Nesprin-1 and -2 are involved in the pathogenesis of Emery–Dreifuss muscular dystrophy and are critical for nuclear envelope integrity

Abstract

Emery-Dreifuss muscular dystrophy (EDMD) is a heterogeneous late-onset disease involving skeletal muscle wasting and heart defects caused, in a minority of cases, by mutations in either of two genes encoding the inner nuclear membrane (INM) proteins, emerin and lamins A/C. Nesprin-1 and -2 are multi-isomeric, spectrin-repeat proteins that bind both emerin and lamins A/C and form a network in muscle linking the nucleoskeleton to the INM, the outer nuclear membrane, membraneous organelles, the sarcomere and the actin cytoskeleton. Thus, disruptions in nesprin/lamin/emerin interactions might play a role in the muscle-specific pathogenesis of EDMD. Screening for DNA variations in the genes encoding nesprin-1 (SYNE1) and nesprin-2 (SYNE2) in 190 probands with EDMD or EDMD-like phenotypes identified four heterozygous missense mutations. Fibroblasts from these patients exhibited nuclear morphology defects and specific patterns of emerin and SUN2 mislocalization. In addition, diminished nuclear envelope localization of nesprins and impaired nesprin/emerin/lamin binding interactions were common features of all EDMD patient fibroblasts. siRNA knockdown of nesprin-1 or -2 in normal fibroblasts reproduced the nuclear morphological changes and mislocalization of emerin and SUN2 observed in patient fibroblasts. Taken together, these data suggest that EDMD may be caused, in part, by uncoupling of the nucleoskeleton and cytoskeleton because of perturbed nesprin/emerin/lamin interactions.

Depletion of Nesprin-2 is associated with an embryonic lethal phenotype in mice

“…The latter increased in number with increasing passage number. The analysis of Nesprin-2 negative MEFs revealed that they had similar phenotypes as has been described previously for MEFs isolated from Nesprin-2 mouse mutants and for cells in which Nesprin-2 was depleted by shRNAs [15,20,23]. In particular, changes in the nuclear morphology and in cell migration resembled those that had been seen previously.…”

“…In human, mutations in the SYNE2 gene cause Emery-Dreifuss muscular dystrophy (EDMD) 5, an autosomal dominant disease[20]. Patients suffering from EDMD harbored a heterozygous DNA variation in the SYNE2 gene leading to a missense mutation pT89M in the C-terminal Nesprin-2β isoform.…”

“…This residue is located in a region of Nesprin-2, which mediates Emerin and LaminA/C interactions [6,21,22]. The mutation led to nuclear deformation and LaminA/C, Emerin and SUN2 mislocalization and altered heterochromatin localization in patient fibroblasts[20]. …”

Mutation in TOR1AIP1 encoding LAP1B in a form of muscular dystrophy: A novel gene related to nuclear envelopathies

“…This gene encodes a type-2 integral membrane protein located in the inner nuclear membrane, LAP1B. Because other proteins of the nuclear membrane such as laminA/C, emerin, nesprin-1 and nesprin-2 are known to cause muscular dystrophy phenotypes, TOR1AIP1 was selected as a possible novel nuclear envelopathy-related gene [14,15]. DNA sequencing of TOR1AIP1 from the genomic DNA of affected individuals IV:2, IV:5 and IV:7 showed that there was a homozygous G deletion at position c.186 (c.186delG) in the first exon of the gene, which was predicted to cause a frameshift leading to a premature stop codon ( Fig.…”

“…This group of diseases known as nuclear envelopathies consist of a wide range of clinical syndromes, including muscular dystrophy, cardiomyopathy, lipodystrophy, mandibuloacral dysplasia, neuropathy, progeria, restrictive dermopathy, arthrogryposis, Pelger-Huet anomaly and leukodystrophy [14,15].…”