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

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

doi:10.1007/s00415-012-6779-9

Cited by 36 publications

(45 citation statements)

References 43 publications

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“…Complex variant repeats were identified at the both ends of the CTG array of DM1 patients of different origin, with an estimated prevalence of 3-5%. 4,5,7,8 In this study we retrospectively revaluated by bi-directional TP-PCR a cohort of 254 Italian DM1 patients estimating a minimum frequency of interrupted expanded alleles of 3.5%, perfectly in line with previous observations. 4,5 Direct sequencing of the entire or partial interrupted alleles, revealed the presence of complex arrays containing Figure 1 TP-PCR analysis of 5′ region of the CTG array in members of family C and in a DM1 patient with an uninterrupted DMPK allele as control (bottom panel, EXP).…”

Section: Discussionsupporting

confidence: 84%

“…This is a matter of particular relevance, considering that all the currently published works described DM1 variant repeats strongly clustered at the 3′-end of the array. 4,5,7 Our study reveal that there is not an absolute polarity in the generation and/or maintenance of non-CTG repeats within the DM1 locus. The identification of sequence interruptions at both ends of the CTG array has also practical consequences for DM1 molecular genetic testing.…”

Section: Discussionmentioning

confidence: 63%

“…19 Data reported so far suggest that the presence of interruptions in the CTG array does not considerably affect the nuclear accumulation of expanded RNAs since muscle tissues from 'atypical' (with interrupted alleles DMPK expanded alleles) DM1 patients showed ribonuclear foci and splicing alterations similar to those observed in muscle from 'classical' (with uninterrupted DMPK expanded alleles) DM1 patients. 7 It is therefore possible that variant repeats might mediate an altered pathology through other mechanisms, such as changing the methylation status of the region up and/or down of the repeat, modulating chromatin structure and the nucleosome assembly. 20,21 A recent paper, reported indeed that the presence of CCG/CTC/ CGG interruptions at the 3′ end of the CTG array is associated with a highly polarized pattern of CpG methylation at the DM1 locus involving regions downstream of the CTG array.…”

Section: Discussionmentioning

confidence: 99%

“…Although the CTG repeat tract is usually uninterrupted in nonexpanded and expanded alleles, in the last few years, pathological variant expansions containing unstable CCG, CTC and GGC sequence interruptions have been reported in rare instances. [4][5][6][7] Complex variant repeats were identified at both ends of the CTG array of DM1 patients of different origin, with an estimated prevalence of 3-5% of cases. [4][5][6][7][8] However, the phenotypical consequences of the interrupted alleles on DM1 patients is still controversial leading either to a complex neurological phenotype or to classical/mild DM1 forms.…”

Section: Introductionmentioning

confidence: 99%

“…[4][5][6][7] Complex variant repeats were identified at both ends of the CTG array of DM1 patients of different origin, with an estimated prevalence of 3-5% of cases. [4][5][6][7][8] However, the phenotypical consequences of the interrupted alleles on DM1 patients is still controversial leading either to a complex neurological phenotype or to classical/mild DM1 forms. 4,5,7 In the present work, we describe the detailed molecular analysis of multiple patients carrying various patterns of interruptions either at the 3′ or 5′ end of the DMPK repeat identified in our cohort of 254 Italian DM1 patients, including three multi-generation families.…”

Section: Introductionmentioning

confidence: 99%

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Identification and characterization of 5′ CCG interruptions in complex DMPK expanded alleles

