A molecular investigation of true dominance in Huntington's disease
| Autor: | Andreas Wyttenbach, David C. Rubinsztein, Yolanda Narain, Robert A. Furlong, Julia Rankin |
|---|---|
| Rok vydání: | 1999 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities Time Factors Huntingtin Mutant Nerve Tissue Proteins Protein aggregation Biology Transfection Trinucleotide Repeats Huntington's disease mental disorders Genetics medicine Animals Humans Allele Alleles Genetics (clinical) Genes Dominant Dominance (genetics) Huntingtin Protein Dose-Response Relationship Drug Wild type Nuclear Proteins Heterozygote advantage Original Articles Exons medicine.disease nervous system diseases Huntington Disease Mutagenesis COS Cells |
| Zdroj: | Journal of Medical Genetics. 36:739-746 |
| ISSN: | 1468-6244 0022-2593 |
| DOI: | 10.1136/jmg.36.10.739 |
| Popis: | Huntington's disease (HD) is thought to show true dominance, since subjects with two mutant alleles have been reported to have similar ages at onset of disease compared to heterozygous sibs. We have investigated this phenomenon using a cell culture model. Protein aggregate formation was used as an indicator for pathology, as intraneuronal huntingtin inclusions are associated with pathology in vitro and in vivo. We showed that cytoplasmic and nuclear aggregates are formed by constructs comprising part of exon 1 of huntingtin with 41, 51, 66, or 72 CAG repeats, in a rate that correlates with repeat number. No inclusions were seen with 21 CAG repeat constructs. Mutant and wild type huntingtin fragments can be sequestered into inclusions seeded by a mutant huntingtin. Wild type huntingtin did not enhance or interfere with protein aggregation. The rate of protein aggregation was dose dependent for all mutant constructs tested. These experiments suggested a model for the dominance observed in HD; the decrease in the age at onset of a mutant homozygote may be small compared to the variance in the age at onset for that specific repeat number in heterozygotes. Our experiments also provide a model, which may explain the different repeat size ranges seen in patients and healthy controls for the different polyglutamine diseases. Keywords: Huntington's disease; huntingtin; CAG repeats; true dominance |
| Databáze: | OpenAIRE |
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