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A molecular investigation of true dominance in Huntington's disease

A molecular investigation of true dominance in Huntington's disease
A molecular investigation of true dominance in Huntington's disease
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
Huntington's disease, huntingtin, CAG repeats, true dominance
0022-2593
739-746
Narain, Yolanda
4ebf43f3-0b45-4bc4-a245-abc8edeb659c
Wyttenbach, Andreas
05019897-52b1-4bb6-b259-5d51abae7540
Rankin, Julia
e10a0f80-2929-4b47-8fa2-8dee01ce39c6
Furlong, Robert.A.
af3f0ae2-e428-4ad0-9ec7-54dae0c27951
Rubinsztein, David.C.
363fea4a-4a87-4ab4-896d-c696d1d40a21
Narain, Yolanda
4ebf43f3-0b45-4bc4-a245-abc8edeb659c
Wyttenbach, Andreas
05019897-52b1-4bb6-b259-5d51abae7540
Rankin, Julia
e10a0f80-2929-4b47-8fa2-8dee01ce39c6
Furlong, Robert.A.
af3f0ae2-e428-4ad0-9ec7-54dae0c27951
Rubinsztein, David.C.
363fea4a-4a87-4ab4-896d-c696d1d40a21

Narain, Yolanda, Wyttenbach, Andreas, Rankin, Julia, Furlong, Robert.A. and Rubinsztein, David.C. (1999) A molecular investigation of true dominance in Huntington's disease. Journal of Medical Genetics, 36, 739-746.

Record type: Article

Abstract

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

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More information

Published date: 1 October 1999
Keywords: Huntington's disease, huntingtin, CAG repeats, true dominance

Identifiers

Local EPrints ID: 56023
URI: http://eprints.soton.ac.uk/id/eprint/56023
ISSN: 0022-2593
PURE UUID: b5dd29b4-c007-42c2-8696-96a80745a3a7

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Date deposited: 06 Aug 2008
Last modified: 09 Jan 2022 08:44

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Contributors

Author: Yolanda Narain
Author: Andreas Wyttenbach
Author: Julia Rankin
Author: Robert.A. Furlong
Author: David.C. Rubinsztein

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