Myotonic Dystrophy Type 1: the heterogeneity of a complex disease in a global research approach

[eng] Myotonic Dystrophy Type 1 (DM1) is a complex disease with a dominant autosomic inheritance caused by a CTG expansion at the end of the DMPK gene. This expansion is very unstable and it is known that is correlated with the severity of the disease. However, DM1 is a multisystemic disease, with a...

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Detalhes bibliográficos
Autor: Ballester López, Alfonsina
Formato: tesis doctoral
Estado:Versión publicada
Fecha de publicación:2020
País:España
Recursos:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/178346
Acesso em linha:https://hdl.handle.net/2445/178346
http://hdl.handle.net/10803/671860
Access Level:acceso abierto
Palavra-chave:Neurociències
Distròfia muscular
Neurosciences
Muscular dystrophy
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oai_identifier_str oai:diposit.ub.edu:2445/178346
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Myotonic Dystrophy Type 1: the heterogeneity of a complex disease in a global research approach
title Myotonic Dystrophy Type 1: the heterogeneity of a complex disease in a global research approach
spellingShingle Myotonic Dystrophy Type 1: the heterogeneity of a complex disease in a global research approach
Ballester López, Alfonsina
Neurociències
Distròfia muscular
Neurosciences
Muscular dystrophy
title_short Myotonic Dystrophy Type 1: the heterogeneity of a complex disease in a global research approach
title_full Myotonic Dystrophy Type 1: the heterogeneity of a complex disease in a global research approach
title_fullStr Myotonic Dystrophy Type 1: the heterogeneity of a complex disease in a global research approach
title_full_unstemmed Myotonic Dystrophy Type 1: the heterogeneity of a complex disease in a global research approach
title_sort Myotonic Dystrophy Type 1: the heterogeneity of a complex disease in a global research approach
dc.creator.none.fl_str_mv Ballester López, Alfonsina
author Ballester López, Alfonsina
author_facet Ballester López, Alfonsina
author_role author
dc.contributor.none.fl_str_mv Nogales Gadea, Gisela
Universitat de Barcelona. Facultat de Medicina i Ciències de la Salut
dc.subject.none.fl_str_mv Neurociències
Distròfia muscular
Neurosciences
Muscular dystrophy
topic Neurociències
Distròfia muscular
Neurosciences
Muscular dystrophy
description [eng] Myotonic Dystrophy Type 1 (DM1) is a complex disease with a dominant autosomic inheritance caused by a CTG expansion at the end of the DMPK gene. This expansion is very unstable and it is known that is correlated with the severity of the disease. However, DM1 is a multisystemic disease, with a high heterogeneity in the clinical manifestation and with no cure yet. The main pathomolecular mechanism, although the is incomplete information, it is caused by the accumulation of toxic RNA aggregates called RNA foci, product from the CTG expansion. In the present thesis we analyzed the genetic complexity of DM1. First, studying different methods that are currently used to size the CTG expansion in DM1 patients and compare the results between them. We have seen that different methodologies yield different results, and thus, manifesting the need of establishing a universal method in the DM1 community for sizing the CTG expansion in patients with DM1. We also studied the genetic instability present in three tissues of DM1 patients: blood, muscle and skin. We have seen that the three tissues have CTG instability, with longer expansions present in muscle and skin compared to blood. Moreover, we have seen that only the estimated progenitor Resumen de la Tesis: Myotonic Dystrophy Type 1 (DM1) is a complex disease with a dominant autosomic inheritance caused by a CTG expansion at the end of the DMPK gene. This expansion is very unstable and it is known that is correlated with the severity of the disease. However, DM1 is a multisystemic disease, with a high heterogeneity in the clinical manifestation and with no cure yet. The main pathomolecular mechanism, although the is incomplete information, it is caused by the accumulation of toxic RNA aggregates called RNA foci, product from the CTG expansion. In the present thesis we analyzed the genetic complexity of DM1. First, studying different methods that are currently used to size the CTG expansion in DM1 patients and compare the results between them. We have seen that different methodologies yield different results, and thus, manifesting the need of establishing a universal method in the DM1 community for sizing the CTG expansion in patients with DM1. We also studied the genetic instability present in three tissues of DM1 