Abstract
Laminopathies are a group of rare disorders due to mutation in LMNA gene. Depending on the mutation, they may affect striated muscles, adipose tissues, nerves or are multisystemic with various accelerated ageing syndromes. Although the diverse pathomechanisms responsible for laminopathies are not fully understood, several therapeutic approaches have been evaluated in patient cells or animal models, ranging from gene therapies to cell and drug therapies. This review is focused on these therapies with a strong focus on striated muscle laminopathies and premature ageing syndromes.
Highlights
We describe the pathophysiological mechanisms implicated in laminopathies, i.e., the diseases due to LMNA gene mutations, with a focus on SML and premature ageing syndromes, and associated preclinical therapies that have been developed over the years
Seventy-five percent of LMNA mutations that causes FPLD2 are missense mutations encompassing the IgG-like domain [39,40,41]. These mutations have been shown to perturb the interaction of lamin A/C with several partners, including SREBP1, a transcription factor involved in adipocyte differentiation [42]
We examined the involvement of oxidative stress in the progression of cardiac disease in LmnaH222P/H222P mice and showed that LMNA cardiomyopathy is associated with increased oxidative stress and depletion of glutathione (GSH)
Summary
Lamins are divided into two categories: A-type lamins, encoded by the LMNA gene, and B-type lamins, encoded by the LMNB1 and LMNB2 genes They display an N-terminal unstructured head domain, a central helical rod domain involved in their assembly into filaments and a globular C-terminal tail that contains a nuclear localization signal and an immunoglobulin-like (IgG-like) fold involved in protein-protein interactions [1]. The LMNA gene has 12 exons, among which exon 10 contains an alternative splice site giving rise to two major isoforms: lamin A and C These two isoforms are identical in their first 566 amino-acids and vary in their C-terminal tail, with six unique carboxyl-terminal amino-acids for lamin C and 98 for lamin A [2].
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