Myotonic dystrophy type 2 and modifier genes: an update on clinical and pathomolecular aspects

Meola, G.; Cardani, Rosanna

doi:10.1007/s10072-016-2805-5

Cited by 36 publications

(30 citation statements)

References 102 publications

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“…Recent studies, however, have proposed an additional pathomechanism whereby the repeat expansions undergo RAN translation [6], albeit the mechanism by which RAN products contribute to disease is unknown. A recent review on this topic provides an excellent overview of the increasingly complex mechanisms behind myotonic dystrophy [64]. …”

Section: Ran Translation Beyond Als/ftdmentioning

confidence: 99%

Lost in Translation: Evidence for Protein Synthesis Deficits in ALS/FTD and Related Neurodegenerative Diseases

Lehmkuhl

Zarnescu

2018

Advances in Neurobiology

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Cells utilize a complex network of proteins to regulate translation, involving post-transcriptional processing of RNA and assembly of the ribosomal unit. Although the complexity provides robust regulation of proteostasis, it also offers several opportunities for translational dysregulation, as has been observed in many neurodegenerative disorders. Defective mRNA localization, mRNA sequatration, inhibited ribogenesis, mutant tRNA synthetases, and translation of hexanucleotide expansions have all been associated with neurodegenerative disease. Here, we review dysregulation of translation in the context of age-related neurodegeneration and discuss novel methods to interrogate translation. This review primarily focuses on amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), a spectrum disorder heavily associated with RNA metabolism, while also analyzing translational inhibition in the context of related neurodegenerative disorders such as Alzheimer's disease and Huntington's disease and the translation-related pathomechanisms common in neurodegenerative disease.

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Section: Ran Translation Beyond Als/ftdmentioning

confidence: 99%

Lost in Translation: Evidence for Protein Synthesis Deficits in ALS/FTD and Related Neurodegenerative Diseases

Lehmkuhl

Zarnescu

2018

Advances in Neurobiology

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“…Myotonia may occasionally cause severe impairment of limb or bulbar function (speech or swallowing) in patients with DM1, but this is rare in DM2 [13]. In DM2, clinical myotonia is present in less than 50% of patients and electrical myotonia is variable and can be difficult to elicit [13,23]. However, modifier genes, specifically SCN4A and CLCN1, can change the severity of myotonia in DM2.…”

Section: Skeletal Musclementioning

confidence: 99%

Myotonic Dystrophies: Targeting Therapies for Multisystem Disease

2018

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Myotonic dystrophy is an autosomal dominant muscular dystrophy not only associated with muscle weakness, atrophy, and myotonia but also prominent multisystem involvement. There are 2 similar, but distinct, forms of myotonic dystrophy; type 1 is caused by a CTG repeat expansion in the DMPK gene, and type 2 is caused by a CCTG repeat expansion in the CNBP gene. Type 1 is associated with distal limb, neck flexor, and bulbar weakness and results in different phenotypic subtypes with variable onset from congenital to very late-onset as well as variable signs and symptoms. The classically described adult-onset form is the most common. In contrast, myotonic dystrophy type 2 is adult-onset or late-onset, has proximal predominant muscle weakness, and generally has less severe multisystem involvement. In both forms of myotonic dystrophy, the best characterized disease mechanism is a RNA toxic gain-of-function during which RNA repeats form nuclear foci resulting in sequestration of RNA-binding proteins and, therefore, dysregulated splicing of premessenger RNA. There are currently no disease-modifying therapies, but clinical surveillance, preventative measures, and supportive treatments are used to reduce the impact of muscular impairment and other systemic involvement including cataracts, cardiac conduction abnormalities, fatigue, central nervous system dysfunction, respiratory weakness, dysphagia, and endocrine dysfunction. Exciting preclinical progress has been made in identifying a number of potential strategies including genome editing, small molecule therapeutics, and antisense oligonucleotide-based therapies to target the pathogenesis of type 1 and type 2 myotonic dystrophies at the DNA, RNA, or downstream target level.

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“…Myotonic dystrophies (DMs) are autosomal dominant nucleotide repeat expansion disorders with skeletal muscle myotonia and weakness, as well as cardiac arrhythmias and heart failure (1)(2)(3). Type 1 (DM1) is caused by a CTG trinucleotide expansion in 3′ untranslated region of DMPK gene (4-6), while type 2 (DM2) arises from a CCTG tetranucleotide expansion in intron 1 of the CNBP (previously known as the ZNF9) gene (7,8).…”

Section: Introductionmentioning

confidence: 99%

“…Although DM1 and DM2 share the common theme of nucleotide repeat expansion and some clinical features, there are key clinical differences. Notably, DM2 typically has a later age of onset despite having a significantly larger nucleotide repeat expansion (2). There is considerable overlap among the clinical findings in DM1 and DM2 with progressive skeletal muscle weakness and cardiac complications (21)(22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

Distinct pathological signatures in human cellular models of myotonic dystrophy subtypes

Kim

Barefield

et al. 2019

JCI Insight

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Myotonic dystrophy type 2 and modifier genes: an update on clinical and pathomolecular aspects

Cited by 36 publications

References 102 publications

Lost in Translation: Evidence for Protein Synthesis Deficits in ALS/FTD and Related Neurodegenerative Diseases

Lost in Translation: Evidence for Protein Synthesis Deficits in ALS/FTD and Related Neurodegenerative Diseases

Myotonic Dystrophies: Targeting Therapies for Multisystem Disease

Distinct pathological signatures in human cellular models of myotonic dystrophy subtypes

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