Skeletal Muscle Laminopathies: A Review of Clinical and Molecular Features

Abstract

LMNA-related disorders are caused by mutations in the LMNA gene, which encodes for the nuclear envelope proteins, lamin A and C, via alternative splicing. Laminopathies are associated with a wide range of disease phenotypes, including neuromuscular, cardiac, metabolic disorders and premature aging syndromes. The most frequent diseases associated with mutations in the LMNA gene are characterized by skeletal and cardiac muscle involvement. This review will focus on genetics and clinical features of laminopathies affecting primarily skeletal muscle. Although only symptomatic treatment is available for these patients, many achievements have been made in clarifying the pathogenesis and improving the management of these diseases.

Keywords: Emery-Dreifuss muscular dystrophy; LMNA gene; arrhythmia; cardiomyopathy; congenital muscular dystrophy; laminopathies; limb-girdle muscular dystrophy.

Figure 1

Description of typical clinical features of LMNA-related dystrophy (LMNA-RD). Patient affected by LGMD1B phenotype: note the lumbar lordosis (A) and upper limb abduction weakness (B); patient with LGMD1B: note the humeral atrophy and absence of scapular winging, which is typically associated with EDMD2 (C); patient affected by EDMD2 phenotype: note the elbow flexion contractures and wasting of humeral muscles (D).

Figure 2

This is a schematic representation of the LMNA gene (A) and the lamin A/C protein (B). Mutations associated with laminopathy and identified in Italian patients are indicated with the corresponding nucleotide (A) or amino acid (B) changes. The globular head and tail domains are shown as an oval. The coil 1 (segments 1A and 1B), and coil 2 (segments 2A and 2B), constituting the α-helical rod domain, are shown as rectangles. Double lines represent linkers L1, L2 and L12. NLS = nuclear location signal; Ig = immunoglobulin. Modified from Neurology 2014, 83, 1634–1644 [5].