Abstract
Emery-Dreifuss muscular dystrophy (EDMD) is a late onset-disease characterized by skeletal muscle wasting and heart defects with associated risk of sudden death. The autosomal dominant form of the disease is caused by mutations in the LMNA gene encoding LaminA and C, the X-linked form results from mutations in the gene encoding the inner nuclear membrane protein Emerin (STA). Both Emerin and LaminA/C interact with the nuclear envelope proteins Nesprin-1 and -2 and mutations in genes encoding C-terminal isoforms of Nesprin-1 and -2 have also been implicated in EDMD. Here we analyse primary fibroblasts from patients affected by either Duchenne muscular dystrophy (DMD) or Emery-Dreifuss muscular dystrophy/Charcot-Marie-Tooth syndrome (EDMD/CMT) that in addition to the disease causing mutations harbour mutations in the Nesprin-1 gene and in the SUN1 and SUN2 gene, respectively. SUN proteins together with the Nesprins form the core of the LINC complex which connects the nucleus with the cytoskeleton. The mutations are accompanied by changes in cell adhesion, cell migration, senescence, and stress response, as well as in nuclear shape and nuclear envelope composition which are changes characteristic for laminopathies. Our results point to a potential influence of mutations in components of the LINC complex on the clinical outcome and the molecular pathology in the patients.
Highlights
The nuclear envelope (NE) forms an interface between the cytoplasm and the nuclear interior during interphase
We extended the analysis to components of the LINC complex and sequenced in particular coding exons of Nesprin-1␣1, Nesprin-1␣2, Nesprin-2␣1, Nesprin2␣2, Nesprin-21 and Nesprin-22, SUN1 and SUN2
We characterised dermal fibroblasts from patients suffering from Duchenne muscular dystrophy (DMD) and Emery-Dreifuss muscular dystrophy (EDMD)/Charcot-Marie-Tooth disease (CMT)
Summary
The nuclear envelope (NE) forms an interface between the cytoplasm and the nuclear interior during interphase. It is composed of the outer and inner nuclear membranes (ONM and INM, respectively), the nuclear lamina and the nuclear pore complexes (NPCs). The NE proteome comprises several proteins that perform critical functions in the maintenance of nuclear architecture, positioning and migration. Mutations in these proteins lead to a variety of diseases, collectively called laminopathies, including partial lipodystrophy, mandibulolacral dysplasia (MAD), dilated cardiomyopathy, autosomal-dominant limb-girdle muscular dystrophy type 1B (LGMD1B), Charcot-Marie-Tooth neuropathy type. EDMD is typically characterised by the clinical triad of (1) early contractures of the Achilles tendons, elbows and postcervical muscles (with subsequent limitation of neck flexion, but later forward flexion of the entire spine becomes limited); (2) progressive skeletal muscle weakness and wasting with a humero-peroneal predominance at the onset of the disease (i.e. proximal in the upper limbs and distal in the lower limbs) and (3) a life threatening cardiac disease where conduction defects coexist with ventricular and supraventricular arrhythmias, chamber dilation and heart failure
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have