Abstract
The lamin A/C (LMNA) gene codes for nuclear intermediate filaments constitutive of the nuclear lamina. LMNA has 12 exons and alternative splicing of exon 10 results in two major isoforms—lamins A and C. Mutations found throughout the LMNA gene cause a group of diseases collectively known as laminopathies, of which the type, diversity, penetrance and severity of phenotypes can vary from one individual to the other, even between individuals carrying the same mutation. The majority of the laminopathies affect cardiac and/or skeletal muscles. The underlying molecular mechanisms contributing to such tissue-specific phenotypes caused by mutations in a ubiquitously expressed gene are not yet well elucidated. This review will explore the different phenotypes observed in established models of striated muscle laminopathies and their respective contributions to advancing our understanding of cardiac and skeletal muscle-related laminopathies. Potential future directions for developing effective treatments for patients with lamin A/C mutation-associated cardiac and/or skeletal muscle conditions will be discussed.
Highlights
Laminopathies consist of a variety of diseases that affect different tissue types ranging from cardiac muscle (e.g., dilated cardiomyopathy (DCM)), skeletal muscles (e.g., Emery-Dreifuss MuscularDystrophy (EDMD)), adipose tissues (e.g., familial partial lipodystrophy Dunnigan-type 2(FPLD2)) to nervous system (e.g., Charcot-Marie-Tooth disease type 2B1 (CMT2B1)) or affect several systems (e.g., Hutchison Gilford Progeria Syndrome (HGPS))
lamin A/C (LMNA) cause primary laminopathies, while secondary laminopathies are caused by mutations in B-type lamins, proteins involved in prelamin A maturation, or lamin binding partners
The evidence far demonstrates the wide array and importance of the presence and function of A-type lamins in maintaining cellular processes, as indicated by the diversity of diseases caused by LMNA mutations
Summary
Laminopathies consist of a variety of diseases that affect different tissue types ranging from cardiac muscle (e.g., dilated cardiomyopathy (DCM)), skeletal muscles LMNA cause primary (classical) laminopathies, while secondary laminopathies are caused by mutations in B-type lamins, proteins involved in prelamin A maturation, or lamin binding partners. The second relates to the role of lamin A/C in interacting with chromatin and proteins This is evidenced, for instance, by the increased expression and activation of MAPK pathway members in EDMD and DCM [21]. LMNA-related congenital muscular dystrophy (L-CMD) and EDMD are skeletal muscle conditions caused by LMNA mutations with overlapping clinical phenotypes, which include wasting of the upper arm and lower front leg muscles [41]. L-CMD is more severe and has earlier onset but less definitive cardiac presentation compared to EDMD [42]
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