Differences in splicing defects between the grey and white matter in myotonic dystrophy type 1 patients

Nishi, Masamitsu; Kimura, Takashi; Igeta, Masataka; Furuta, Mitsuru; Suenaga, Koichi; Matsumura, Tsuyoshi; Fujimura, Harutoshi; Jinnai, Kenji; Yoshikawa, Hiroaki

doi:10.1371/journal.pone.0224912

Cited by 10 publications

(15 citation statements)

References 35 publications

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“…This analysis identified 176 LSVs that were differentially spliced in cortical neurons from patients with DM1 and disease controls at an estimated dPSI [E(dPSI)] threshold of 0.1 and a confidence threshold of 0.95 ( Supplementary Table 4 ). The LSVs with high E(dPSI) value (>0.3) consisted of several misspliced exons that were previously identified in the DM1 brain ( MAPT exon 2, MBNL2 exon 8 and CLASP2 exon 23), 16 , 19 , 53 indicating the validity of our analysis ( Table 2 , Fig. 5A and Supplementary Fig.…”

Section: Resultssupporting

confidence: 63%

Cell type-specific abnormalities of central nervous system in myotonic dystrophy type 1

Nakamori

Shimizu

Ogawa

et al. 2022

Brain Communications

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Myotonic dystrophy type 1 is a multisystem genetic disorder involving the muscle, heart and CNS. It is caused by toxic RNA transcription from expanded CTG repeats in the 3′-untranslated region of DMPK, leading to dysregulated splicing of various genes and multisystemic symptoms. Although aberrant splicing of several genes has been identified as the cause of some muscular symptoms, the pathogenesis of CNS symptoms prevalent in patients with myotonic dystrophy type 1 remains unelucidated, possibly due to a limitation in studying a diverse mixture of different cell types, including neuronal cells and glial cells. Previous studies revealed neuronal loss in the cortex, myelin loss in the white matter and the presence of axonal neuropathy in patients with myotonic dystrophy type 1. To elucidate the CNS pathogenesis, we investigated cell type-specific abnormalities in cortical neurons, white matter glial cells and spinal motor neurons via laser-capture microdissection. We observed that the CTG repeat instability and cytosine–phosphate–guanine (CpG) methylation status varied among the CNS cell lineages; cortical neurons had more unstable and longer repeats with higher CpG methylation than white matter glial cells, and spinal motor neurons had more stable repeats with lower methylation status. We also identified splicing abnormalities in each CNS cell lineage, such as DLGAP1 in white matter glial cells and CAMKK2 in spinal motor neurons. Furthermore, we demonstrated that aberrant splicing of CAMKK2 is associated with abnormal neurite morphology in myotonic dystrophy type 1 motor neurons. Our laser-capture microdissection-based study revealed cell type-dependent genetic, epigenetic and splicing abnormalities in myotonic dystrophy type 1 CNS, indicating the significant potential of cell type-specific analysis in elucidating the CNS pathogenesis.

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Section: Resultssupporting

confidence: 63%

Cell type-specific abnormalities of central nervous system in myotonic dystrophy type 1

Nakamori

Shimizu

Ogawa

et al. 2022

Brain Communications

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“…Interestingly, TCF3 can regulate IL-6 signaling, which is disturbed in DM1 ( 69 , 70 ). Since there are differences in splicing aberrations between brain regions in DM1, our findings may not always be representative for other brain regions than the frontal cortex ( 71 ).…”

Section: Discussionmentioning

confidence: 89%

A comprehensive atlas of fetal splicing patterns in the brain of adult myotonic dystrophy type 1 patients

Degener

Cruchten

Otero

et al. 2022

NAR Genomics and Bioinformatics

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In patients with myotonic dystrophy type 1 (DM1), dysregulation of RNA-binding proteins like MBNL and CELF1 leads to alternative splicing of exons and is thought to induce a return to fetal splicing patterns in adult tissues, including the central nervous system (CNS). To comprehensively evaluate this, we created an atlas of developmentally regulated splicing patterns in the frontal cortex of healthy individuals and DM1 patients, by combining RNA-seq data from BrainSpan, GTEx and DM1 patients. Thirty-four splice events displayed an inclusion pattern in DM1 patients that is typical for the fetal situation in healthy individuals. The regulation of DM1-relevant splicing patterns could partly be explained by changes in mRNA expression of the splice regulators MBNL1, MBNL2 and CELF1. On the contrary, interindividual differences in splicing patterns between healthy adults could not be explained by differential expression of these splice regulators. Our findings lend transcriptome-wide evidence to the previously noted shift to fetal splicing patterns in the adult DM1 brain as a consequence of an imbalance in antagonistic MBNL and CELF1 activities. Our atlas serves as a solid foundation for further study and understanding of the cognitive phenotype in patients.

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“…Interestingly, TCF3 can regulate IL-6 signaling, which is disturbed in DM1 (68, 69). Since there are differences in splicing aberrations between brain regions in DM1, our findings may not always be representative for other brain regions than the frontal cortex (70).…”

Section: Discussionmentioning

confidence: 89%

A comprehensive atlas of fetal splicing patterns in the brain of adult myotonic dystrophy type 1 patients

Degener

Cruchten

Otero

et al. 2021

Preprint

View full text Add to dashboard Cite

In patients with myotonic dystrophy type 1 (DM1), dysregulation of RNA-binding proteins like MBNL and CELF1 leads to alternative splicing of exons and is thought to induce a return to fetal splicing patterns in adult tissues, including the central nervous system (CNS). To comprehensively evaluate this, we created an atlas of developmentally regulated splicing patterns in the frontal cortex of healthy individuals and DM1 patients by combining RNA-seq data from BrainSpan, GTEx and DM1 patients. Thirty four splice events displayed an inclusion pattern in DM1 patients that is typical for the fetal situation in healthy individuals. The regulation of DM1-relevant splicing patterns could partly be explained by changes in mRNA expression of the splice regulators MBNL1, MBNL2 and CELF1. On the contrary, interindividual differences in splicing patterns between healthy adults could not be explained by differential expression of these splice regulators. Our findings lend transcriptome-wide evidence to the previously noted shift to fetal splicing patterns in the adult DM1 brain as a consequence of an imbalance in antagonistic MBNL and CELF1 activities. Our atlas serves as a solid foundation for further study and understanding of the cognitive phenotype in patients.

show abstract

Differences in splicing defects between the grey and white matter in myotonic dystrophy type 1 patients

Cited by 10 publications

References 35 publications

Cell type-specific abnormalities of central nervous system in myotonic dystrophy type 1

Cell type-specific abnormalities of central nervous system in myotonic dystrophy type 1

A comprehensive atlas of fetal splicing patterns in the brain of adult myotonic dystrophy type 1 patients

A comprehensive atlas of fetal splicing patterns in the brain of adult myotonic dystrophy type 1 patients

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