An enhanced Q175 knock-in mouse model of Huntington disease with higher mutant huntingtin levels and accelerated disease phenotypes

Department of Drug Design and Pharmacology

An enhanced Q175 knock-in mouse model of Huntington disease with higher mutant huntingtin levels and accelerated disease phenotypes

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

An enhanced Q175 knock-in mouse model of Huntington disease with higher mutant huntingtin levels and accelerated disease phenotypes. / Southwell, Amber L; Smith-Dijak, Amy; Kay, Chris; Sepers, Marja; Villanueva, Erika B; Parsons, Matthew P; Xie, Yuanyun; Anderson, Lisa; Felczak, Boguslaw; Waltl, Sabine; Ko, Seunghyun; Cheung, Daphne; Dal Cengio, Louisa; Slama, Ramy; Petoukhov, Eugenia; Raymond, Lynn A; Hayden, Michael R.

In: Human Molecular Genetics, Vol. 25, No. 17, 01.09.2016, p. 3654-3675.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Southwell, AL, Smith-Dijak, A, Kay, C, Sepers, M, Villanueva, EB, Parsons, MP, Xie, Y, Anderson, L, Felczak, B, Waltl, S, Ko, S, Cheung, D, Dal Cengio, L, Slama, R, Petoukhov, E, Raymond, LA & Hayden, MR 2016, 'An enhanced Q175 knock-in mouse model of Huntington disease with higher mutant huntingtin levels and accelerated disease phenotypes', Human Molecular Genetics, vol. 25, no. 17, pp. 3654-3675. https://doi.org/10.1093/hmg/ddw212

APA

Southwell, A. L., Smith-Dijak, A., Kay, C., Sepers, M., Villanueva, E. B., Parsons, M. P., Xie, Y., Anderson, L., Felczak, B., Waltl, S., Ko, S., Cheung, D., Dal Cengio, L., Slama, R., Petoukhov, E., Raymond, L. A., & Hayden, M. R. (2016). An enhanced Q175 knock-in mouse model of Huntington disease with higher mutant huntingtin levels and accelerated disease phenotypes. Human Molecular Genetics, 25(17), 3654-3675. https://doi.org/10.1093/hmg/ddw212

Vancouver

Southwell AL, Smith-Dijak A, Kay C, Sepers M, Villanueva EB, Parsons MP et al. An enhanced Q175 knock-in mouse model of Huntington disease with higher mutant huntingtin levels and accelerated disease phenotypes. Human Molecular Genetics. 2016 Sep 1;25(17):3654-3675. https://doi.org/10.1093/hmg/ddw212

Author

Southwell, Amber L ; Smith-Dijak, Amy ; Kay, Chris ; Sepers, Marja ; Villanueva, Erika B ; Parsons, Matthew P ; Xie, Yuanyun ; Anderson, Lisa ; Felczak, Boguslaw ; Waltl, Sabine ; Ko, Seunghyun ; Cheung, Daphne ; Dal Cengio, Louisa ; Slama, Ramy ; Petoukhov, Eugenia ; Raymond, Lynn A ; Hayden, Michael R. / An enhanced Q175 knock-in mouse model of Huntington disease with higher mutant huntingtin levels and accelerated disease phenotypes. In: Human Molecular Genetics. 2016 ; Vol. 25, No. 17. pp. 3654-3675.

Bibtex

@article{929aed90a8124466b02b7a21968d5c1d,

title = "An enhanced Q175 knock-in mouse model of Huntington disease with higher mutant huntingtin levels and accelerated disease phenotypes",

abstract = "Huntington disease (HD) model mice with heterozygous knock-in (KI) of an expanded CAG tract in exon 1 of the mouse huntingtin (Htt) gene homolog genetically recapitulate the mutation that causes HD, and might be favoured for preclinical studies. However, historically these mice have failed to phenotypically recapitulate the human disease. Thus, homozygous KI mice, which lack wildtype Htt, and are much less relevant to human HD, have been used. The zQ175 model was the first KI mouse to exhibit significant HD-like phenotypes when heterozygous. In an effort to exacerbate HD-like phenotypes and enhance preclinical utility, we have backcrossed zQ175 mice to FVB/N, a strain highly susceptible to neurodegeneration. These Q175F mice display significant HD-like phenotypes along with sudden early death from fatal seizures. The zQ175 KI allele retains a floxed neomycin resistance cassette upstream of the Htt gene locus and produces dramatically reduced mutant Htt as compared to the endogenous wildtype Htt allele. By intercrossing with mice expressing cre in germ line cells, we have excised the neo cassette from Q175F mice generating a new line, Q175FΔneo (Q175FDN). Removal of the neo cassette resulted in a ∼2 fold increase in mutant Htt and rescue of fatal seizures, indicating that the early death phenotype of Q175F mice is caused by Htt deficiency rather than by mutant Htt. Additionally, Q175FDN mice exhibit earlier onset and a greater variety and severity of HD-like phenotypes than Q175F mice or any previously reported KI HD mouse model, making them valuable for preclinical studies.",

