Somatic expansion of premutation alleles and the role of the mismatch repair and base excision repair proteins on repeat expansion in a mouse model of the fragile X-related disorders

Simple item page
dc.contributor.advisorParker, Iqbalen_ZA
dc.contributor.advisoren_ZA
dc.contributor.advisorUsdin, Karenen_ZA
dc.contributor.authorLokanga, Rachel Adiheen_ZA
dc.date.accessioned2016-07-27T10:22:17Z
dc.date.available2016-07-27T10:22:17Z
dc.date.issued2016en_ZA
dc.description.abstractThe Fragile X-related disorders arise from an unusual mutation in the X-linked FMR1 gene. The mutation involves expansion, or an increase in the number of repeats, in a CGG•CCG repeat tract located in its 5' untranslated region. FMR1 alleles carrying 55-200 repeats are called Premutation (PM) alleles, and cause Fragile X associated tremor/ataxia syndrome (FXTAS) and Fragile X-associated primary ovarian insufficiency (FXPOI). FMR1 alleles having more than 200 repeats are referred to as full mutation (FM) alleles and cause Fragile X syndrome (FXS). These different alleles arise by intergenerational expansion of the repeat tract from smaller unstable alleles by a mechanism that is unknown. We have shown that in addition to germ line expansion, somatic expansion also occurs in a human cell line in vivo and in a FX PM mouse model. In the mouse model, we found that the extent of somatic instability is dependent on age, gender and tissue. Specifically, organs such as brain, liver and gonads are susceptible to expand more than heart and kidney and expansion is much more frequent in males than in females. No differences were found between male and female mice in the levels of the DNA repair proteins that had already been implicated in repeat expansion in model systems of other disorders thought to arise via a similar mechanism. Neither were there any differences between males and females in the amounts of proteins produced from X-linked DNA repair genes. We also showed that estrogen did not protect against expansion. However, we found that PM alleles expanded exclusively when they were located on the active X chromosome. Thus some of the differences between males and xii females in the level of somatic expansion might be due to the fact that females undergo X inactivation and thus have the PM allele on the inactive X chromosome in half (~50%) of their cells. It also indicates that transcription and/or an open chromatin configuration is required for expansion in the FX PM mouse.en_ZA
dc.identifier.apacitationLokanga, R. A. (2016). <i>Somatic expansion of premutation alleles and the role of the mismatch repair and base excision repair proteins on repeat expansion in a mouse model of the fragile X-related disorders</i>. (Thesis). University of Cape Town ,Faculty of Health Sciences ,Division of Medical Biochemistry. Retrieved from http://hdl.handle.net/11427/20853en_ZA
dc.identifier.chicagocitationLokanga, Rachel Adihe. <i>"Somatic expansion of premutation alleles and the role of the mismatch repair and base excision repair proteins on repeat expansion in a mouse model of the fragile X-related disorders."</i> Thesis., University of Cape Town ,Faculty of Health Sciences ,Division of Medical Biochemistry, 2016. http://hdl.handle.net/11427/20853en_ZA
dc.identifier.citationLokanga, R. 2016. Somatic expansion of premutation alleles and the role of the mismatch repair and base excision repair proteins on repeat expansion in a mouse model of the fragile X-related disorders. University of Cape Town.en_ZA
dc.identifier.ris TY - Thesis / Dissertation AU - Lokanga, Rachel Adihe AB - The Fragile X-related disorders arise from an unusual mutation in the X-linked FMR1 gene. The mutation involves expansion, or an increase in the number of repeats, in a CGG•CCG repeat tract located in its 5' untranslated region. FMR1 alleles carrying 55-200 repeats are called Premutation (PM) alleles, and cause Fragile X associated tremor/ataxia syndrome (FXTAS) and Fragile X-associated primary ovarian insufficiency (FXPOI). FMR1 alleles having more than 200 repeats are referred to as full mutation (FM) alleles and cause Fragile X syndrome (FXS). These different alleles arise by intergenerational expansion of the repeat tract from smaller unstable alleles by a mechanism that is unknown. We have shown that in addition to germ line expansion, somatic expansion also occurs in a human cell line in vivo and in a FX PM mouse model. In the mouse model, we found that the extent of somatic instability is dependent on age, gender and tissue. Specifically, organs such as brain, liver and gonads are susceptible to expand more than heart and kidney and expansion is much more frequent in males than in females. No differences were found between male and female mice in the levels of the DNA repair proteins that had already been implicated in repeat expansion in model systems of other disorders thought to arise via a similar mechanism. Neither were there any differences between males and females in the amounts of proteins produced from X-linked DNA repair genes. We also showed that estrogen did not protect against expansion. However, we found that PM alleles expanded exclusively when they were located on the active X chromosome. Thus some of the differences between males and xii females in the level of somatic expansion might be due to the fact that females undergo X inactivation and thus have the PM allele on the inactive X chromosome in half (~50%) of their cells. It also indicates that transcription and/or an open chromatin configuration is required for expansion in the FX PM mouse. DA - 2016 DB - OpenUCT DP - University of Cape Town LK - https://open.uct.ac.za PB - University of Cape Town PY - 2016 T1 - Somatic expansion of premutation alleles and the role of the mismatch repair and base excision repair proteins on repeat expansion in a mouse model of the fragile X-related disorders TI - Somatic expansion of premutation alleles and the role of the mismatch repair and base excision repair proteins on repeat expansion in a mouse model of the fragile X-related disorders UR - http://hdl.handle.net/11427/20853 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/20853
dc.identifier.vancouvercitationLokanga RA. Somatic expansion of premutation alleles and the role of the mismatch repair and base excision repair proteins on repeat expansion in a mouse model of the fragile X-related disorders. [Thesis]. University of Cape Town ,Faculty of Health Sciences ,Division of Medical Biochemistry, 2016 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/20853en_ZA
dc.language.isoengen_ZA
dc.publisher.departmentDivision of Medical Biochemistryen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.subject.otherMedical Biochemistryen_ZA
dc.titleSomatic expansion of premutation alleles and the role of the mismatch repair and base excision repair proteins on repeat expansion in a mouse model of the fragile X-related disordersen_ZA
dc.typeDoctoral Thesis
dc.type.qualificationlevelDoctoral
dc.type.qualificationnamePhDen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceThesisen_ZA
Files
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
thesis_hsf_2016_lokanga_rachel_adihe..pdf
Size:
6.46 MB
Format:
Adobe Portable Document Format
Description:
Download
Collections
PhD / Doctoral