et al. 2016

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Myotonic dystrophy type 1 is a multisystemic autosomal dominant disorder caused by the expansion of (CTG) n triplets in the 3'UTR of the DMPK gene, on chromosome 19q13.3. In the last years, few DM1 patients with different patterns of CCG/CTC interruptions at the 3′ end of the DMPK expanded tract have been described. However, the role of these interruptions in DM1 pathogenesis is still unclear. To study the frequency, stability and the structure of DMPK variant expanded alleles in the Italian population, we have re-evaluated 254 Italian DM1 patients using triplet-primed PCR (TP-PCR), at both the 3′ and 5′ ends of the CTG expansion. In addition, three DM1 families were also investigated in order to analyze the intergenerational stability of the interrupted DMPK alleles. Fourteen DM1 patients showed a TP-PCR electrophoretic profile indicating CCG/CTC interruptions within the CTG expansion. Interestingly, interruptions have been detected and, for the first time, sequenced at the 5′ end of the CTG array. Analysis of five intergenerational transmissions revealed a substantial intrafamilial stability of the DM1 mutation among relatives. Our results support the hypothesis that CCG/CTC interruptions within the DMPK expanded alleles have a stabilizing effect on the mutational dynamics and can modulate the severity of symptoms in DM1 patients.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification and characterization of 5′ CCG interruptions in complex DMPK expanded alleles

et al. 2016

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Unusual association of a unique CAG interruption in 5′ of DM1 CTG repeats with intergenerational contractions and low somatic mosaicism

et al. 2018

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Myotonic dystrophy type 1 (DM1) is a dominant multisystemic disorder associated with high variability of symptoms and anticipation. DM1 is caused by an unstable CTG repeat expansion that usually increases in successive generations and tissues. DM1 family pedigrees have shown that ∼90% and 10% of transmissions result in expansions and contractions of the CTG repeat, respectively. To date, the mechanisms of CTG repeat contraction remain poorly documented in DM1. In this report, we identified two new DM1 families with apparent contractions and no worsening of DM1 symptoms in two and three successive maternal transmissions. A new and unique CAG interruption was found in 5' of the CTG expansion in one family, whereas multiple 5' CCG interruptions were detected in the second family. We showed that these interruptions are associated with maternal intergenerational contractions and low somatic mosaicism in blood. By specific triplet-prime PCR, we observed that CTG repeat changes (contractions/expansions) occur preferentially in 3' of the interruptions for both families.

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A DM1 family with interruptions associated with atypical symptoms and late onset but not with a milder phenotype

et al. 2019

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Carriage of interruptions in CTG repeats of the myotonic dystrophy protein kinase gene has been associated with a broad spectrum of myotonic dystrophy type 1 (DM1) phenotypes, mostly mild. However, the data available on interrupted DM1 patients and their phenotype are scarce. We studied 49 Spanish DM1 patients, whose clinical phenotype was evaluated in depth. Blood DNA was obtained and analyzed through triplet-primed polymerase chain reaction (PCR), long PCR-Southern blot, small pool PCR, AciI digestion, and sequencing. Five patients of our registry (10%), belonging to the same family, carried CCG interruptions at the 3′-end of the CTG expansion. Some of them presented atypical traits such as very late onset of symptoms ( > 50 years) and a severe axial and proximal weakness requiring walking assistance. They also showed classic DM1 symptoms including cardiac and respiratory dysfunction, which were severe in some of them. Sizes and interrupted allele patterns were determined, *Alfonsina Ballester-Lopez and Emma Koehorst contributed equally to this work. and we found a contraction and an expansion in two intergenerational transmissions.Our study contributes to the observation that DM1 patients carrying interruptions present with atypical clinical features that can make DM1 diagnosis difficult, with a later than expected age of onset and a previously unreported aging-related severe disease manifestation. K E Y W O R D S atypical symptoms, interruptions, late onset, myotonic dystrophy type 1, severe phenotype, Steinert disease, variant repeats SUPPORTING INFORMATION Additional supporting information may be found online in the Supporting Information section. How to cite this article: Ballester-Lopez A, Koehorst E, Almendrote M, et al. A DM1 family with interruptions associated with atypical symptoms and late onset but not with a milder phenotype. Human Mutation. 2020;41:420-431.

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

Cited by 36 publications

References 43 publications

Identification and characterization of 5′ CCG interruptions in complex DMPK expanded alleles

Identification and characterization of 5′ CCG interruptions in complex DMPK expanded alleles

Unusual association of a unique CAG interruption in 5′ of DM1 CTG repeats with intergenerational contractions and low somatic mosaicism

A DM1 family with interruptions associated with atypical symptoms and late onset but not with a milder phenotype

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