keywords = "Animals, Behavior, Animal, Crosses, Genetic, Disease Models, Animal, Gene Knock-In Techniques/methods, Heterozygote, Humans, Huntingtin Protein/genetics, Huntington Disease/genetics, Mice, Mutation, Phenotype",

author = "Southwell, {Amber L} and Amy Smith-Dijak and Chris Kay and Marja Sepers and Villanueva, {Erika B} and Parsons, {Matthew P} and Yuanyun Xie and Lisa Anderson and Boguslaw Felczak and Sabine Waltl and Seunghyun Ko and Daphne Cheung and {Dal Cengio}, Louisa and Ramy Slama and Eugenia Petoukhov and Raymond, {Lynn A} and Hayden, {Michael R}",

year = "2016",

month = sep,

day = "1",

doi = "10.1093/hmg/ddw212",

language = "English",

volume = "25",

pages = "3654--3675",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "17",

}

RIS

TY - JOUR

T1 - An enhanced Q175 knock-in mouse model of Huntington disease with higher mutant huntingtin levels and accelerated disease phenotypes

AU - Southwell, Amber L

AU - Smith-Dijak, Amy

AU - Kay, Chris

AU - Sepers, Marja

AU - Villanueva, Erika B

AU - Parsons, Matthew P

AU - Xie, Yuanyun

AU - Anderson, Lisa

AU - Felczak, Boguslaw

AU - Waltl, Sabine

AU - Ko, Seunghyun

AU - Cheung, Daphne

AU - Dal Cengio, Louisa

AU - Slama, Ramy

AU - Petoukhov, Eugenia

AU - Raymond, Lynn A

AU - Hayden, Michael R

PY - 2016/9/1

Y1 - 2016/9/1

N2 - Huntington disease (HD) model mice with heterozygous knock-in (KI) of an expanded CAG tract in exon 1 of the mouse huntingtin (Htt) gene homolog genetically recapitulate the mutation that causes HD, and might be favoured for preclinical studies. However, historically these mice have failed to phenotypically recapitulate the human disease. Thus, homozygous KI mice, which lack wildtype Htt, and are much less relevant to human HD, have been used. The zQ175 model was the first KI mouse to exhibit significant HD-like phenotypes when heterozygous. In an effort to exacerbate HD-like phenotypes and enhance preclinical utility, we have backcrossed zQ175 mice to FVB/N, a strain highly susceptible to neurodegeneration. These Q175F mice display significant HD-like phenotypes along with sudden early death from fatal seizures. The zQ175 KI allele retains a floxed neomycin resistance cassette upstream of the Htt gene locus and produces dramatically reduced mutant Htt as compared to the endogenous wildtype Htt allele. By intercrossing with mice expressing cre in germ line cells, we have excised the neo cassette from Q175F mice generating a new line, Q175FΔneo (Q175FDN). Removal of the neo cassette resulted in a ∼2 fold increase in mutant Htt and rescue of fatal seizures, indicating that the early death phenotype of Q175F mice is caused by Htt deficiency rather than by mutant Htt. Additionally, Q175FDN mice exhibit earlier onset and a greater variety and severity of HD-like phenotypes than Q175F mice or any previously reported KI HD mouse model, making them valuable for preclinical studies.

AB - Huntington disease (HD) model mice with heterozygous knock-in (KI) of an expanded CAG tract in exon 1 of the mouse huntingtin (Htt) gene homolog genetically recapitulate the mutation that causes HD, and might be favoured for preclinical studies. However, historically these mice have failed to phenotypically recapitulate the human disease. Thus, homozygous KI mice, which lack wildtype Htt, and are much less relevant to human HD, have been used. The zQ175 model was the first KI mouse to exhibit significant HD-like phenotypes when heterozygous. In an effort to exacerbate HD-like phenotypes and enhance preclinical utility, we have backcrossed zQ175 mice to FVB/N, a strain highly susceptible to neurodegeneration. These Q175F mice display significant HD-like phenotypes along with sudden early death from fatal seizures. The zQ175 KI allele retains a floxed neomycin resistance cassette upstream of the Htt gene locus and produces dramatically reduced mutant Htt as compared to the endogenous wildtype Htt allele. By intercrossing with mice expressing cre in germ line cells, we have excised the neo cassette from Q175F mice generating a new line, Q175FΔneo (Q175FDN). Removal of the neo cassette resulted in a ∼2 fold increase in mutant Htt and rescue of fatal seizures, indicating that the early death phenotype of Q175F mice is caused by Htt deficiency rather than by mutant Htt. Additionally, Q175FDN mice exhibit earlier onset and a greater variety and severity of HD-like phenotypes than Q175F mice or any previously reported KI HD mouse model, making them valuable for preclinical studies.

KW - Animals

KW - Behavior, Animal

KW - Crosses, Genetic

KW - Disease Models, Animal

KW - Gene Knock-In Techniques/methods

KW - Heterozygote

KW - Humans

KW - Huntingtin Protein/genetics

KW - Huntington Disease/genetics

KW - Mice

KW - Mutation

KW - Phenotype

U2 - 10.1093/hmg/ddw212

DO - 10.1093/hmg/ddw212

M3 - Journal article

C2 - 27378694

VL - 25

SP - 3654

EP - 3675

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 17

ER -

ID: 236603152