Laminopathies and lamin‐associated signaling pathways

Abstract

Laminopathies are genetic diseases due to mutations or altered post-translational processing of nuclear envelope/lamina proteins. The majority of laminopathies are caused by mutations in the LMNA gene, encoding lamin A/C, but manifest as diverse pathologies including muscular dystrophy, lipodystrophy, neuropathy, and progeroid syndromes. Lamin-binding proteins implicated in laminopathies include lamin B2, nuclear envelope proteins such as emerin, MAN1, LBR, and nesprins, the nuclear matrix protein matrin 3, the lamina-associated polypeptide, LAP2alpha and the transcriptional regulator FHL1. Thus, the altered functionality of a nuclear proteins network appears to be involved in the onset of laminopathic diseases. The functional interplay among different proteins involved in this network implies signaling partners. The signaling effectors may either modify nuclear envelope proteins and their binding properties, or use nuclear envelope/lamina proteins as platforms to regulate signal transduction. In this review, both aspects of lamin-linked signaling are presented and the major pathways so far implicated in laminopathies are summarized.

A novel homozygous p.Arg527Leu LMNA mutation in two unrelated Egyptian families causes overlapping mandibuloacral dysplasia and progeria syndrome

“…13 Their phenotypes are quite diverse, most probably owing to the multiple molecular functions of lamin A, including the regulation of gene transcription, chromatin organization, DNA replication, maintenance of nuclear integrity, and mechanotransduction, that might be diversely affected by various mutations. 35,36 A difficulty arises when genotype-phenotype correlations are being made. In some laminopathies, there is a good correlation between the specific mutations of LMNA and the clinical manifestations of the disease; in others, multiple mutations present in distinct parts of LMNA might all result in a similar phenotype; in still other cases, the mutation of a single residue might result in a diverse phenotypes.…”

Intracellular partitioning of cell organelles and extraneous nanoparticles during mitosis

“…can drastically alter the expression profile of the cell [27]. The most striking example is probably molecular aging in Hutchinson-Gilford progeria syndrome, which is the result of a single mutation in lamin A [28].…”

Role of the nuclear envelope in the pathogenesis of age-related bone loss and osteoporosis

“…31,32 The most widely studied mechanism is the interaction between prelamin A and sterol-regulatory binding protein 1 (SREBP1). Prelamin A and SREBP1 co-localize in the nuclear rim, which coincides with the downregulation of PPAR expression.…”