RNA mis‐splicing in children with congenital myotonic dystrophy is associated with physical function
Abstract Objectives Dysregulated RNA alternative splicing is the hallmark of myotonic dystrophy type 1 (DM1). However, the association between RNA mis‐splicing and physical function in children with the most severe form of disease, congenital myotonic dystrophy (CDM), is unknown. Methods Eighty‐two...
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| Format: | Article |
| Language: | English |
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Wiley
2024-12-01
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| Series: | Annals of Clinical and Translational Neurology |
| Online Access: | https://doi.org/10.1002/acn3.52224 |
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| author | Julia M. Hartman Kobe Ikegami Marina Provenzano Kameron Bates Amanda Butler Aileen S. Jones Kiera N. Berggren Jeanne Dekdebrun Marnee J. McKay Jennifer N. Baldwin Kayla M. D. Cornett Joshua Burns Michael Kiefer Nicholas E. Johnson Melissa A. Hale the DMCRN Consortium |
| author_facet | Julia M. Hartman Kobe Ikegami Marina Provenzano Kameron Bates Amanda Butler Aileen S. Jones Kiera N. Berggren Jeanne Dekdebrun Marnee J. McKay Jennifer N. Baldwin Kayla M. D. Cornett Joshua Burns Michael Kiefer Nicholas E. Johnson Melissa A. Hale the DMCRN Consortium |
| author_sort | Julia M. Hartman |
| collection | DOAJ |
| description | Abstract Objectives Dysregulated RNA alternative splicing is the hallmark of myotonic dystrophy type 1 (DM1). However, the association between RNA mis‐splicing and physical function in children with the most severe form of disease, congenital myotonic dystrophy (CDM), is unknown. Methods Eighty‐two participants (42 adults with DM1 and 40 children with CDM) with muscle biopsies and measures of myotonia, motor function, and strength were combined from five observational studies. Data were normalized and correlated with an aggregate measure of alternative splicing dysregulation, [MBNL]inferred, in skeletal muscle biopsies. Multiple linear regression analysis was performed to predict [MBNL]inferred using clinical outcome measures alone. Similar analyses were performed to predict 12‐month physical function using baseline metrics. Results Myotonia (measured via vHOT) was significantly correlated with RNA mis‐splicing in our cross‐sectional population of all DM1 individuals; CDM participants alone displayed no myotonia despite a similar range of RNA mis‐splicing. Measures of motor performance and muscle strength were significantly associated with [MBNL]inferred in our cohort of all DM1 individuals and when assessing children with CDM independently. Multiple linear regression analyses yielded two models capable of predicting [MBNL]inferred from select clinical outcome assessments alone in all subjects (adjusted R2 = 0.6723) or exclusively in children with CDM (adjusted R2 = 0.5875). Interpretation Our findings establish significant correlations between skeletal muscle performance and a composite measure of alternative splicing dysregulation, [MBNL]inferred, in DM1. The strength of these correlations and the development of predictive models will assist in designing efficacious clinical trials for individuals with DM1, particularly CDM. |
| format | Article |
| id | doaj-art-39ea475afc2640619fc2a601ba893d7c |
| institution | Kabale University |
| issn | 2328-9503 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Annals of Clinical and Translational Neurology |
| spelling | doaj-art-39ea475afc2640619fc2a601ba893d7c2024-12-17T16:12:21ZengWileyAnnals of Clinical and Translational Neurology2328-95032024-12-0111123175319110.1002/acn3.52224RNA mis‐splicing in children with congenital myotonic dystrophy is associated with physical functionJulia M. Hartman0Kobe Ikegami1Marina Provenzano2Kameron Bates3Amanda Butler4Aileen S. Jones5Kiera N. Berggren6Jeanne Dekdebrun7Marnee J. McKay8Jennifer N. Baldwin9Kayla M. D. Cornett10Joshua Burns11Michael Kiefer12Nicholas E. Johnson13Melissa A. Hale14the DMCRN ConsortiumMedical Scientist Training Program Virginia Commonwealth University Richmond Virginia 23298 USACenter for Inherited Myology Research Virginia Commonwealth University Richmond Virginia 23298 USACenter for Inherited Myology Research Virginia Commonwealth University Richmond Virginia 23298 USACenter for Inherited Myology Research