Nuclear lamina remodelling and its implications for human disease

Abstract

The intermediate filament A- and B-type lamins are key architectural components of the nuclear lamina, a proteinaceous meshwork that lies underneath the inner nuclear membrane. In the past decade, many different monogenic human diseases have been linked to mutations in various components of the nuclear lamina. Mutations in LMNA (encoding lamin A and C) cause a variety of human diseases, collectively called laminopathies. These include cardiomyopathies, muscular dystrophies, lipodystrophies and progeroid syndromes. In addition, elevated levels of lamin B1, attributable to genomic duplications of the LMNB1 locus, cause adult-onset autosomal dominant leukodystrophy. The molecular mechanism(s) enabling the mutations and perturbations of the nuclear lamina to give rise to such a wide variety of diseases that affect various tissues remains unclear. The composition of the nuclear lamina changes dynamically during development, between cell types and even within the same cell during differentiation and ageing. Here, we discuss the functional and cellular aspects of lamina remodelling and their implications for the tissue-specific nature of laminopathies.

Heterochromatin loss as a determinant of progerin‐induced DNA damage in Hutchinson–Gilford Progeria

“…The loss and disorganization of heterochromatin during aging is now well‐documented, from the loss of lamina‐associated heterochromatin during normal and premature aging (McCord et al, ; Shumaker et al, ; Tsurumi & Li, ; Whitton et al, ; Zhang et al, ), to oxidative‐stress induced aging (Osanai et al, ) and aging of the immune system (Keenan & Allan ). Heterochromatin loss is accompanied by extensive remodelling of the nuclear lamina (Chojnowski, Ong, & Dreesen, ; Dreesen et al, ), and it has been proposed to be determinant of aging in yeast, flies and worms (Tsurumi & Li, ). However, the functional role of the heterochromatin loss in HGPS and how it relates to other progerin‐induced defects remains unclear.…”

“…Heterochromatin loss is accompanied by extensive remodelling of the nuclear lamina (Chojnowski, Ong, & Dreesen, 2014;Dreesen et al, 2013), and it has been proposed to be determinant of aging in yeast, flies and worms (Tsurumi & Li, 2012). However, the functional role of the heterochromatin loss in HGPS and how it relates to other progerin-induced defects remains unclear.…”

Bursting the Bubble – Nuclear Envelope Rupture as a Path to Genomic Instability?

“…Mutations in the lamin genes, particularly LMNA , cause a broad spectrum of diseases called laminopathies. These include Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy, and the segmental aging disease Hutchinson-Gilford progeria syndrome [62, 63]. While lamin levels are altered in many cancers [44], most laminopathies do not correlate with increased cancer incidence or enhanced metastatic potential.…”

Lamin B1 mediated demyelination: Linking Lamins, Lipids and Leukodystrophies

“…5,6 Autosomal Dominant Leukodystrophy is caused by mutations involving the Lamin B1 gene While at least 12 distinct disorders have been associated with mutations in the LMNA gene, only one disease, Autosomal Dominant Leukodystrophy (ADLD), has so far been linked to mutations involving lamin B1. 7,8 The majority of ADLD cases are caused by duplications involving the lamin B1 gene locus that results in increased lamin B1 protein expression. 8,9 A recent report described a deletion upstream of the lamin B1 gene that resulted in a variant ADLD phenotype.…”