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Muscle single-cell analysis reveals that RNA foci accumulation is linked to muscle dysfunction in patients with myotonic dystrophy type I
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  • Judit Núñez-Manchón,
  • Alfonsina Ballester-Lopez,
  • Ian Linares-Pardo,
  • Emma Koehorst,
  • Ana Maria Cobo,
  • Jaume Col-Cantí,
  • Adolfo Lopez de Munain,
  • Alejandro Lucia,
  • Darren Monckton,
  • Sarah Cumming,
  • Jonathan Magaña,
  • Laura Palomo,
  • Francesc Solé,
  • Guillem Pintos-Morell,
  • Giuseppe Lucente,
  • Miriam Almendrote,
  • Alba Ramos-Fransi,
  • Alicia Martínez-Piñeiro,
  • Gisela Nogales-Gadea
Judit Núñez-Manchón
Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol
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Alfonsina Ballester-Lopez
Fundacio Institut d'Investigacio en Ciencies de la Salut Germans Trias i Pujol
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Ian Linares-Pardo
Hospital Universitari Germans Trias i Pujol
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Emma Koehorst
Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol
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Ana Maria Cobo
Hôpital Marin de Hendaye
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Jaume Col-Cantí
Hospital Universitari Germans Trias i Pujol
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Adolfo Lopez de Munain
Biodonostia Health Research Institute
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Alejandro Lucia
Universidad Europea de Madrid
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Darren Monckton
University of Glasgow
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Sarah Cumming
University of Glasgow
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Jonathan Magaña
National Institute of Rehabilitation Luis Guillermo Ibarra Ibarra
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Laura Palomo
José Carreras Leukaemia Foundation
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Francesc Solé
José Carreras Leukaemia Foundation
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Guillem Pintos-Morell
Hospital Vall d'Hebron
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Giuseppe Lucente
Hospital Universitari Germans Trias i Pujol
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Miriam Almendrote
Hospital Universitari Germans Trias i Pujol
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Alba Ramos-Fransi
Hospital Universitari Germans Trias i Pujol
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Alicia Martínez-Piñeiro
Hospital Universitari Germans Trias i Pujol
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Gisela Nogales-Gadea
Foundation Institute of Research in Health Sciences Germans Trias i Pujol
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Abstract

Single cell analysis has numerous potential applications, for instance in the context of myotonic dystrophy type I (DM1). This disease is caused by a CTG expansion in the dystrophia myotonica-protein kinase (DMPK) gene, with CTG expansion length being heterogeneous not only between tissues but also between cells in the same tissue. We studied muscle pathophysiology from five patients with DM1 at single cell level, including RNA foci (i.e., nuclear DMPK-transcribed aggregates that trap proteins) and splicing alterations (caused by trapping of important splicing regulator proteins by the RNA foci). Single cell myoblasts were heterogeneous in RNA foci load, with most showing 0 to 3 foci. The percentage of myoblasts carrying foci differed among patients, ranging from 29 to 99%. We found a significant direct correlation between mean and median number of RNA foci in myoblasts and patients’ endurance capacity (r=-0.975, p=0.005). Although the expression of DMPK and MBNL1 transcripts was variable among the myoblasts, no relationship was found between RNA foci number and their expression in individual cells. CTG size in muscle correlated with patients´ disease onset. In summary, single cell analysis poses some technical challenges but allows an in-depth analysis of heterogeneous molecular alterations in patients with DM1.