Development and Validation of a New Molecular Diagnostic Assay for Detection of Myotonic Dystrophy Type 2

Valaperta, Rea; Lombardi, Fortunata; Cardani, Rosanna; Fossati, Barbara; Brigonzi, Elisa; Merli, Ilaria; Sansone, Valeria; Merletti, G; Spina, Edoardo; Meola, G.; Costa, Elena

doi:10.1089/gtmb.2015.0135

Cited by 8 publications

(3 citation statements)

References 28 publications

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“…The diagnosis of DM was based upon the clinical diagnostic criteria set by the International Consortium for Myotonic Dystrophy [22]. DM1 and DM2 genotyping was performed on genomic DNA extracted from peripheral blood leukocytes as previously described [23–24]. DM2 diagnosis was performed by fluorescence in situ hybridization on muscle frozen sections using a (CAGG) 5 probe as previously reported by Cardani et al [25] to verify the presence of nuclear accumulation of mutant RNA.…”

Section: Methodsmentioning

confidence: 99%

Aberrant insulin receptor expression is associated with insulin resistance and skeletal muscle atrophy in myotonic dystrophies

et al. 2019

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Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are autosomal dominant multisystemic disorders linked to two different genetic loci and characterized by several features including myotonia, muscle atrophy and insulin resistance. The aberrant alternative splicing of insulin receptor (IR) gene and post-receptor signalling abnormalities have been associated with insulin resistance, however the precise molecular defects that cause metabolic dysfunctions are still unknown. Thus, the aims of this study were to investigate in DM skeletal muscle biopsies if beyond INSR missplicing, altered IR protein expression could play a role in insulin resistance and to verify if the lack of insulin pathway activation could contribute to skeletal muscle wasting. Our analysis showed that DM skeletal muscle exhibits a lower expression of the insulin receptor in type 1 fibers which can contribute to the defective activation of the insulin pathway. Moreover, the aberrant insulin signalling activation leads to a lower activation of mTOR and to an increase in MuRF1 and Atrogin-1/MAFbx expression, possible explaining DM skeletal muscle fiber atrophy. Taken together our data indicate that the defective insulin signalling activation can contribute to skeletal muscle features in DM patients and are probably linked to an aberrant specific-fiber type expression of the insulin receptor.

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Section: Methodsmentioning

confidence: 99%

Aberrant insulin receptor expression is associated with insulin resistance and skeletal muscle atrophy in myotonic dystrophies

et al. 2019

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“…DM2 molecular diagnosis was performed by fluorescence in situ hybridization (FISH; see below) on muscle sections and by genetic test performed on blood DNA according to Valaperta et al . 23 .…”

Section: Methodsmentioning

confidence: 99%

SCN4A as modifier gene in patients with myotonic dystrophy type 2

Binda

Renna

Bosè

et al. 2018

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A patient with an early severe myotonia diagnosed for Myotonic Dystrophy type 2 (DM2) was found bearing the combined effects of DM2 mutation and Nav1.4 S906T substitution. To investigate the mechanism underlying his atypical phenotype,whole-cell patch-clamp in voltage- and current-clamp mode was performed in myoblasts and myotubes obtained from his muscle biopsy. Results characterizing the properties of the sodium current and of the action potentials have been compared to those obtained in muscle cells derived from his mother, also affected by DM2, but without the S906T polymorphism. A faster inactivation kinetics and a +5 mV shift in the availability curve were found in the sodium current recorded in patient’s myoblasts compared to his mother. 27% of his myotubes displayed spontaneous activity. Patient’s myotubes showing a stable resting membrane potential had a lower rheobase current respect to the mother’s while the overshoot and the maximum slope of the depolarizing phase of action potential were higher. These findings suggest that SCN4A polymorphisms may be responsible for a higher excitability of DM2 patients sarcolemma, supporting the severe myotonic phenotype observed. We suggest SCN4A as a modifier factor and that its screening should be performed in DM2 patients with uncommon clinical features.

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“…Clinical and bioptic diagnosis of DM1 was genetically confirmed by Southern blot-based kit ( 14 ). Clinical diagnosis of DM2 was confirmed by both fluorescence in situ hybridization on muscle frozen sections using a (CAGG) 5 probe and by Southern blot-based kit ( 15 ).…”

Section: Methodsmentioning

confidence: 99%

Circulating Irisin Is Reduced in Male Patients with Type 1 and Type 2 Myotonic Dystrophies

et al. 2017

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ContextMyotonic dystrophies (DM) are dominantly inherited muscle disorders characterized by myotonia, muscle weakness, and wasting. The reasons for sarcopenia in DMs are uncleared and multiple factors are involved. Irisin, a positive hormone regulator of muscle growth and bone, may play a role.ObjectivesTo investigate (1) circulating irisin in a series of DM1 and DM2 male patients compared with healthy controls and (2) the relationships between irisin and anthropometric, metabolic and hormonal parameters.Design and study participantsThis is a cross-sectional study. Fasting blood samples for glucometabolic, gonadic, bone markers, and irisin were collected from 28 ambulatory DM1, 10 DM2, and 23 age-matched healthy male subjects. Body composition and bone mineralization [bone mineral density (BMD)] were measured by DEXA. Echocardiographic assessment and visceral adiposity, namely, liver and epicardial fat, were investigated by ultrasound. Irisin released from cultured myotubes derived from 3 DM1, 3 DM2, and 3 healthy donors was assayed.ResultsPlasma irisin levels were definitely lower in both DM1 and DM2 patients than in controls with no difference between DM1 and DM2. Irisin released from DM1 and DM2 myotubes was similar to that released from myotubes of the non-DM donors, though diabetic DM2 myotubes released more irisin than DM1 myotubes. There was no correlation between irisin and muscle strength or lean mass in both DM1 and DM2 patients. In DM1 patients, plasma irisin levels correlated negatively with oxygen consumption and positively with insulin resistance, while in DM2 patients plasma irisin levels positively correlated with fat mass at arms and legs levels. No correlation with visceral fat, left ventricular mass, and gonadal hormones could be detected. In both DM1 and DM2 patients, legs BMD parameters positively correlated with plasma irisin levels.ConclusionPlasma irisin is reduced in both DM1 and DM2 male patients likely reflecting muscle mass reduction. Moreover, insulin resistance may contribute to modulation of plasma irisin in DM1 patients. The irisin-mediated cross talk muscle–adipose tissue–bone may be active also in the male myotonic dystrophies’ model.

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Development and Validation of a New Molecular Diagnostic Assay for Detection of Myotonic Dystrophy Type 2

Cited by 8 publications

References 28 publications

Aberrant insulin receptor expression is associated with insulin resistance and skeletal muscle atrophy in myotonic dystrophies

Aberrant insulin receptor expression is associated with insulin resistance and skeletal muscle atrophy in myotonic dystrophies

SCN4A as modifier gene in patients with myotonic dystrophy type 2

Circulating Irisin Is Reduced in Male Patients with Type 1 and Type 2 Myotonic Dystrophies

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