Immunohistochemistry on a panel of Emery–Dreifuss muscular dystrophy samples reveals nuclear envelope proteins as inconsistent markers for pathology

Thành, Phú Lê; Meinke, Peter; Korfali, Nadia; Sršeň, Vlastimil; Robson, Michael I.; Wehnert, Manfred; Schöser, Benedikt; Sewry, Caroline A.; Schirmer, Eric C.

doi:10.1016/j.nmd.2016.12.003

Cited by 14 publications

(15 citation statements)

References 47 publications

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“…In EDMD2 mature muscle, we observed mis-localization of Samp1 from the nuclear envelope of myonuclei. In fact, double immunolabeling of Samp1 and laminin alpha 2, which lines the basal lamina of myofibers, demonstrated that nuclei inside control muscle fibers were Samp1 positive and the protein was located at the nuclear periphery, which was previously reported in Reference [ 30 ], while interstitial nuclei presented a faint staining ( Figure 4 d). In EDMD2 myonuclei bearing the H506P LMNA mutation [ 32 ], Samp1 was mis-localized in the vast majority (80%) of examined myofibers ( Figure 4 d) possibly due to a loss of interaction with farnesylated prelamin A, which is dramatically reduced in EDMD2 muscle fibers [ 15 ].…”

Section: Resultssupporting

confidence: 78%

“…Although we observe a uniform distribution of Samp1 in the nuclear envelope, loss of prelamin A farnesylation [ 15 ] causes Samp1 mislocalization from the nuclear poles. Moreover, in EDMD2 myotubes, Samp1 is overall preserved at the nuclear envelope, which is reported in Reference [ 30 ], but it is missing from the nuclear poles. Thus, a protein platform including farnesylated prelamin A, SUN proteins, and Samp1 is located at the nuclear poles of myonuclei and it is disrupted in EDMD2.…”

Section: Introductionsupporting

confidence: 68%

“…In EDMD2 mature muscle, Samp1 is almost completely mis-localized from the nuclear envelope with a low percentage of negative nuclei. A previous study [ 30 ] showed that Samp1 is correctly localized in myofibers from EDMD2 patients. As for other nuclear envelope proteins analyzed by the same authors [ 30 ], the different outcome of our Samp1 study may be related to the different LMNA mutation.…”

Section: Discussionmentioning

confidence: 99%

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Samp1 Mislocalization in Emery-Dreifuss Muscular Dystrophy

Mattioli

Columbaro

Jafferali

et al. 2018

Cells

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LMNA linked-Emery-Dreifuss muscular dystrophy (EDMD2) is a rare disease characterized by muscle weakness, muscle wasting, and cardiomyopathy with conduction defects. The mutated protein lamin A/C binds several nuclear envelope components including the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex and the inner nuclear membrane protein Samp1 (Spindle Associated Membrane Protein 1). Considering that Samp1 is upregulated during muscle cell differentiation and it is involved in nuclear movement, we hypothesized that it could be part of the protein platform formed by LINC proteins and prelamin A at the myotube nuclear envelope and, as previously demonstrated for those proteins, could be affected in EDMD2. Our results show that Samp1 is uniformly distributed at the nuclear periphery of normal human myotubes and committed myoblasts, but its anchorage at the nuclear poles is related to the presence of farnesylated prelamin A and it is disrupted by the loss of prelamin A farnesylation. Moreover, Samp1 is absent from the nuclear poles in EDMD2 myotubes, which shows that LMNA mutations associated with muscular dystrophy, due to reduced prelamin A levels in muscle cell nuclei, impair Samp1 anchorage. Conversely, SUN1 pathogenetic mutations do not alter Samp1 localization in myotubes, which suggests that Samp1 lies upstream of SUN1 in nuclear envelope protein complexes. The hypothesis that Samp1 is part of the protein platform that regulates microtubule nucleation from the myotube nuclear envelope in concert with pericentrin and LINC components warrants future investigation. As a whole, our data identify Samp1 as a new contributor to EDMD2 pathogenesis and our data are relevant to the understanding of nuclear clustering occurring in laminopathic muscle.

