Dynamics and variability of transcriptomic dysregulation in congenital myotonic dystrophy during pediatric development

Hale, Melissa A.; Bates, Kameron; Provenzano, Marina; Johnson, Nicholas E.

doi:10.1093/hmg/ddac254

Cited by 5 publications

(19 citation statements)

References 76 publications

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“…Total RNA sequencing was performed on RNA extracted from all muscle biopsies and [MBNL] inferred values were derived for each individual as previously described 27,28 . In brief, percent-spliced in (PSI) values from 9 skipped exon splicing events with high predictive power of overall global mis-splicing in DM1 muscle were used to calculate [MBNL] inferred 27,28 . [MBNL] inferred values and CDM participants sub-cohort classifications were previously defined 28 .…”

Section: Methodsmentioning

confidence: 99%

“…In brief, percent-spliced in (PSI) values from 9 skipped exon splicing events with high predictive power of overall global mis-splicing in DM1 muscle were used to calculate [MBNL] inferred 27,28 . [MBNL] inferred values and CDM participants sub-cohort classifications were previously defined 28 . CDM sub-cohort classification of included individuals was defined based on age and [MBNL] inferred .…”

Section: Methodsmentioning

confidence: 99%

“…Muscle biopsies from adult DM1 participants were collected with either a Bergstrom or 14-gauge argon Supercore needle of the tibialis anterior (TA) as previously described 38 . Muscle biopsies of the vastus lateralis from CDM children were obtained using either an open surgical technique or a 14-gauge Argon Supercore needle 28 . In all studies, biopsies were not performed in individuals with known bleeding disorders, a history of anti-coagulation medication use, or a platelet count less than 50,000.…”

Section: Muscle Biopsy Collection and Derivation Of [Mbnl] Inferredmentioning

confidence: 99%

“…[MBNL] inferred values and CDM participants sub-cohort classifications were previously defined 28 . CDM sub-cohort classification of included individuals was defined based on age and [MBNL] inferred .…”

Section: Muscle Biopsy Collection and Derivation Of [Mbnl] Inferredmentioning

confidence: 99%

“…Previous work by our group has characterized global splicing dysregulation in skeletal muscle of DM1 adults and a cohort of children with CDM using a composite measure of MBNL-dependent splicing, [MBNL] inferred . This representative metric of free intracellular MBNL concentration strongly correlates with global splicing dysregulation as captured by total RNA sequencing 27,28 .…”

Section: Introductionmentioning

confidence: 99%

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RNA mis-splicing in children with myotonic dystrophy is associated with physical function

Hartman,

Ikegami,

Provenzano

et al. 2024

Preprint

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ObjectivesDysregulated 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.Methods82 participants (42 DM1 adults & 40 CDM children) 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]inferredin skeletal muscle biopsies. Multiple linear regression analysis was performed to predict [MBNL]inferredusing clinical outcome measures alone. Similar analyses were performed to predict 12-month physical function using baseline metrics.ResultsMyotonia (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]inferredin our cohort of all DM1 individuals and when assessing CDM children independently. Multiple linear regression analyses yielded two models capable of predicting [MBNL]inferredfrom select clinical outcome assessments alone in all subjects (adjusted R2= 0.6723) or exclusively in CDM children (adjusted R2= 0.5875).InterpretationOur 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 the predictive models will assist in designing efficacious clinical trials for individuals with DM1, particularly CDM.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Muscle Biopsy Collection and Derivation Of [Mbnl] Inferredmentioning

confidence: 99%

Section: Muscle Biopsy Collection and Derivation Of [Mbnl] Inferredmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

RNA mis-splicing in children with myotonic dystrophy is associated with physical function

Hartman,

Ikegami,

Provenzano

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

RNA mis‐splicing in children with congenital myotonic dystrophy is associated with physical function

Hartman,

Ikegami,

Provenzano

et al. 2024

Ann Clin Transl Neurol

View full text Add to dashboard Cite

ObjectivesDysregulated 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.MethodsEighty‐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.ResultsMyotonia (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).InterpretationOur 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.

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Revealing myopathy spectrum: integrating transcriptional and clinical features of human skeletal muscles with varying health conditions

Zhong,

Sian,

Johari

et al. 2024

Commun Biol

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Myopathy refers to a large group of heterogeneous, rare muscle diseases. Bulk RNA-sequencing has been utilized for the diagnosis and research of these diseases for many years. However, the existing valuable sequencing data often lack integration and clinical interpretation. In this study, we integrated bulk RNA-sequencing data from 1221 human skeletal muscles (292 with myopathies, 929 controls) from both databases and our local samples. By applying a method similar to single-cell analysis, we revealed a general spectrum of muscle diseases, ranging from healthy to mild disease, moderate muscle wasting, and severe muscle disease. This spectrum was further partly validated in three specific myopathies (97 muscles) through clinical features including trinucleotide repeat expansion, magnetic resonance imaging fat fraction, pathology, and clinical severity scores. This spectrum helped us identify 234 genuinely healthy muscles as unprecedented controls, providing a new perspective for deciphering the hallmark genes and pathways among different myopathies. The newly identified featured genes of general myopathy, inclusion body myositis, and titinopathy were highly expressed in our local muscles, as validated by quantitative polymerase chain reaction.

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Dynamics and variability of transcriptomic dysregulation in congenital myotonic dystrophy during pediatric development

Cited by 5 publications

References 76 publications

RNA mis-splicing in children with myotonic dystrophy is associated with physical function

RNA mis-splicing in children with myotonic dystrophy is associated with physical function

RNA mis‐splicing in children with congenital myotonic dystrophy is associated with physical function

Revealing myopathy spectrum: integrating transcriptional and clinical features of human skeletal muscles with varying health conditions

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