Molecular, clinical, and muscle studies in myotonic dystrophy type 1 (DM1) associated with novel variant CCG expansions

Massimo Santoro, Marcella Masciullo, Roberta Pietrobono, Giulia Conte, Anna Modoni, Maria Laura E Bianchi, Valentina Rizzo, Maria Grazia Pomponi, Giorgio Tasca, Giovanni Neri, Gabriella Silvestri

Research output: Contribution to journalArticle

Abstract

We assessed clinical, molecular and muscle histopathological features in five unrelated Italian DM1 patients carrying novel variant pathological expansions containing CCG interruptions within the 30-end of the CTG array at the DMPK locus, detected by bidirectional triplet primed PCR (TP-PCR) and sequencing. Three patients had a negative DM1 testing by routine long-range PCR; the other two patients were identified among 100 unrelated DM1 cases and re-evaluated to estimate the prevalence of variant expansions. The overall prevalence was 4.8 % in our study cohort. There were no major clinical differences between variant and non-variant DM1 patients, except for cognitive involvement. Muscle RNA-FISH, immunofluorescence for MBNL1 and RT-PCR analysis documented the presence of ribonuclear inclusions, their co-localization with MBNL1, and an aberrant splicing pattern involved in DM1 pathogenesis, without any obvious differences between variant and non-variant DM1 patients. Therefore, this study shows that the CCG interruptions at the 30-end of expanded DMPK alleles do not produce qualitative effects on the RNA-mediated toxic gain-of-function in DM1 muscle tissues. Finally, our results support the conclusion that different patterns of CCG interruptions within the CTG array could modulate the DM1 clinical phenotype, variably affecting the mutational dynamics of the variant repeat.

Original languageEnglish
Pages (from-to)1245-1257
Number of pages13
JournalJournal of Neurology
Volume260
Issue number5
DOIs
Publication statusPublished - May 2013

Keywords

  • Myotonic dystrophy type 1
  • Steinert's disease
  • Variant expansions

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology
  • Medicine(all)

Fingerprint Dive into the research topics of 'Molecular, clinical, and muscle studies in myotonic dystrophy type 1 (DM1) associated with novel variant CCG expansions'. Together they form a unique fingerprint.

  • Cite this

    Santoro, M., Masciullo, M., Pietrobono, R., Conte, G., Modoni, A., Bianchi, M. L. E., Rizzo, V., Pomponi, M. G., Tasca, G., Neri, G., & Silvestri, G. (2013). Molecular, clinical, and muscle studies in myotonic dystrophy type 1 (DM1) associated with novel variant CCG expansions. Journal of Neurology, 260(5), 1245-1257. https://doi.org/10.1007/s00415-012-6779-9