2014
DOI: 10.1371/journal.pgen.1004605
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Abstract: Proteins of the nuclear envelope (NE) are associated with a range of inherited disorders, most commonly involving muscular dystrophy and cardiomyopathy, as exemplified by Emery-Dreifuss muscular dystrophy (EDMD). EDMD is both genetically and phenotypically variable, and some evidence of modifier genes has been reported. Six genes have so far been linked to EDMD, four encoding proteins associated with the LINC complex that connects the nucleus to the cytoskeleton. However, 50% of patients have no identifiable m… Show more

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Cited by 148 publications
(177 citation statements)
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“…In addition, mutations just up or downstream of the variable region were found in muscular dystrophies (A201V, G338S, W377C). 39 Therefore, non-redundant function of SUN1 variants might contribute to the pathogenic mechanism of laminopathies.…”
Section: Pathological Functions Of the Linc Complexmentioning
confidence: 99%
“…In addition, mutations just up or downstream of the variable region were found in muscular dystrophies (A201V, G338S, W377C). 39 Therefore, non-redundant function of SUN1 variants might contribute to the pathogenic mechanism of laminopathies.…”
Section: Pathological Functions Of the Linc Complexmentioning
confidence: 99%
“…In this context, elevated TGFbeta 2 and Akt/mTOR activation could also be the cause of reduced lamin A and prelamin A levels [15,17] at the cardiomyocyte nuclear envelope, a condition that favors LINC disorganization [12]. In agreement with this pathogenetic hypothesis, Erk 1/2 activation has been demonstrated in the presence of pathogenetic LMNA and SYNE1 mutations [7,13], and altered positioning of muscle nuclei has been demonstrated in LMNA, SYNE1 and SUN1 -linked Emery-Dreifuss muscular dystrophy with cardiomyopathy [1214,18]. …”
Section: Pathogenetic Pathways In Cardiolaminopathiesmentioning
confidence: 92%
“…The connection with extranuclear signal transducers is ensured by the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex, a protein chain including integral proteins of the inner and outer nuclear membrane, such as SUN1/2 and nesprin1/2 (encoded by SYNE1/2 genes), attached to lamins on the nuclear side and to actin and other cytoskeleton constituents on the cytoplasmic side. LINC proteins are reduced [12,13] or even mutated [13,14] in patients affected by cardiolaminopathies. The proven effect of LINC disorganization and reduced interplay between LINC components and lamins in laminopathic muscle cells is defective myonuclear positioning [12,14], which is a cause of altered muscle cell functionality [14].…”
Section: Pathogenetic Pathways In Cardiolaminopathiesmentioning
confidence: 99%
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“…Moreover, lamin A and prelamin A regulate nuclear positioning through functional interaction with SUN1 and nesprins, key constituents of the LINC complex connecting the nucleoskeleton to the cytoskeleton. The relevance of the latter function is highlighted by the effects elicited in muscle by either lamin A/C or SUN1 mutations, 19 which lead to myonuclear clustering and aberrant distribution of myonuclear domains.…”
Section: The Nuclear Envelopementioning
confidence: 99%