Phenotypic Spectrum of Dystrophinopathy Due to Duchenne Muscular Dystrophy Exon 2 Duplications

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000013246
Author(s):  
Alberto A Zambon ◽  
Megan A Waldrop ◽  
Roxane Alles ◽  
Robert B Weiss ◽  
Sara Conroy ◽  
...  
Keyword(s):  
Vital Capacity ◽  
Full Length ◽  
Time To Event ◽  
Rank Tests ◽  
Entry Site ◽  
Internal Ribosome Entry ◽  
Exon 2 ◽  
Phenotypic Spectrum ◽  
Age Related ◽  
New Treatments

Background and Objectives:To describe the phenotypic spectrum of dystrophinopathy in a large cohort of individuals with DMD exon 2 duplications (Dup2), whom may be particularly amenable to therapies directed at restoring expression of either full-length dystrophin, or nearly full-length dystrophin through utilization of the DMD exon 5 internal ribosome entry site (IRES).Methods:In this retrospective observational study, we analyzed data from large genotype-phenotype databases (the United Dystrophinopathy Project [UDP] and the Italian DMD network) and classified subjects into Duchenne (DMD), intermediate (IMD), or Becker (BMD) phenotypes. Log-rank tests for time-to event variables were used to compare age at loss of ambulation (LOA) in Dup2 subjects versus non-Dup2 controls in the UDP database, and for comparisons between steroid-treated vs. steroid-naive Dup2 subjects.Results:Among 66 Dup2 subjects (UDP=40, Italy=26), 61% percent were classified as DMD, 9% as IMD, and 30% as BMD. Median age at last observation was 15.4 years [IQR 8.79-26.0], and 75% had been on corticosteroids for at least 6 months. Age at LOA differed significantly between Dup2 DMD subjects and historical non-Dup2 DMD controls (p<0.001). Valid spirometry was limited but suggested a delay in the typical age-related decline in forced vital capacity, and 24 of 55 subjects with adequate cardiac data had cardiomyopathy.Discussion:Some Dup2 patients display a milder disease course than non-Dup2 DMD controls, and prolonged ambulation with corticosteroids suggests the potential of IRES activation as a molecular mechanism. As Dup2-targeted therapies reach clinical applications, this information is critical to aid in the interpretation of the efficacy of new treatments.

scholarly journals Ovine PRNP untranslated region and promoter haplotype diversity

2009 ◽  
Vol 90 (5) ◽  
pp. 1289-1293 ◽  
Author(s):  
Ginny C. Saunders ◽  
Saira Cawthraw ◽  
Susan J. Mountjoy ◽  
Anna C. Tout ◽  
Anthony R. Sayers ◽  
...  
Keyword(s):  
Untranslated Region ◽  
Transmissible Spongiform Encephalopathy ◽  
Haplotype Diversity ◽  
Spongiform Encephalopathy ◽  
Entry Site ◽  
Internal Ribosome Entry ◽  
Exon 2 ◽  
Coding Regions ◽  
Healthy Control ◽  
Promoter Haplotype

The diversity and possible contribution of non-coding regions of the prion protein (PrP) gene (PRNP) to transmissible spongiform encephalopathy susceptibility and PrP regulation are not fully known. This study defined ten ovine PRNP promoters and five untranslated region (UTR) haplotypes found in atypical and classical scrapie cases and healthy control sheep. A greater diversity of promoter and UTR haplotypes was observed in conjunction with the ARQ PrP allele (seven promoter and four UTR haplotypes), while it was observed that the other alleles were linked with a limited number of haplotypes, such as ARR, found to be linked to only two promoter and one UTR haplotypes. In silico analysis identified potential transcription factor binding sites that differed in the promoter haplotype variants. Furthermore, a 5′ UTR internal ribosome entry site motif was identified in exon 2 and highlights a possible role for this exon in regulating PrP expression at the translational level.

scholarly journals TNFR1-d2 carrying the p.(Thr79Met) pathogenic variant is a potential novel actor of TNFα/TNFR1 signalling regulation in the pathophysiology of TRAPS

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Cécile Rittore ◽  
Déborah Méchin ◽  
Elodie Sanchez ◽  
Léa Marinèche ◽  
Vuthy Ea ◽  
...  
Keyword(s):  
Cell Fate ◽  
De Novo ◽  
Control Cell ◽  
Pathogenic Variant ◽  
Full Length ◽  
Entry Site ◽  
Gene Encoding ◽  
Exon 2 ◽  
Cell Fate Decisions ◽  
The Impact

AbstractBinding of tumour necrosis factor α (TNFα) to its receptor (TNFR1) is critical for both survival and death cellular pathways. TNFα/TNFR1 signalling is complex and tightly regulated at different levels to control cell fate decisions. Previously, we identified TNFR1-d2, an exon 2-spliced transcript of TNFRSF1A gene encoding TNFR1, whose splicing may be modulated by polymorphisms associated with inflammatory disorders. Here, we investigated the impact of TNFRSF1A variants involved in TNFR-associated periodic syndrome (TRAPS) on TNFR1-d2 protein expression and activity. We found that TNFR1-d2 could be translated by using an internal translation initiation codon and a de novo internal ribosome entry site (IRES), which resulted in a putative TNFR1 isoform lacking its N-terminal region. The kinetic of assembly of TNFR1-d2 clusters at the cell surface was reduced as compared with full-length TNFR1. Although co-localized with the full-length TNFR1, TNFR1-d2 neither activated nuclear factor (NF)-κB signalling, nor interfered with TNFR1-induced NF-κB activation. Translation of TNFR1-d2 carrying the severe p.(Thr79Met) pathogenic variant (also known as T50M) was initiated at the mutated codon, resulting in an elongated extracellular domain, increased speed to form preassembled clusters in absence of TNFα, and constitutive NF-κB activation. Overall, TNFR1-d2 might reflect the complexity of the TNFR1 signalling pathways and could be involved in TRAPS pathophysiology of patients carrying the p.(Thr79Met) disease-causing variant.

scholarly journals Optimising assessment of dark adaptation data using time to event analysis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Bethany E. Higgins ◽  
Giovanni Montesano ◽  
Alison M. Binns ◽  
David P. Crabb
Keyword(s):  
Censored Data ◽  
Dark Adaptation ◽  
Age Related Macular Degeneration ◽  
Event Analysis ◽  
Sample Sizes ◽  
Time To Event ◽  
Recording Time ◽  
Age Related ◽  
Data Points ◽  
Adaptation Data

AbstractIn age-related macular degeneration (AMD) research, dark adaptation has been found to be a promising functional measurement. In more severe cases of AMD, dark adaptation cannot always be recorded within a maximum allowed time for the test (~ 20–30 min). These data are recorded either as censored data-points (data capped at the maximum test time) or as an estimated recovery time based on the trend observed from the data recorded within the maximum recording time. Therefore, dark adaptation data can have unusual attributes that may not be handled by standard statistical techniques. Here we show time-to-event analysis is a more powerful method for analysis of rod-intercept time data in measuring dark adaptation. For example, at 80% power (at α = 0.05) sample sizes were estimated to be 20 and 61 with uncapped (uncensored) and capped (censored) data using a standard t-test; these values improved to 12 and 38 when using the proposed time-to-event analysis. Our method can accommodate both skewed data and censored data points and offers the advantage of significantly reducing sample sizes when planning studies where this functional test is an outcome measure. The latter is important because designing trials and studies more efficiently equates to newer treatments likely being examined more efficiently.

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