TY - JOUR
T1 - Molecular, clinical, and muscle studies in myotonic dystrophy type 1 (DM1) associated with novel variant CCG expansions
AU - Santoro, Massimo
AU - Masciullo, Marcella
AU - Pietrobono, Roberta
AU - Conte, Giulia
AU - Modoni, Anna
AU - Bianchi, Maria Laura Ester
AU - Rizzo, Valentina
AU - Pomponi, Maria Grazia
AU - Tasca, Giorgio
AU - Neri, Giovanni
AU - Silvestri, Gabriella
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
KW - myotonic dystrophy
KW - myotonic dystrophy
UR - http://hdl.handle.net/10807/38637
U2 - 10.1007/s00415-012-6779-9
DO - 10.1007/s00415-012-6779-9
M3 - Article
SN - 0340-5354
SP - 1245
EP - 1257
JO - Journal of Neurology
JF - Journal of Neurology
ER -