Furthermore, by using progeroid mice deficient in ZMPSTE24 (zinc metalloprotease STE24 homologue) involved in lamin A maturation, we have demonstrated that, besides these abnormal cellular responses to stress, dysregulation of the somatotropic axis is responsible for some of the alterations associated with progeria.
Recent studies on HGPS (due to mutations of the <i>LMNA</i> gene encoding for the nucleoskeletal proteins lamin A/C) have reported disruptions in cellular and molecular mechanisms modulating genomic stability and stem cell populations, thus giving the nuclear lamina a relevant function in nuclear organization, epigenetic regulation and in the maintenance of the stem cell pool.
Hutchinson-Gilford progeria syndrome (HGPS) is an accelerated aging disorder caused by mutations in LMNA leading to expression of a truncated prelamin A variant termed progerin.
A recent study finds that LMNA, a gene targeted for mutation in Hutchinson Gilford Progeria Syndrome, may control the onset of aging-associated decline in normal fibroblasts.
Age-related nuclear defects are caused by sporadic use, in healthy individuals, of the same cryptic splice site in lamin A whose constitutive activation causes HGPS.
Background Hutchinson-Gilford progeria syndrome (HGPS) is a rare disease caused by pathogenic variants in the LMNA gene, which leads to premature aging.
Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature-aging syndrome caused by a dominant mutation in the gene encoding lamin A, which leads to an aberrantly spliced and processed protein termed progerin.
LMNA-linked progerias can be grouped into two classes: (1) the processing-deficient, early onset "typical" progerias (e.g., HGPS), and (2) the processing-proficient "atypical" progeria syndromes (APS) that are later in onset.
Mutations in the lamin A gene (LMNA) cause severe genetic disorders, one of which is Hutchinson-Gilford progeria syndrome (HGPS), a disease triggered by a dominant mutant named progerin.
The most frequent HGPS-associated LMNA mutation results in a protein, termed progerin, with an internal 50 amino acid deletion and, unlike normal A-type lamins, stable farnesylation.
In this study, we describe the development of a tissue-specific mouse model that overexpresses the most common HGPS mutation (LMNA, c.1824C>T, p.G608G) in osteoblasts.
Previous work has shown that treatment of HGPS cells with the mTOR inhibitor rapamycin or with the rapamycin analog everolimus corrects several of the phenotypes seen at the cellular level-at least in part by increasing autophagy and reducing the amount of progerin, the toxic form of lamin A that is overproduced in HGPS patients.
Dermal fibroblasts in Hutchinson-Gilford progeria syndrome with the lamin A G608G mutation have dysmorphic nuclei and are hypersensitive to heat stress.
We found that the mutant lamin A responsible for HGPS, known as progerin, could not bind to proteins related to the DNA damage response, including DNA-dependent protein kinase (DNA-PK).
One proposed mechanism for the more severe symptoms in patients with RD compared with HGPS is that higher levels of farnesylated lamin A are produced in RD.
HGPS is one of several progeroid syndromes caused by mutations in the LMNA gene encoding the nuclear structural proteins lamins A and C. In classic HGPS the mutation G608G leads to the formation of a toxic lamin A protein called progerin.
Since the discovery of LMNA mutations in highly heterogeneous human disorders (including cardiac and muscular dystrophies, lipodystrophies and progeria), the number of functions described for lamin A/C has expanded.
LMNA gene mutations are associated with a variety of degenerative diseases and devastating premature aging syndromes such as Hutchinson-Gilford Progeria Syndrome (HGPS) and Restrictive Dermopathy (RD).
Interestingly, aberrant alternative splicing of the LMNA gene via the usage of a cryptic splice site has been shown to be the cause of most cases of Hutchinson-Gilford progeria syndrome (HGPS), a rare genetic condition characterized by an accelerated aging phenotype due to the accumulation of a truncated form of lamin A known as progerin.