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1.
Acta Neuropathol ; 139(6): 1089-1104, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32236737

RESUMEN

RYR1 encodes the type 1 ryanodine receptor, an intracellular calcium release channel (RyR1) on the skeletal muscle sarcoplasmic reticulum (SR). Pathogenic RYR1 variations can destabilize RyR1 leading to calcium leak causing oxidative overload and myopathy. However, the effect of RyR1 leak has not been established in individuals with RYR1-related myopathies (RYR1-RM), a broad spectrum of rare neuromuscular disorders. We sought to determine whether RYR1-RM affected individuals exhibit pathologic, leaky RyR1 and whether variant location in the channel structure can predict pathogenicity. Skeletal muscle biopsies were obtained from 17 individuals with RYR1-RM. Mutant RyR1 from these individuals exhibited pathologic SR calcium leak and increased activity of calcium-activated proteases. The increased calcium leak and protease activity were normalized by ex-vivo treatment with S107, a RyR stabilizing Rycal molecule. Using the cryo-EM structure of RyR1 and a new dataset of > 2200 suspected RYR1-RM affected individuals we developed a method for assigning pathogenicity probabilities to RYR1 variants based on 3D co-localization of known pathogenic variants. This study provides the rationale for a clinical trial testing Rycals in RYR1-RM affected individuals and introduces a predictive tool for investigating the pathogenicity of RYR1 variants of uncertain significance.


Asunto(s)
Calcio/metabolismo , Enfermedades Musculares/metabolismo , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Animales , Citoplasma/metabolismo , Humanos , Músculo Esquelético/metabolismo , Enfermedades Musculares/terapia , Canal Liberador de Calcio Receptor de Rianodina/genética , Retículo Sarcoplasmático/metabolismo
2.
Cell Rep Methods ; 2(3): 100175, 2022 03 28.
Artículo en Inglés | MEDLINE | ID: mdl-35475221

RESUMEN

Using the Drosophila melanogaster Hox gene Ultrabithorax (Ubx) as an example, we demonstrate the use of three heterologous DNA-binding protein systems-LacI/LacO, ParB1/ParS1, and ParB2/ParS2-to label genomic loci in imaginal discs with the insertion of a small DNA tag. We compare each system, considering the impact of labeling in genomic regions (1) inside versus outside of a transcribed gene body and (2) with varying chromatin accessibility. We demonstrate the value of this system by interrogating the relationship between gene expression level and enhancer-promoter distance, as well as inter-allelic distance at the Ubx locus. We find that the distance between an essential intronic cis-regulatory element, anterobithorax (abx), and the promoter does not vary with expression level. In contrast, inter-allelic distance correlates with Ubx expression level.


Asunto(s)
Proteínas de Drosophila , Drosophila , Animales , Drosophila/genética , Drosophila melanogaster/genética , Factores de Transcripción/genética , Proteínas de Homeodominio/genética , Proteínas de Drosophila/genética , Discos Imaginales/metabolismo , Genómica
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