De novo LMNA mutations cause a new form of congenital muscular dystrophy

Abstract

The LMNA mutations identified appear to correlate with a relatively severe phenotype. Our results further broaden the spectrum of laminopathies and define a new disease entity that we suggest is best classified as a congenital muscular dystrophy (LMNA-related congenital muscular dystrophy, or L-CMD).

Cellular micro-environments reveal defective mechanosensing responses and elevated YAP signaling in LMNA-mutated muscle precursors

“…Clinical details of patients are given in supplementary material Table S1. More detailed description of patient P3 has been previously reported (Quijano-Roy et al, 2008). Control myoblasts (WT-1 to WT-4) were obtained from four control subjects without muscular disorders (C1 to C4) (supplementary material Table S1).…”

“…Mutations in the LMNA gene, which encodes for A-type lamins (lamin A/C), cause laminopathies, a highly heterogeneous group of disorders, including muscular dystrophies and cardiomyopathies (Worman and Bonne, 2007;Bertrand et al, 2011). The severity of the skeletal muscle myopathy is highly variable, the most severe being the LMNA-related congenital muscular dystrophy (L-CMD), that is characterized by an early onset of muscle hypotonia and weakness, joint contractures, spinal stiffness and respiratory involvement (Quijano-Roy et al, 2008).…”

“…Because tissue architecture and stiffness of the cell microenvironment have a major impact on the spatial arrangement and dynamic regulation of the cytoskeleton and focal adhesion sites (Pelham and Wang, 1997;Abbott, 2003;Chiron et al, 2012;Lee et al, 2012), and thus on cell mechanosensing, myoblasts from four non-related patients exhibiting L-CMD (Quijano-Roy et al, 2008) and four controls (supplementary material Table S1) were examined in a three-dimensional (3D) soft microenvironment as well as on two-dimensional (2D) substrates of various stiffness. Our data reveal that LMNA-mutated cells (hereafter referred to as LMNA cells) present severe defects in their capacity to sense the stiffness of their environment and to respond to mechanical stress.…”

Congenital muscular dystrophy. Part II: a review of pathogenesis and therapeutic perspectives

“…Most of the different genes involved with the pathogenesis of the CMD subtypes are related to the function of the dystrophin-glycoproteins associated complex (DGC) in the sarcolemma and extracellular matrix and their mutations lead either to defects in the glycosylation of alpha-dystroglycan (alpha-dystroglycanopathies) or to abnormalities of extracellular matrix proteins (MDC1A and collagen VI related disorders) [1][2][3][4][5][6][7] . A fourth subtype, rigid spine CMD, is related to a defect of an endoplasmic reticulum protein, selenoprotein N 9 , and recently a new subtype 10 was associated to a defect of a nuclear protein, lamin A/C. last month, the first part of this review focused on the clinical and diagnostic aspects of the different subtypes of CMD.…”

MicroRNAs in hereditary and sporadic premature aging syndromes and other laminopathies

“…Additionally, three other forms (EDMD 4, 5, and 7) implicate other nuclear envelope proteins (SYNE1, SYNE2, and TMEM43). Another laminopathy called congenital muscular dystrophy (autosomal dominant, OMIM #613205) causes muscle weakness from the first year of life, which could be associated with a “dropped head” syndrome phenotype (Quijano‐Roy et al., 2008). Two other laminopathies have a cardiac phenotype.…”