How can progeria be detected

This condition is very rare; it is reported to occur in 1 in 4 million newborns worldwide. More than cases have been reported in the scientific literature since the condition was first described in This protein plays an important role in determining the shape of the nucleus within cells. It is an essential scaffolding supporting component of the nuclear envelope, which is the membrane that surrounds the nucleus.

Mutations that cause Hutchinson-Gilford progeria syndrome result in the production of an abnormal version of the lamin A protein. The altered protein makes the nuclear envelope unstable and progressively damages the nucleus, making cells more likely to die prematurely. Researchers are working to determine how these changes lead to the characteristic features of Hutchinson-Gilford progeria syndrome.

Hutchinson-Gilford progeria syndrome is considered an autosomal dominant condition, which means one copy of the altered gene in each cell is sufficient to cause the disorder. The condition results from new mutations in the LMNA gene, and almost always occurs in people with no history of the disorder in their family. Genetics Home Reference has merged with MedlinePlus.

Learn more. The information on this site should not be used as a substitute for professional medical care or advice. Contact a health care provider if you have questions about your health. Hutchinson-Gilford progeria syndrome. Chromatin was stained with DAPI blue. Careful analysis of brightly labeled nuclei with anti-LMNA GG revealed that the truncated lamin A was distributed in dot-like or cable-like structures Fig. The intra- and transnuclear cable-like structures detected with anti-LMNA GG were also labeled with emerin or nucleoporin Abs, suggesting that they associated with the membrane compartment.

These results indicated increased NE invaginations. In nuclei containing low levels of progerin, the mutant protein colocalized with wild-type lamin A and lamin B1 within the nuclear lamina, and emerin and nucleoporin Abs showed a normal distribution pattern data not shown. Those numerous invaginations were composed of a double membrane containing nuclear pores, with some regions exhibiting high pore density; they also remained in close apposition with the nuclear lamina and the chromatin Fig.

Increased NE invaginations have been reported in cells permanently overexpressing prenylated lamins or components of the NE lamin B receptor or nucleoporin , which resembled the ones observed in HGPS fibroblasts at late PPDs 20 , Although few, small nuclear invaginations are detected in control fibroblasts; HGPS nuclei exhibit numerous, large nuclear invaginations recognizable by the presence of a high density of clustered nuclear pores.

Scale bar, 0. Normal prelamin A processing involves an orchestrated sequence of modifications: farnesylation, carboxyl methylation of the cysteine residue within the CSIM motif, proteolytic cleavage of SIM, and finally cleavage of 15 residues along with its farnesyl moiety to generate the mature lamin A Because last cleavage cannot occur in LMNA GG, progerin retains its farnesyl group, stabilizing progerin interactions with the inner nuclear membrane 12 — In this scenario, progerin would force the inward growth of the NE to increase the surface area that can accommodate the excess progerin accumulation in HGPS.

When farnesylation was inhibited in control cells, the lamin A precursor was present in nuclear foci but was mostly accumulated in the lamina where it is assembled, giving rise to a strong nuclear rim staining Fig. Progerin was also detected in nuclear foci similarly to wild-type prelamin A Fig. Progerin formed large aggregates within the nucleoplasm that sometimes overlapped with the wild-type prelamin A. Seventy-two hours after treatment, whereas wild-type prelamin A was still predominantly detected at the NE and in some nucleoplasmic foci Fig.

These results suggest that unfarnesylated progerin lost its ability to bind the NE and to assemble into the lamina, thus restoring a more regular nuclear shape for the majority of the HGPS cells Fig. FTI treatment prevents nuclear deformations and delocalizes progerin. Shown are average percentages of cells with abnormally shaped nuclei for each treatment or time course error bars at one SD.

Late passage control fibroblasts continued to grow and exhibited only a slow decline in their proliferative index when compared with early PPDs Fig. These observations prompted us to examine whether HGPS cells were entering premature senescence. A The proliferative index, determined by anti-Ki labeling, was shown to decline faster in HGPS cells than in control cells.

Merged images are indicated. These results indicate that senescent cells accumulated prematurely in HGPS fibroblast cultures. This finding indicates that HGPS fibroblasts, concomitantly with the accumulation of mutant lamin A, withdraw from the cell cycle either via the apoptotic pathway as reported in ref. To gain insight on the cellular effects of progerin, we examined cellular migration, an important function in a variety of physiological aspects.

We used a migration assay in which fibroblasts could demonstrate both inherent and directional motility in response to a chemotatic stimulus Understanding the cellular mechanism underlying the clinical sequelae of HGPS requires the identification of the cellular targets of progerin in vivo. Connective tissue was very dense with thick fibrous structures throughout the dermis. The anti-LMNA GG Ab showed a very restricted pattern of distribution, with positively labeled nuclei localized within the blood vessels, some cells surrounding the sweat glands and in arrector pili muscle.

In the epidermis, very few keratinocytes were positively stained with anti-LMNA GG in the uppermost layer of the epidermis data not shown. We confirmed that the brightest signal obtained with anti-LMNA GG was indeed located within the vascular system and that the positively labeled nuclei were primarily smooth muscle and endothelial cells Fig. Thus, we have provided in vivo evidence for the presence of progerin in vascular cells.

We also have provided support for a direct relation between progerin and atherosclerosis in HGPS. Triple merged signals are indicated. The mutant lamin A accumulates primarily in the vascular cells, smooth muscle cells, and endothelial cells. Note the presence of A-type lamins in most nuclei from the epidermal and dermal compartments.

SBG, sebaceous glands. Previously, autopsies of a few HGPS cases demonstrated severe smooth muscle cell depletion in atherosclerotic aorta media 30 , The rare remaining smooth muscle cells had aberrant cellular shape, ballooning mitochondria, and increased cytoplasmic density Those observations suggested that smooth muscle cells in HGPS were hypersensitive to hemodynamic and ischemic stress and may become defective in restoring vascular integrity after injury In uninjured blood vessels, smooth muscle and endothelial cells are mostly quiescent.

In HGPS subjects, vascular smooth muscle cells may be subjected to increased mechanical stress, forcing them to undergo several cellular divisions to regenerate vascular tissue. The build-up of nuclear progerin may occur as cells reach a high number of PPDs.

This phenomenon could be the cause of the detected progerin accumulation in vascular cell nuclei of HGPS skin sections. In such a setting, cells would progressively lose their capacity to grow and migrate and would either become apoptotic or senescent.

All those progerin-dependent cellular changes might contribute to the vascular deterioration responsible for the progression of atherosclerosis in HGPS subjects. In conclusion, this article addresses the in vivo cellular and tissue localization of a mutant lamin A progerin responsible for severe, premature atherosclerosis in HGPS. Progerin accumulates primarily in vascular cells and can be regarded as a key player in the onset of atherosclerosis, the primary cause of death for HGPS patients.

Normalization of cellular function by preventing progerin accumulation, expression, or posttranslational modification by using treatments such as farnesyltransferase inhibitor or genetic therapies 32 show promise as treatments that could significantly reduce disease progression in HGPS children.

The lamin A GG amino acid sequence reading frame was determined in refs. Preimmune and immune sera were characterized by Western blot analysis and by indirect immunofluorescence on HGPS and control fibroblasts. We used in parallel three previously established control dermal fibroblast cultures.

A child suffering from progeria usually has arthritis and cardiac issues which makes it very difficult to be on par with normal children. Hesitate to seek help from doctors, friends and support groups.

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