patients: blood, muscle and skin. We have seen that the three tissues have CTG instability, with longer expansions present in muscle and skin compared to blood. Moreover, we have seen that only the estimated progenitor CTG expansion found in muscle correlates with the age of disease onset of these patients. We studied as well the presence of interruptions in the CTG expansion and how these variant repeats can affect the genetic transmission in between generations and the phenotype of the patients. After analyzing a cohort of 49 DM1 patients we have seen that 10% of the patients carried CCG interruptions. Moreover, the presence of interruptions resulted, in one case, in a contraction of the CTG expansion in between generations, but also resulted in an expansion of the CTG track in the other case, linked to anticipation. As it has been previously described, we have seen that the presence of interruptions can be linked to non-typical phenotypic traits of DM1, such as proximal weakness. However, contrary of what is believed, we have seen that patients carrying interruptions can develop a clinical phenotype with a high severity. We also studied the pathomolecular mechanism of RNA gain-of function, trough 3D imaging. We studied myoblasts cells derived from DM1 patients, analyzing the presence of RNA toxic aggregates. 3D imaging allowed us to have a full characterization of the cell, quantifying the number of the RNA toxic aggregates and studying the relationship between the main molecular players. We have seen that the CTG expansion leads the number of RNA foci that is accumulated in the cell and the number of the RNA foci correlates with the DMPK expression. We have seen as well that the RNA foci is not only present in the nucleus, but also in the cytoplasm, and the area of these toxic aggregates is related with its presence in the cytoplasm. Finally, we studied the efficacy (reduction of RNA foci number) and toxicity (cell mortality) of a promising therapeutic approach for DM1, using antisense oligonucleotides with BNANC modifications, in cells derived from DM1 patients. We have studied the treatment response in three different subtypes, since due to the multisystemic nature of DM1, it is necessary to know how the different cells would react to a specific treatment. We have seen that the RNA foci reduction and the cell mortality is different in fibroblasts, lymphoblasts and myoblasts of Dm1 patients. Myoblasts, derived from one of the most affected tissues in DM1 patients, are the cells responding less to the treatment, which highlights the importance to perform experiments in order to improve the delivery in these cells. Moreover, we have seen that the treatment response seems to not be related with the CTG expansion size.
publishDate 2020
dc.date.none.fl_str_mv 2020
dc.type.none.fl_str_mv info:eu-repo/semantics/doctoralThesis
info:eu-repo/semantics/publishedVersion
format doctoralThesis
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/178346
http://hdl.handle.net/10803/671860
url https://hdl.handle.net/2445/178346
http://hdl.handle.net/10803/671860
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv cc by-nc-nd (c) Ballester López, Alfonsina, 2021
http://creativecommons.org/licenses/by-nc-nd/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by-nc-nd (c) Ballester López, Alfonsina, 2021
http://creativecommons.org/licenses/by-nc-nd/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv Tesis Doctorals - Facultat - Medicina i Ciències de la Salut
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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spelling Myotonic Dystrophy Type 1: the heterogeneity of a complex disease in a global research approachBallester López, AlfonsinaNeurociènciesDistròfia muscularNeurosciencesMuscular dystrophy[eng] Myotonic Dystrophy Type 1 (DM1) is a complex disease with a dominant autosomic inheritance caused by a CTG expansion at the end of the DMPK gene. This expansion is very unstable and it is known that is correlated with the severity of the disease. However, DM1 is a multisystemic disease, with a high heterogeneity in the clinical manifestation and with no cure yet. The main pathomolecular mechanism, although the is incomplete information, it is caused by the accumulation of toxic RNA aggregates called RNA foci, product from the CTG expansion. In the present thesis we analyzed the genetic complexity of DM1. First, studying different methods that are currently used to size the CTG expansion in DM1 patients and compare the results between them. We have seen that different methodologies yield different results, and thus, manifesting the need of establishing a universal method in the