先天性肌营养不良症患儿的 RNA 错接与身体功能有关。

IF 4.4 2区 医学 Q1 CLINICAL NEUROLOGY Annals of Clinical and Translational Neurology Pub Date : 2024-10-25 DOI:10.1002/acn3.52224
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
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引用次数: 0

摘要

目的:RNA替代剪接失调是1型肌营养不良症(DM1)的特征。然而,RNA错误剪接与最严重的先天性肌营养不良症(CDM)患儿的身体功能之间的关系尚不清楚:将五项观察性研究中的 82 名参与者(42 名患有 DM1 的成人和 40 名患有 CDM 的儿童)的肌肉活检结果以及肌张力、运动功能和力量测量结果进行合并。对数据进行了归一化处理,并将其与骨骼肌活检样本中替代剪接失调的综合测量值[MBNL]推断值相关联。进行了多元线性回归分析,仅使用临床结果指标预测[MBNL]推断值。使用基线指标预测 12 个月的身体功能也进行了类似的分析:结果:在我们的横断面人群中,所有 DM1 患者的肌张力(通过 vHOT 测量)与 RNA 错剪显著相关;尽管 RNA 错剪的范围相似,但 CDM 患者却没有肌张力。在我们的所有 DM1 群体中,以及在对 CDM 儿童进行独立评估时,运动表现和肌肉力量的测量结果与[MBNL]推断结果显著相关。多元线性回归分析得出了两个模型,能够预测所有受试者(调整后 R2 = 0.6723)或 CDM 患儿(调整后 R2 = 0.5875)仅从选定的临床结果评估中推断出的[MBNL]:我们的研究结果表明,在DM1患者中,骨骼肌表现与替代剪接失调的综合指标[MBNL]推断之间存在明显的相关性。这些相关性的强度和预测模型的开发将有助于为 DM1 患者,尤其是 CDM 患者设计有效的临床试验。
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RNA mis-splicing in children with congenital myotonic dystrophy is associated with physical function.

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.

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来源期刊
Annals of Clinical and Translational Neurology
Annals of Clinical and Translational Neurology Medicine-Neurology (clinical)
CiteScore
9.10
自引率
1.90%
发文量
218
审稿时长
8 weeks
期刊介绍: Annals of Clinical and Translational Neurology is a peer-reviewed journal for rapid dissemination of high-quality research related to all areas of neurology. The journal publishes original research and scholarly reviews focused on the mechanisms and treatments of diseases of the nervous system; high-impact topics in neurologic education; and other topics of interest to the clinical neuroscience community.
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