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

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

Risultato della ricerca: Contributo in rivistaArticolo in rivista

31 Citazioni (Scopus)

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 3'-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 3'-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.
Lingua originaleEnglish
pagine (da-a)1245-1257
Numero di pagine13
RivistaJournal of Neurology
DOI
Stato di pubblicazionePubblicato - 2012

Keywords

  • myotonic dystrophy

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