Virginia Commonwealth University Richmond Virginia 23298 USACenter for Inherited Myology Research Virginia Commonwealth University Richmond Virginia 23298 USACenter for Inherited Myology Research Virginia Commonwealth University Richmond Virginia 23298 USACenter for Inherited Myology Research Virginia Commonwealth University Richmond Virginia 23298 USADepartment of Neurology University of Rochester School of Medicine and Dentistry Rochester New York 14642 USASydney School of Health Sciences, Faculty of Medicine and Health The University of Sydney Sydney New South Wales 2006 AustraliaSydney School of Health Sciences, Faculty of Medicine and Health The University of Sydney Sydney New South Wales 2006 AustraliaSydney School of Health Sciences, Faculty of Medicine and Health The University of Sydney Sydney New South Wales 2006 AustraliaSydney School of Health Sciences, Faculty of Medicine and Health The University of Sydney Sydney New South Wales 2006 AustraliaCenter for Inherited Myology Research Virginia Commonwealth University Richmond Virginia 23298 USACenter for Inherited Myology Research Virginia Commonwealth University Richmond Virginia 23298 USACenter for Inherited Myology Research Virginia Commonwealth University Richmond Virginia 23298 USAAbstract Objectives Dysregulated RNA alternative splicing is the hallmark of myotonic dystrophy type 1 (DM1). However, the association between RNA mis‐splicing and physical function in children with the most severe form of disease, congenital myotonic dystrophy (CDM), is unknown. Methods Eighty‐two participants (42 adults with DM1 and 40 children with CDM) with muscle biopsies and measures of myotonia, motor function, and strength were combined from five observational studies. Data were normalized and correlated with an aggregate measure of alternative splicing dysregulation, [MBNL]inferred, in skeletal muscle biopsies. Multiple linear regression analysis was performed to predict [MBNL]inferred using clinical outcome measures alone. Similar analyses were performed to predict 12‐month physical function using baseline metrics. Results Myotonia (measured via vHOT) was significantly correlated with RNA mis‐splicing in our cross‐sectional population of all DM1 individuals; CDM participants alone displayed no myotonia despite a similar range of RNA mis‐splicing. Measures of motor performance and muscle strength were significantly associated with [MBNL]inferred in our cohort of all DM1 individuals and when assessing children with CDM independently. Multiple linear regression analyses yielded two models capable of predicting [MBNL]inferred from select clinical outcome assessments alone in all subjects (adjusted R2 = 0.6723) or exclusively in children with CDM (adjusted R2 = 0.5875). Interpretation Our findings establish significant correlations between skeletal muscle performance and a composite measure of alternative splicing dysregulation, [MBNL]inferred, in DM1. The strength of these correlations and the development of predictive models will assist in designing efficacious clinical trials for individuals with DM1, particularly CDM.https://doi.org/10.1002/acn3.52224 |
| spellingShingle | Julia M. Hartman Kobe Ikegami Marina Provenzano Kameron Bates Amanda Butler Aileen S. Jones Kiera N. Berggren Jeanne Dekdebrun Marnee J. McKay Jennifer N. Baldwin Kayla M. D. Cornett Joshua Burns Michael Kiefer Nicholas E. Johnson Melissa A. Hale the DMCRN Consortium RNA mis‐splicing in children with congenital myotonic dystrophy is associated with physical function Annals of Clinical and Translational Neurology |
| title | RNA mis‐splicing in children with congenital myotonic dystrophy is associated with physical function |
| title_full | RNA mis‐splicing in children with congenital myotonic dystrophy is associated with physical function |
| title_fullStr | RNA mis‐splicing in children with congenital myotonic dystrophy is associated with physical function |
| title_full_unstemmed | RNA mis‐splicing in children with congenital myotonic dystrophy is associated with physical function |
| title_short | RNA mis‐splicing in children with congenital myotonic dystrophy is associated with physical function |
| title_sort | rna mis splicing in children with congenital myotonic dystrophy is associated with physical function |
| url | https://doi.org/10.1002/acn3.52224 |
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