DM1 community for sizing the CTG expansion in patients with DM1. We also studied the genetic instability present in three tissues of DM1 patients: blood, muscle and skin. We have seen that the three tissues have CTG instability, with longer expansions present in muscle and skin compared to blood. Moreover, we have seen that only the estimated progenitor Resumen de la Tesis: Myotonic Dystrophy Type 1 (DM1) is a complex disease with a dominant autosomic inheritance caused by a CTG expansion at the end of the DMPK gene. This expansion is very unstable and it is known that is correlated with the severity of the disease. However, DM1 is a multisystemic disease, with a high heterogeneity in the clinical manifestation and with no cure yet. The main pathomolecular mechanism, although the is incomplete information, it is caused by the accumulation of toxic RNA aggregates called RNA foci, product from the CTG expansion. In the present thesis we analyzed the genetic complexity of DM1. First, studying different methods that are currently used to size the CTG expansion in DM1 patients and compare the results between them. We have seen that different methodologies yield different results, and thus, manifesting the need of establishing a universal method in the DM1 community for sizing the CTG expansion in patients with DM1. We also studied the genetic instability present in three tissues of DM1 patients: blood, muscle and skin. We have seen that the three tissues have CTG instability, with longer expansions present in muscle and skin compared to blood. Moreover, we have seen that only the estimated progenitor CTG expansion found in muscle correlates with the age of disease onset of these patients. We studied as well the presence of interruptions in the CTG expansion and how these variant repeats can affect the genetic transmission in between generations and the phenotype of the patients. After analyzing a cohort of 49 DM1 patients we have seen that 10% of the patients carried CCG interruptions. Moreover, the presence of interruptions resulted, in one case, in a contraction of the CTG expansion in between generations, but also resulted in an expansion of the CTG track in the other case, linked to anticipation. As it has been previously described, we have seen that the presence of interruptions can be linked to non-typical phenotypic traits of DM1, such as proximal weakness. However, contrary of what is believed, we have seen that patients carrying interruptions can develop a clinical phenotype with a high severity. We also studied the pathomolecular mechanism of RNA gain-of function, trough 3D imaging. We studied myoblasts cells derived from DM1 patients, analyzing the presence of RNA toxic aggregates. 3D imaging allowed us to have a full characterization of the cell, quantifying the number of the RNA toxic aggregates and studying the relationship between the main molecular players. We have seen that the CTG expansion leads the number of RNA foci that is accumulated in the cell and the number of the RNA foci correlates with the DMPK expression. We have seen as well that the RNA foci is not only present in the nucleus, but also in the cytoplasm, and the area of these toxic aggregates is related with its presence in the cytoplasm. Finally, we studied the efficacy (reduction of RNA foci number) and toxicity (cell mortality) of a promising therapeutic approach for DM1, using antisense oligonucleotides with BNANC modifications, in cells derived from DM1 patients. We have studied the treatment response in three different subtypes, since due to the multisystemic nature of DM1, it is necessary to know how the different cells would react to a specific treatment. We have seen that the RNA foci reduction and the cell mortality is different in fibroblasts, lymphoblasts and myoblasts of Dm1 patients. Myoblasts, derived from one of the most affected tissues in DM1 patients, are the cells responding less to the treatment, which highlights the importance to perform experiments in order to improve the delivery in these cells. Moreover, we have seen that the treatment response seems to not be related with the CTG expansion size.Nogales Gadea, GiselaUniversitat de Barcelona. Facultat de Medicina i Ciències de la Salut2020info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/178346http://hdl.handle.net/10803/671860Tesis Doctorals - Facultat - Medicina i Ciències de la Salutreponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaIngléscc by-nc-nd (c) Ballester López, Alfonsina, 2021http://creativecommons.org/licenses/by-nc-nd/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1783462026-05-27T06:46:51Z
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