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Myotonic Dystrophy-A Progeroid Disease?

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Myotonic Dystrophy-A Progeroid Disease?

Peter Meinke et al. Front Neurol.

Abstract

Myotonic dystrophies (DM) are slowly progressing multisystemic disorders caused by repeat expansions in the DMPK or CNBP genes. The multisystemic involvement in DM patients often reflects the appearance of accelerated aging. This is partly due to visible features such as cataracts, muscle weakness, and frontal baldness, but there are also less obvious features like cardiac arrhythmia, diabetes or hypogammaglobulinemia. These aging features suggest the hypothesis that DM could be a segmental progeroid disease. To identify the molecular cause of this characteristic appearance of accelerated aging we compare clinical features of DM to "typical" segmental progeroid disorders caused by mutations in DNA repair or nuclear envelope proteins. Furthermore, we characterize if this premature aging effect is also reflected on the cellular level in DM and investigate overlaps with "classical" progeroid disorders. To investigate the molecular similarities at the cellular level we use primary DM and control cell lines. This analysis reveals many similarities to progeroid syndromes linked to the nuclear envelope. Our comparison on both clinical and molecular levels argues for qualification of DM as a segmental progeroid disorder.

Keywords: DNA repair; myotonic dystrophy; nuclear envelope; premature aging; segmental progeroid disorder.

Figures

Figure 1
Figure 1
Cell cycle regulatory proteins in myotonic dystrophy. Western Blot and quantification of primary control, DM1 and DM2 myoblasts for cell cycle regulatory proteins p21 (A) and p16 (B). DM1 samples are ordered according their diagnosed repeat length from left (small repeat) to right (long repeat).
Figure 2
Figure 2
Lamina proteins in myotonic dystrophy. Western Blot and quantification of primary control, DM1 and DM2 myoblasts for lamin A and lamin C (A) and lamin B1 (B). DM1 samples are ordered according their diagnosed repeat length from left (small repeat) to right (long repeat).
Figure 3
Figure 3
Nuclear envelope invaginations in myotonic dystrophy. Immunofluorescence staining of primary control, DM1 and DM2 myoblasts for (A) emerin and Ki-67 showing nuclear envelope invagination in DM1 and DM2 myoblasts, (B) confirmation of nuclear envelope invaginations by lamin A/C staining and (C) quantification of these structures in DM and control cell lines—standard deviation is shown. White arrows indicate invaginations of the nuclear envelope. Scale bar 10 μm.
Figure 4
Figure 4
Nuclear envelope invaginations in myotonic dystrophy and control myotubes. Immunofluorescence staining of primary control, DM1 and DM2 myotubes for (A) emerin and (B) lamin A/C showing nuclear envelope invagination in DM1 myotubes. White arrows indicate invaginations of the nuclear envelope. Scale bar 10 μm.
Figure 5
Figure 5
Myotonic dystrophy as a facet of progeroid syndromes? Schematic of affected nuclear regions and pathways in DM and nuclear envelope as well as DNA repair linked progeroid syndromes.

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