Three-dimensional imaging in myotonic dystrophy type 1: Linking molecular alterations with disease phenotype. (August 2020)

• Record Type: Journal Article
• Authors: Ballester-Lopez, Alfonsina; Núñez-Manchón, Judit; Koehorst, Emma; Linares-Pardo, Ian; Almendrote, Miriam; Lucente, Giuseppe; Guanyabens, Nicolau; Lopez-Osias, Marta; Suárez-Mesa, Adrián; Hanick, Shaliza Ann; Chojnacki, Jakub; Lucia, Alejandro; Pintos-Morell, Guillem; Coll-Cantí, Jaume; Martínez-Piñeiro, Alicia; Ramos-Fransi, Alba; Nogales-Gadea, Gisela
• Is Part Of: Neurology. Volume 6:Number 4(2020)
• Publication Date: 2020-08
• Subjects: Neurogenetics -- Periodicals; 616.80442
• DOI: 10.1212/NXG.0000000000000484
• Languages: English
• ISSNs: 2376-7839

Abstract

Abstract : Objective: We aimed to determine whether 3D imaging reconstruction allows identifying molecular:clinical associations in myotonic dystrophy type 1 (DM1). Methods: We obtained myoblasts from 6 patients with DM1 and 6 controls. We measured cytosine-thymine-guanine (CTG) expansion and detected RNA foci and muscleblind like 1 (MBNL1) through 3D reconstruction. We studied dystrophia myotonica protein kinase (DMPK) expression and splicing alterations of MBNL1, insulin receptor, and sarcoplasmic reticulum Ca(2+)-ATPase 1. Results: Three-dimensional analysis showed that RNA foci (nuclear and/or cytoplasmic) were present in 45%–100% of DM1-derived myoblasts we studied (range: 0–6 foci per cell). RNA foci represented <0.6% of the total myoblast nuclear volume. CTG expansion size was associated with the number of RNA foci per myoblast ( r = 0.876 [95% confidence interval 0.222–0.986]) as well as with the number of cytoplasmic RNA foci ( r = 0.943 [0.559–0.994]). Although MBNL1 colocalized with RNA foci in all DM1 myoblast cell lines, colocalization only accounted for 1% of total MBNL1 expression, with the absence of DM1 alternative splicing patterns. The number of RNA foci was associated with DMPK expression ( r = 0.967 [0.079–0.999]). On the other hand, the number of cytoplasmic RNA foci was correlated with the age at disease onset ( r = −0.818 [−0.979 to 0.019]). Conclusions: CTG expansion size modulates RNA foci number in myoblasts derived from patients with DM1. MBNL1 sequestration plays only a minor role in the pathobiology of the disease in these cells. Higher number of cytoplasmic RNA foci is related to an early onset of the disease, a finding that should be corroborated in future studies.