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Efficient CRISPR/Cas9-mediated editing of trinucleotide repeat expansion in myotonic dystrophy patient-derived iPS and myogenic cells Vrije Universiteit Brussel KU Leuven

Sumitava Dastidar, Kshitiz Singh, Debanjana Majumdar, Nisha Nair, Yanfang Fu, Deepak Reyon, Ermira Samara, Mattia FM Gerbil, Arnaud F. Klein
CRISPR/Cas9 is an attractive platform to potentially correct dominant genetic diseases by gene editing with unprecedented precision. In the current proof-of-principle study, we explored the use of CRISPR/Cas9 for gene-editing in myotonic dystrophy type-1 (DM1), an autosomal-dominant muscle disorder, by excising the CTG-repeat expansion in the 3'-untranslated-region (UTR) of the human myotonic dystrophy protein kinase (DMPK) gene in DM1 ...

Huntington's and myotonic dystrophy hESCs: down-regulated trinucleotide repeat instability and mismatch repair machinery expression upon differentiation Vrije Universiteit Brussel

Anna Seriola Petit, Claudia Spits, Pierre Hilven, Patrick Haentjens, Karen Sermon
Huntington's disease (HD) and myotonic dystrophy (DM1) are caused by trinucleotide repeat expansions. The repeats show different instability patterns according to the disorder, cell type and developmental stage. Here we studied the behavior of these repeats in DM1- and HD-derived human embryonic stem cells (hESCs) before and after differentiation, and its relationship to the DNA mismatch repair (MMR). The relatively small (CAG)44 HD expansion ...

Large-scale assessment of polyglutamine repeat expansions in Parkinson disease Vrije Universiteit Brussel Universiteit Antwerpen

Lisa Wang, Jan O Aasly, Grazia Annesi, Soraya Bardien, Maria Bozi, Alexis Brice, Jonathan Carr, Sun J Chung, Carl Clarke, David Crosiers, et al.

OBJECTIVES: We aim to clarify the pathogenic role of intermediate size repeat expansions of SCA2, SCA3, SCA6, and SCA17 as risk factors for idiopathic Parkinson disease (PD).

METHODS: We invited researchers from the Genetic Epidemiology of Parkinson's Disease Consortium to participate in the study. There were 12,346 cases and 8,164 controls genotyped, for a total of 4 repeats within the SCA2, SCA3, SCA6, and SCA17 genes. Fixed- and ...

Discrepancies in reporting the CAG repeat lengths for Huntington's disease Vrije Universiteit Brussel KU Leuven

Oliver W Quarrell, Olivia Handley, Kirsty O'Donovan, Christine Dumoulin, Maria Ramos-Arroyo, Ida Biunno, Peter Bauer, Margaret Kline, Sylvie De Raedt

Huntington's disease results from a CAG repeat expansion within the Huntingtin gene; this is measured routinely in diagnostic laboratories. The European Huntington's Disease Network REGISTRY project centrally measures CAG repeat lengths on fresh samples; these were compared with the original results from 121 laboratories across 15 countries. We report on 1326 duplicate results; a discrepancy in reporting the upper allele occurred in 51% of ...

FRA2A is a CGG repeat expansion associated with silencing of AFF3 Universiteit Antwerpen

Sofie Metsu, Liesbeth Rooms, Jacqueline Rainger, Geert Vandeweyer, Frank Kooy, et al.
Folate-sensitive fragile sites (FSFS) are a rare cytogenetically visible subset of dynamic mutations. Of the eight molecularly characterized FSFS, four are associated with intellectual disability (ID). Cytogenetic expression results from CGG trinucleotide-repeat expansion mutation associated with local CpG hypermethylation and transcriptional silencing. The best studied is the FRAXA site in the FMR1 gene, where large expansions cause fragile X ...

Normal and mutant HTT interact to affect clinical severity and progression in Huntington disease Vrije Universiteit Brussel

N A Aziz, C K Jurgens, W M C van Roon-Mom, G-j B Van Ommen, Tom Stijnen, Raymund A C Roos, Sylvie De Raedt

OBJECTIVE: Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion in the HD gene (HTT). We aimed to assess whether interaction between CAG repeat sizes in the mutant and normal allele could affect disease severity and progression.

METHODS: Using linear regression and mixed-effects models, the influence of mutant and normal CAG repeat sizes interaction was assessed on 1) age at ...

CpG Methylation, a Parent-of-Origin Effect for Maternal-Biased Transmission of Congenital Myotonic Dystrophy Vrije Universiteit Brussel

Lise Barbé, Stella Lanni, Arturo Lopez-Castel, Silvie Franck, Claudia Spits, K. Keymolen, Sara Seneca, Stephanie Tomé, Ioana Miron, Julie Letourneau, et al.

CTG repeat expansions in DMPK cause myotonic dystrophy (DM1) with a continuum of severity and ages of onset. Congenital DM1 (CDM1), the most severe form, presents distinct clinical features, large expansions, and almost exclusive maternal transmission. The correlation between CDM1 and expansion size is not absolute, suggesting contributions of other factors. We determined CpG methylation flanking the CTG repeat in 79 blood samples from 20 ...

Unravelling the link between neurodevelopmental disorders and short tandem CGG-repeat expansions Universiteit Antwerpen

Dale Annear, Frank Kooy
Neurodevelopmental disorders (NDDs) encompass a diverse group of disorders characterised by impaired cognitive abilities and developmental challenges. Short tandem repeats (STRs), repetitive DNA sequences found throughout the human genome, have emerged as potential contributors to NDDs. Specifically, the CGG trinucleotide repeat has been implicated in a wide range of NDDs, including Fragile X Syndrome (FXS), the most common inherited form of ...

CGG Short Tandem Repeats bij Onverklaarde Verstandelijke Beperking en Autisme Universiteit Antwerpen

Dale Annear
STR-related disorders result from expanded specific STR loci. Fragile X Syndrome (FXS) is an example caused by an expanded CGG trinucleotide STR in the FMR1 gene. The link between CGG STRs and neurological disorders is growing as more CGG STR disorders are found. Primarily, neurodevelopmental, neurodegenerative, and neuropsychiatric disorders are associated with pathogenic CGG STR expansions. In CGG STR-related neurodevelopmental disorders ...

Identification of the molecular key drivers in disease development in myotonic dystrophy type I. Vrije Universiteit Brussel

Lise Barbé
Myotonic dystrophy type I is the most common muscular dytrophy and is caused by an unstable trinucleotide ‘CTG’ repeat. Due to incomplete understanding of the repeat behaviour, the disease remains incurable. With this thesis, I further characterized two main molecular aspects of the disease being DNA methylation and its role in inheritance of the most severe forms of the disease and the influence of mismatch repair on repeat instability. The ...