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Section: Resultssupporting

confidence: 78%

Section: Introductionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

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Samp1 Mislocalization in Emery-Dreifuss Muscular Dystrophy

Mattioli

Columbaro

Jafferali

et al. 2018

Cells

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“…Samp1 also interacts with the LINC complex protein, Sun1 22 , 23 , which is also implicated in EDMD. A recent study 32 showed that Samp1 distributed abnormally, in some, but not all EDMD patient cells. The strong and clear requirement for Samp1 in differentiation of C2C12 myoblasts presented here may provide new insights in the pathological development in EDMD.…”

Section: Discussionmentioning

confidence: 96%

Spindle associated membrane protein 1 (Samp1) is required for the differentiation of muscle cells

Jafferali

Figueroa

Hasan

et al. 2017

Sci Rep

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Muscles are developed and regenerated in a differentiation process called myogenesis, which involves components of the nuclear envelope. We have investigated Samp1 (Spindle Associated Membrane Protein 1), a transmembrane nuclear envelope protein, which interacts with emerin and lamin A, both of which are linked to Emery-Dreifuss muscular dystrophy (EDMD). We found that the levels of Samp1 increased seven-fold during differentiation of mouse C2C12 muscle progenitor cells. To test if Samp1 could have a role in myogenesis we developed stable C2C12 knockdown cell lines expressing short hairpin RNA targeting Samp1 expression. The Samp1 depleted C2C12 cells displayed normal mobility and normal distribution of emerin and lamin A. However, Samp1 depletion increased ERK signaling and completely blocked differentiation of C2C12 cells, which failed to express myogenic marker proteins and failed to form myotubes. The block in myogenesis in Samp1 depleted cells was completely rescued by ectopic expression of RNAi resistant human Samp1, showing that Samp1 is required for muscle differentiation.

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“…21 Distinct, clinically useful immunohistochemistry findings have not been established in the other EDMD subtypes. 112…”

Section: Muscle Pathologymentioning

confidence: 99%

Emery‐Dreifuss muscular dystrophy

et al. 2019

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Emery‐Dreifuss muscular dystrophy (EDMD) is a rare muscular dystrophy, but is particularly important to diagnose due to frequent life‐threatening cardiac complications. EDMD classically presents with muscle weakness, early contractures, cardiac conduction abnormalities and cardiomyopathy, although the presence and severity of these manifestations vary by subtype and individual. Associated genes include EMD, LMNA, SYNE1, SYNE2, FHL1, TMEM43, SUN1, SUN2, and TTN, encoding emerin, lamin A/C, nesprin‐1, nesprin‐2, FHL1, LUMA, SUN1, SUN2, and titin, respectively. The Online Mendelian Inheritance in Man database recognizes subtypes 1 through 7, which captures most but not all of the associated genes. Genetic diagnosis is essential whenever available, but traditional diagnostic tools can help steer the evaluation toward EDMD and assist with interpretation of equivocal genetic test results. Management is primarily supportive, but it is important to monitor patients closely, especially for potential cardiac complications. There is a high potential for progress in the treatment of EDMD in the coming years.

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Immunohistochemistry on a panel of Emery–Dreifuss muscular dystrophy samples reveals nuclear envelope proteins as inconsistent markers for pathology

Abstract: HighlightsAltered distribution of EDMD-linked proteins is not a general characteristic of EDMD.Tissue-specific proteins exhibit altered distributions in some EDMD patients.Variation in redistributed proteins in EDMD may underlie its clinical variability.

Cited by 14 publications

References 47 publications

Samp1 Mislocalization in Emery-Dreifuss Muscular Dystrophy

Samp1 Mislocalization in Emery-Dreifuss Muscular Dystrophy

Spindle associated membrane protein 1 (Samp1) is required for the differentiation of muscle cells

Emery‐Dreifuss muscular dystrophy

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