of Huntington Disease.
Galen E.B. Wright,Jennifer A. Collins,Chris Kay,Cassandra L. McDonald,Egor Dolzhenko,Qingwen Xia,Kristina Becanovic,Kristina Becanovic,Britt I. Drögemöller,Alicia Semaka,Charlotte Nguyen,Charlotte Nguyen,Brett Trost,Fiona Richards,Emilia K. Bijlsma,Ferdinando Squitieri,Colin J. D. Ross,Stephen W. Scherer,Stephen W. Scherer,Michael A. Eberle,Ryan K. C. Yuen,Ryan K. C. Yuen,Michael R. Hayden +22 more
TL;DR: The findings indicate that the number of uninterrupted CAG repeats, which is lengthened by the LOI, is the most significant contributor to AOO of HD and is more significant than polyglutamine length, which was not altered in these individuals.
Journal ArticleDOI
In vivo evaluation of candidate allele-specific mutant huntingtin gene silencing antisense oligonucleotides
Amber L. Southwell,Niels H. Skotte,Holly Kordasiewicz,Michael E. Østergaard,Andrew T. Watt,Jeffrey B. Carroll,Crystal N. Doty,Erika B. Villanueva,Eugenia Petoukhov,Kuljeet Vaid,Yuanyun Xie,Susan M. Freier,Eric E. Swayze,Punit P. Seth,Clarence Frank Bennett,Michael R. Hayden +15 more
TL;DR: Four well-tolerated lead ASOs are identified that potently and selectively silence muHTT at a broad range of doses throughout the central nervous system for 16 weeks or more after a single intracerebroventricular (ICV) injection, and could provide a therapeutic option for individuals afflicted with HD.
Journal ArticleDOI
Huntington disease reduced penetrance alleles occur at high frequency in the general population
Chris Kay,Jennifer A. Collins,Zosia Miedzybrodzka,Steven J. Madore,Erynn S. Gordon,Norman P. Gerry,Mark Davidson,Ramy A. Slama,Michael R. Hayden +8 more
TL;DR: HD alleles with a CAG repeat length of 36–38 occur at high frequency in the general population, likely due to low penetrance, and another important contributing factor may be reduced ascertainment of HD in those of older age.
Journal ArticleDOI
CAG size-specific risk estimates for intermediate allele repeat instability in Huntington disease
Alicia Semaka,Chris Kay,Crystal N. Doty,Jennifer A. Collins,Emilia K. Bijlsma,Fiona Richards,Y. Paul Goldberg,Michael R. Hayden +7 more
TL;DR: The data provided provide novel insights into the origins of new mutations for HD and the CAG size-specific risk estimates inform clinical practice and provide accurate risk information for persons who receive an IA predictive test result.
References
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Journal ArticleDOI
A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes
Marcy E. MacDonald,Christine Ambrose,Mabel P. Duyao,Richard H. Myers,Carol Lin,Lakshmi Srinidhi,Glenn Barnes,Sherryl A.M. Taylor,Marianne James,Nicolet Groot,Heather MacFarlane,Barbara Jenkins,Mary Anne Anderson,Nancy S. Wexler,James F. Gusella,Gillian P. Bates,Sarah Baxendale,Holger Hummerich,Susan F. Kirby,Mike North,S. Youngman,Richard Mott,Günther Zehetner,Zdenek Sedlacek,Annemarie Poustka,Anna-Maria Frischauf,Hans Lehrach,Alan Buckler,Deanna M. Church,Lynn Doucette-Stamm,Michael Conlon O'Donovan,Laura Riba-Ramirez,Manish A. Shah,Vincent P. Stanton,Scott A. Strobel,Karen M. Draths,Jennifer L. Wales,Peter B. Dervan,David E. Housman,Michael R. Altherr,Rita Shiang,Leslie M. Thompson,Thomas J. Fielder,John J. Wasmuth,Danilo A. Tagle,John Valdes,Lawrence W. Elmer,Marc W. Allard,Lucio H. Castilla,Manju Swaroop,Kris Blanchard,Francis S. Collins,Russell G. Snell,Tracey Holloway,Kathleen Gillespie,Nicole A. Datson,Duncan Shaw,Peter S. Harper +57 more
TL;DR: In this article, the authors used haplotype analysis of linkage disequilibrium to spotlight a small segment of 4p16.3 as the likely location of the defect, which is expanded and unstable on HD chromosomes.
Journal Article
A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group.
Manish A. Shah,Nicole A. Datson,Lakshmi Srinidhi,Vincent P. Stanton,Marcy E. MacDonald,Marc W. Allard,S. Youngman,Anna-Maria Frischauf,Richard Mott,KM Draths,Günther Zehetner,C. O’Donovan,Thomas J. Fielder,Bruce G. Jenkins,Manju Swaroop,Sherryl A.M. Taylor,Lynn Doucette-Stamm,Heather MacFarlane,Scott A. Strobel,H. E. McFarlane,Alan Buckler,Nicolet Groot,Holger Hummerich,Deanna M. Church,M. A. Anderson,Marianne James,Glenn Barnes,M. Christine,Francis S. Collins,Mabel P. Duyao,Peter B. Dervan,Gillian P. Bates,T Holloway,Peter S. Harper,TW Mcdonald,M North,K Blanchard,John J. Wasmuth,D. Shaw,Hans Lehrach,Danilo A. Tagle,Annemarie Poustka,David E. Housman,T. Huntington,Zdenek Sedlacek,Laura Riba,Susan F. Kirby,Carol Lin,Richard H. Myers,Leslie M. Thompson,Russell G. Snell,Michael Conlon O'Donovan,K Gillespie,Rita Shiang,Nancy S. Wexler,Christine Ambrose,J. F. Gusella,Sarah Baxendale,N. Groat,John Valdes +59 more
TL;DR: The Huntington's disease mutation involves an unstable DNA segment, similar to those described in fragile X syndrome, spino-bulbar muscular atrophy, and myotonic dystrophy, acting in the context of a novel 4p16.3 gene to produce a dominant phenotype.
Journal ArticleDOI
A Worldwide Study of the Huntington's Disease Mutation: The Sensitivity and Specificity of Measuring CAG Repeats
B. Kremer,Paul Goldberg,S E Andrew,J Theilmann,H Telenius,J Zeisler,Ferdinando Squitieri,Biaoyang Lin,Bassett A,E. Almqvist +9 more
TL;DR: CAG trinucleotide expansion is the molecular basis of Huntington's disease worldwide and is a highly sensitive and specific marker for inheritance of the disease mutation.
Journal Article
Phenotypic characterization of individuals with 30-40 CAG repeats in the Huntington disease (HD) gene reveals HD cases with 36 repeats and apparently normal elderly individuals with 36-39 repeats.
David C. Rubinsztein,Jayne Leggo,Rhian Coles,E. Almqvist,Biancalana,Jean Jaques Cassiman,Chotai K,Connarty M,Crauford D,Curtis A,Curtis D,Mark Davidson,Differ Am,Catherine Dodé,A Dodge,Marina Frontali,N G Ranen,O C Stine,M. Sherr,M. H. Abbott,Mary L. Franz,Colin A. Graham,Peter S. Harper,John C. Hedreen,Michael R. Hayden +24 more
TL;DR: Optimized methods for reliable sizing of CAG repeats are optimized and cases that demonstrate the dangers of using PCR assays that include both the CAG and CCG polymorphisms are shown.
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