Preliminary Findings on CTG Expansion Determination in Different Tissues from Patients with Myotonic Dystrophy Type 1

Ballester-Lopez, Alfonsina; Koehorst, Emma; Linares-Pardo, Ian; Núñez-Manchón, Judit; Almendrote, Míriam; Lucente, Giuseppe; Arbex, Andrea; Puente, Carles Puente; Lucı́a, Alejandro; Monckton, Darren G.; Cumming, Sarah A.; Pintos-Morell, Guillem; Coll-Cantí, Jaume; Ramos‐Fransí, Alba; Martínez-Piñeiro, Alicia; Nogales‐Gadea, Gisela

doi:10.3390/genes11111321

Cited by 6 publications

(7 citation statements)

References 21 publications

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“…In an FXD mouse model, blood shows much less expansion than the brain 48 . A similar difference between the extent of expansion in blood and brain has been reported in other Repeat Expansion Diseases 55 – 58 . Thus, in PM carriers where expansion can be detected in blood, the extent of expansion in the brain maybe even larger.…”

Section: Discussionsupporting

confidence: 84%

Both cis and trans-acting genetic factors drive somatic instability in female carriers of the FMR1 premutation

Hwang

Hayward

Zafarullah

et al. 2022

Sci Rep

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The fragile X mental retardation (FMR1) gene contains an expansion-prone CGG repeat within its 5′ UTR. Alleles with 55–200 repeats are known as premutation (PM) alleles and confer risk for one or more of the FMR1 premutation (PM) disorders that include Fragile X-associated Tremor/Ataxia Syndrome (FXTAS), Fragile X-associated Primary Ovarian Insufficiency (FXPOI), and Fragile X-Associated Neuropsychiatric Disorders (FXAND). PM alleles expand on intergenerational transmission, with the children of PM mothers being at risk of inheriting alleles with > 200 CGG repeats (full mutation FM) alleles) and thus developing Fragile X Syndrome (FXS). PM alleles can be somatically unstable. This can lead to individuals being mosaic for multiple size alleles. Here, we describe a detailed evaluation of somatic mosaicism in a large cohort of female PM carriers and show that 94% display some evidence of somatic instability with the presence of a series of expanded alleles that differ from the next allele by a single repeat unit. Using two different metrics for instability that we have developed, we show that, as with intergenerational instability, there is a direct relationship between the extent of somatic expansion and the number of CGG repeats in the originally inherited allele and an inverse relationship with the number of AGG interruptions. Expansions are progressive as evidenced by a positive correlation with age and by examination of blood samples from the same individual taken at different time points. Our data also suggests the existence of other genetic or environmental factors that affect the extent of somatic expansion. Importantly, the analysis of candidate single nucleotide polymorphisms (SNPs) suggests that two DNA repair factors, FAN1 and MSH3, may be modifiers of somatic expansion risk in the PM population as observed in other repeat expansion disorders.

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Section: Discussionsupporting

confidence: 84%

Both cis and trans-acting genetic factors drive somatic instability in female carriers of the FMR1 premutation

Hwang

Hayward

Zafarullah

et al. 2022

Sci Rep

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“…Our study population consisted of ten DM1 patients, of which the clinical characteristics have been, in part, described previously ( Table 1 , [ 12 , 13 ]). Eight out of ten DM1 patients provided skin and muscle biopsies, whereas from the other two only lymphoblastoid cell lines were available.…”

Section: Resultsmentioning

confidence: 99%

Characterization of RAN Translation and Antisense Transcription in Primary Cell Cultures of Patients with Myotonic Dystrophy Type 1

Koehorst

Núñez-Manchón

Ballester-Lopez

et al. 2021

JCM

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Myotonic Dystrophy type 1 (DM1) is a muscular dystrophy with a multi-systemic nature. It was one of the first diseases in which repeat associated non-ATG (RAN) translation was described in 2011, but has not been further explored since. In order to enhance our knowledge of RAN translation in DM1, we decided to study the presence of DM1 antisense (DM1-AS) transcripts (the origin of the polyglutamine (polyGln) RAN protein) using RT-PCR and FISH, and that of RAN translation via immunoblotting and immunofluorescence in distinct DM1 primary cell cultures, e.g., myoblasts, skin fibroblasts and lymphoblastoids, from ten patients. DM1-AS transcripts were found in all DM1 cells, with a lower expression in patients compared to controls. Antisense RNA foci were found in the nuclei and cytoplasm of a subset of DM1 cells. The polyGln RAN protein was undetectable in all three cell types with both approaches. Immunoblots revealed a 42 kD polyGln containing protein, which was most likely the TATA-box-binding protein. Immunofluorescence revealed a cytoplasmic aggregate, which co-localized with the Golgi apparatus. Taken together, DM1-AS transcript levels were lower in patients compared to controls and a small portion of the transcripts included the expanded repeat. However, RAN translation was not present in patient-derived DM1 cells, or was in undetectable quantities for the available methods.

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“…Однако корреляция генотип-фенотип имеет место не во всех случаях из-за соматической нестабильности мутантных аллелей. Наибольшей стабильностью CTGповторов обладают лейкоциты по сравнению с миоцитами и фибробластами [8]. Таким образом, соматический мозаицизм наблюдается как в различных тканях, так и в пределах одной ткани.…”

Section: этиология и патогенезunclassified

“…Сердечно-сосудистые нарушения. Нарушения со стороны сердечно-сосудистой системы наряду с дыхательной недостаточностью являются ведущими причинами смерти у пациентов при классической форме МД1 [8]. Кардиологические симптомы обычно проявляются в виде прогрессирующей атриовентрикулярной блокады, несколько реже -дисфункции синусового узла, желудочковой и предсердной фибрилляции и трепетания предсердий [28,50].…”

Section: о б з о р ы и л е к ц и и / R E V I E W S a N D L E C T U R E Sunclassified

Clinical characteristics of different forms of myotonic dystrophy type 1

Erokhina

Melnik

Vlodavets

2023

Rus. ž. det. nevrol.

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Myotonic dystrophy type 1 (DM1) is one of the most common neuromuscular diseases with an autosomal dominant type of inheritance associated with expansion in the DMPK gene. A distinctive feature of the disease is the presence of muscle symptoms and multisystemic. Depending on the age of onset and the number of CTG repeats, there are congenital, infantile, juvenile, classic (adult) form and a form with a late onset. Each form is characterized by its own features of the onset, course of the disease, heterogeneity of clinical manifestations, which makes it difficult to make a timely diagnosis. Increasing the awareness of physicians of all specialties about the nature of the course of various forms will make it possible to diagnose MD1 at an earlier stage, improve the prognosis and quality of life of patients. The article provides a literature review that demonstrates the spectrum of clinical manifestations in various forms of MD1.

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Preliminary Findings on CTG Expansion Determination in Different Tissues from Patients with Myotonic Dystrophy Type 1

Cited by 6 publications

References 21 publications

Both cis and trans-acting genetic factors drive somatic instability in female carriers of the FMR1 premutation

Both cis and trans-acting genetic factors drive somatic instability in female carriers of the FMR1 premutation

Characterization of RAN Translation and Antisense Transcription in Primary Cell Cultures of Patients with Myotonic Dystrophy Type 1

Clinical characteristics of different forms of myotonic dystrophy type 1

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