Deciphering the mechanisms underlying brain alterations and cognitive impairment in congenital myotonic dystrophy
Myotonic dystrophy type 1 (DM1) is a multisystemic and heterogeneous disorder caused by the expansion of CTG repeats in the 3’ UTR of the myotonic dystrophy protein kinase (DMPK) gene. There is a congenital form (CDM1) of the disease characterized by severe hypotonia, respiratory insufficiency as we...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-12-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996121002813 |
| _version_ | 1798033114809761792 |
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| author | Thiéry De Serres-Bérard Marion Pierre Mohamed Chahine Jack Puymirat |
| author_facet | Thiéry De Serres-Bérard Marion Pierre Mohamed Chahine Jack Puymirat |
| author_sort | Thiéry De Serres-Bérard |
| collection | DOAJ |
| description | Myotonic dystrophy type 1 (DM1) is a multisystemic and heterogeneous disorder caused by the expansion of CTG repeats in the 3’ UTR of the myotonic dystrophy protein kinase (DMPK) gene. There is a congenital form (CDM1) of the disease characterized by severe hypotonia, respiratory insufficiency as well as developmental delays and intellectual disabilities. CDM1 infants manifest important brain structure abnormalities present from birth while, in contrast, older patients with adult-onset DM1 often present neurodegenerative features and milder progressive cognitive deficits. Promising therapies targeting central molecular mechanisms contributing to the symptoms of adult-onset DM1 are currently in development, but their relevance for treating cognitive impairment in CDM1, which seems to be a partially distinct neurodevelopmental disorder, remain to be elucidated. Here, we provide an update on the clinical presentation of CDM1 and review recent in vitro and in vivo models that have provided meaningful insights on its consequences in development, with a particular focus on the brain. We discuss how enhanced toxic gain-of-function of the mutated DMPK transcripts with larger CUG repeats and the resulting dysregulation of RNA-binding proteins may affect the developing cortex in utero. Because the methylation of CpG islets flanking the trinucleotide repeats has emerged as a strong biomarker of CDM1, we highlight the need to investigate the tissue-specific impacts of these chromatin modifications in the brain. Finally, we outline promising potential therapeutic treatments for CDM1 and propose future in vitro and in vivo models with great potential to shed light on this disease. |
| first_indexed | 2024-04-11T20:23:52Z |
| format | Article |
| id | doaj.art-8759f92d2eac44d2beeb669ed7d4ec37 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-04-11T20:23:52Z |
| publishDate | 2021-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-8759f92d2eac44d2beeb669ed7d4ec372022-12-22T04:04:43ZengElsevierNeurobiology of Disease1095-953X2021-12-01160105532Deciphering the mechanisms underlying brain alterations and cognitive impairment in congenital myotonic dystrophyThiéry De Serres-Bérard0Marion Pierre1Mohamed Chahine2Jack Puymirat3LOEX, CHU de Québec-Université Laval Research Center, Quebec City, Canada; CERVO Brain Research Center, Institut universitaire en santé mentale de Québec, Quebec City, CanadaCERVO Brain Research Center, Institut universitaire en santé mentale de Québec, Quebec City, CanadaCERVO Brain Research Center, Institut universitaire en santé mentale de Québec, Quebec City, Canada; Department of Medicine, Faculty of Medicine, Université Laval, Quebec City, Canada; Corresponding author at: CERVO Brain Research Center, Institut universitaire en santé mentale de Québec, 2601 chemin de la Canardière, Quebec City G1J 2G3, Canada.LOEX, CHU de Québec-Université Laval Research Center, Quebec City, Canada; Department of Medicine, Faculty of Medicine, Université Laval, Quebec City, CanadaMyotonic dystrophy type 1 (DM1) is a multisystemic and heterogeneous disorder caused by the expansion of CTG repeats in the 3’ UTR of the myotonic dystrophy protein kinase (DMPK) gene. There is a congenital form (CDM1) of the disease characterized by severe hypotonia, respiratory insufficiency as well as developmental delays and intellectual disabilities. CDM1 infants manifest important brain structure abnormalities present from birth while, in contrast, older patients with adult-onset DM1 often present neurodegenerative features and milder progressive cognitive deficits. Promising therapies targeting central molecular mechanisms contributing to the symptoms of adult-onset DM1 are currently in development, but their relevance for treating cognitive impairment in CDM1, which seems to be a partially distinct neurodevelopmental disorder, remain to be elucidated. Here, we provide an update on the clinical presentation of CDM1 and review recent in vitro and in vivo models that have provided meaningful insights on its consequences in development, with a particular focus on the brain. We discuss how enhanced toxic gain-of-function of the mutated DMPK transcripts with larger CUG repeats and the resulting dysregulation of RNA-binding proteins may affect the developing cortex in utero. Because the methylation of CpG islets flanking the trinucleotide repeats has emerged as a strong biomarker of CDM1, we highlight the need to investigate the tissue-specific impacts of these chromatin modifications in the brain. Finally, we outline promising potential therapeutic treatments for CDM1 and propose future in vitro and in vivo models with great potential to shed light on this disease.http://www.sciencedirect.com/science/article/pii/S0969996121002813Congenital myotonic dystrophyMyotonic dystrophy type 1Brain developmentAlternative splicingDMPKMBNL |
| spellingShingle | Thiéry De Serres-Bérard Marion Pierre Mohamed Chahine Jack Puymirat Deciphering the mechanisms underlying brain alterations and cognitive impairment in congenital myotonic dystrophy Neurobiology of Disease Congenital myotonic dystrophy Myotonic dystrophy type 1 Brain development Alternative splicing DMPK MBNL |
| title | Deciphering the mechanisms underlying brain alterations and cognitive impairment in congenital myotonic dystrophy |
| title_full | Deciphering the mechanisms underlying brain alterations and cognitive impairment in congenital myotonic dystrophy |
| title_fullStr | Deciphering the mechanisms underlying brain alterations and cognitive impairment in congenital myotonic dystrophy |
| title_full_unstemmed | Deciphering the mechanisms underlying brain alterations and cognitive impairment in congenital myotonic dystrophy |
| title_short | Deciphering the mechanisms underlying brain alterations and cognitive impairment in congenital myotonic dystrophy |
| title_sort | deciphering the mechanisms underlying brain alterations and cognitive impairment in congenital myotonic dystrophy |
| topic | Congenital myotonic dystrophy Myotonic dystrophy type 1 Brain development Alternative splicing DMPK MBNL |
| url | http://www.sciencedirect.com/science/article/pii/S0969996121002813 |
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