Trinucleotide repeat length instability and age of onset in Huntington's disease

Duyao, Mabel P.; Ambrose, Christine; Myers, Richard H.; Novelletto, Andrea; Persichetti, Francesca; Frontali, Marina; Folstein, Susan E.; Ross, Christopher A.; Franz, Mary L.; Abbott, Margaret H.

doi:10.1038/ng0893-387

Cited by 983 publications

(593 citation statements)

References 30 publications

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“…Expansion of trinucleotide repeats in other disorders is also influenced by the sex of origin. In Huntington disease, the largest increases in size of the (CAG) n repeat occur predominantly in male transmissions (17); while in myotonic dystrophy female transmissions tend to result in larger expansions (18). Another mutation with a bias in the sex of origin is the 1.5 Mb duplication within 17pl 1.2 that causes Charcot-Marie-Tooth disease type 1 A, which was shown by Palau, ex al.…”

Section: Discussionmentioning

confidence: 93%

Factor VIII gene inversions causing severe hemophilia A originate almost exclusively in male germ cells

et al. 1994

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The factor VIII gene, which Is defective In hemophilia A, Is located In the last megabase of the long arm of the X chromosome. Inversions due to intrachromosomal homologous recombination between mispaired copies of gene A located within intron 22 of the gene and about 500 kb telomerlc to it account for nearly half of all cases of severe hemophilia A. We hypothesized that pairing of Xq with its homolog inhibits the Inversion process, and that, therefore, the event originates predominantly in male germ cells. In all 20 informative cases In which the inversion originated in a maternal grandparent, DNA polymorphism analysis determined that it occurred in the male germline. In addition, all but one of 50 mothers of sporadic cases due to an inversion were carriers. Thus, these data support the hypothesis and Indicate that factor VIII gene inversions leading to severe hemophilia A occur almost exclusively In male germ cells.

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Section: Discussionmentioning

confidence: 93%

Factor VIII gene inversions causing severe hemophilia A originate almost exclusively in male germ cells

et al. 1994

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“…The size of the CAG repeat and the sex of the transmitting parent are known to have a significant role in CAG-tract instability. 4,32 Longer repeats have been shown to exhibit more instability and therefore are more likely to expand on transmission. Spermatogenesis is also believed to be involved in the molecular mechanism of CAG repeat instability in HD, given that expansion is more likely to occur during paternal transmission.…”

Section: Discussionmentioning

confidence: 99%

Huntington disease in the South African population occurs on diverse and ethnically distinct genetic haplotypes

et al. 2013

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Huntington disease (HD) is a neurodegenerative disorder resulting from the expansion of a CAG trinucleotide repeat in the huntingtin (HTT) gene. Worldwide prevalence varies geographically with the highest figures reported in populations of European ancestry. HD in South Africa has been reported in Caucasian, black and mixed subpopulations, with similar estimated prevalence in the Caucasian and mixed groups and a lower estimate in the black subpopulation. Recent studies have associated specific HTT haplotypes with HD in distinct populations. Expanded HD alleles in Europe occur predominantly on haplogroup A (specifically high-risk variants A1/A2), whereas in East Asian populations, HD alleles are associated with haplogroup C. Whether specific HTT haplotypes associate with HD in black Africans and how these compare with haplotypes found in European and East Asian populations remains unknown. The current study genotyped the HTT region in unaffected individuals and HD patients from each of the South African subpopulations, and haplotypes were constructed. CAG repeat sizes were determined and phased to haplotype. Results indicate that HD alleles from Caucasian and mixed patients are predominantly associated with haplogroup A, signifying a similar European origin for HD. However, in black patients, HD occurs predominantly on haplogroup B, suggesting several distinct origins of the mutation in South Africa. The absence of high-risk variants (A1/A2) in the black subpopulation may also explain the reported low prevalence of HD. Identification of haplotypes associated with HD-expanded alleles is particularly relevant to the development of population-specific therapeutic targets for selective suppression of the expanded HTT transcript.

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“…The mean age of onset of HD is 40-50 years, but expansion of the CAG repeat beyond 60 glutamines results in juvenile HD with more severe neuronal dysfunction. The length of the polyQ stretch in Htt is directly correlated to clinical severity of the disease and its penetrance in afflicted individuals (Duyao et al, 1993;Snell et al, 1993). The exact function of the ubiquitously expressed wild-type Htt protein is still elusive;…”

Section: Ii431 Huntington's Diseasementioning

confidence: 99%

Firefly luciferase mutants as sensors of proteome stress

et al. 2011

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Trinucleotide repeat length instability and age of onset in Huntington's disease

Cited by 983 publications

References 30 publications

Factor VIII gene inversions causing severe hemophilia A originate almost exclusively in male germ cells

Factor VIII gene inversions causing severe hemophilia A originate almost exclusively in male germ cells

Huntington disease in the South African population occurs on diverse and ethnically distinct genetic haplotypes

Firefly luciferase mutants as sensors of proteome stress

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