Molecular, clinical, and muscle studies in myotonic dystrophy type 1 (DM1) associated with novel variant CCG expansions
| Autor: | Giovanni Neri, Roberta Pietrobono, Maria Grazia Pomponi, Maria Laura Ester Bianchi, Giulia Conte, Giorgio Tasca, Gabriella Silvestri, Marcella Masciullo, Massimo Santoro, Anna Modoni, Valentina Rizzo |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Adult
Male musculoskeletal diseases congenital hereditary and neonatal diseases and abnormalities medicine.medical_specialty Neurology DNA Mutational Analysis Locus (genetics) Protein Serine-Threonine Kinases Biology Immunofluorescence Myotonic dystrophy Myotonin-Protein Kinase Pathogenesis chemistry.chemical_compound Steinert's disease medicine Humans MBNL1 Allele Muscle Skeletal Myotonic dystrophy type 1 Variant expansions Pathological In Situ Hybridization Fluorescence Aged Neurologic Examination Genetics myotonic dystrophy medicine.diagnostic_test Electromyography RNA-Binding Proteins Exons Middle Aged medicine.disease Settore MED/26 - NEUROLOGIA Italy chemistry Female Neurology (clinical) Trinucleotide Repeat Expansion |
| Zdroj: | Journal of Neurology. 260:1245-1257 |
| ISSN: | 1432-1459 0340-5354 |
| DOI: | 10.1007/s00415-012-6779-9 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink