The post-translational processing of prelamin A has been thoroughly illustrated The farnesylation of a C-terminal cysteine the C of the CAAX motif , endoproteolytic release of the last three amino acids the AAX and methylation of the newly exposed farnesylcysteine residue are involved in the process triggered by prelamin A. Further, ZMPSTE24 an endoplasmic reticulum membrane protease cleaves prelamin A at the C terminus including the farnesylcysteine methyl ester to release a total of 15 more residues to generate the full lamin A.
On the other hand, progerin has been shown to provoke various progerian phenotypes in mice irrespective of being farnesylated or not Also, by knocking down over accumulated SUN1 from primary HGPS cells, they showed that problems like nuclear defects and early cellular senescence got corrected. Over accumulation of SUN1 is considered to play a key role in HGPS and hence holds a promise in designing therapeutic strategies in future.
Various hypotheses have been put forward for the involvement of reactive oxygen species, oxidative stress and defects in the DNA repair mechanism to explain their roles in the accelerated ageing process in the HGPS condition 1. It has been reported that telomere length is shorter in HGPS fibroblasts compared to age-matched controls Another study suggests that mutant lamin A reduces telomere length through a direct effect and that expression of mutant LMNA is a requisite for telomere loss in HGPS The increased cell death in an organism can be due to some aberration in DNA repair mechanism or shortening of telomere or defects in telomeric DNA.
It may be due to either or any combination of these reasons In order to develop a better understanding of the pathogenesis and progression of PSs and design potential therapies, effort has been put in by scientists globally to develop animal models of the same.
Another study showed that homozygous mice carrying autosomal recessive mutation in Lmna gene have a phenotype resembling HGPS, with marked growth retardation, pathologies of skin and bone and death by weeks of age Although the pursuit for finding an effective treatment for HGPS is still on, yet there is still no diagnostic kit available for early detection of the same. Usually in practice, a clinical assessment is done based on the phenotypical evidence and medical history of the child.
Following this, a genetic test for LMNA mutation is commonly done for confirming the diagnosis of HGPS to initiate the treatment programmes early in the progression of the disorder. A case report on HGPS has reported that clinical diagnosis can also be established by radiological findings - diastasis of the sagittal suture with several wormian bones in the skull; hypoplastic mandible with infantile angle; the presence of fish-mouth vertebrae; the occurrence of bilateral coxa valga deformity; resorption of terminal phalanges, etc A class of cancer drugs known as farnesyltransferase inhibitors FTIs has shown promise of reversing the structural abnormalities of the nucleus associated with build up of prelamin A which is one of the characteristics of the cells in the HGPS children.
As the name suggests, these drugs restrict the activity of farnesyltransferase required to make a liaison between farnesyl groups and progerin proteins. FTIs have shown improvement in many of the features of progeria-like mouse model 33 , Specifically, FTIs improve the nuclear shape in the fibroblasts from the patients of PSs 50 and improve nuclear blebbing in the fibroblasts of mouse model with the gene targeted for HGPS This study has tried to explain the low efficiency of FTIs in improving the physical composition of the progeroid mouse models.
In addition, these extended the longevity of the mice significantly The clinical trial conducted in 25 progeroid children over two years has reported that Lonafarnib, a FTI drug, has been successful in facilitating weight gain and improving cardiovascular and skeletal pathologies This is a tremendous achievement in the progress of progeria research that will perhaps pave its way to the discovery of a definite treatment for this rare and complex syndrome.
Progeria or HGPS is a rare syndrome which makes it difficult to study. Due to the efforts of parents of the affected children, a few research groups and the Progeria Research Foundation PRF , the awareness of this syndrome has increased significantly. Research has also proposed probable markers for this syndrome. For example, elevated HA levels have been suggested as specific marker for HGPS 10 , 55 , 56 , but other studies have nullified this by reporting that urinary and serum levels of HA in HGPS patients are comparable with controls Gordon and co-workers 57 did a thorough analysis of the serum and urinary hyaluronidases by both quantitative using ELISA and qualitative using a gel detection method methods and contravened the use of HA as a marker for HGPS.
Hence, the search for an accessible and definite kind of diagnostic marker is still on. The positive or negative interactions between the LMNA gene and other genes controlling ageing and longevity can be studied in appropriate animal models for better understanding of the pathogenesis and progression of HGPS.
A clear perception of the mechanism of pathogenesis of HGPS and other PSs would be helpful in understanding the abnormal conditions in the diverse branches of basic and applied life sciences like molecular biology, basic cellular senescence phenomenon, mitochondrial physiology, oncology, functional genomics and proteomics, dermatology especially dermal physiology, stem-cell biology, and many other degenerative disorders regarding which our knowledge is still meager Thus, discovery of a cure for PS s would not only help the affected children but also a large number of patients suffering from cardiovascular diseases, stroke, cancer, etc.
Proteins linked to HGPS are suspected to play a pivotal role in the ageing process and this could be one of the reasons responsible for making these children predisposed to premature, progressive heart disease. When factors like IGF-1 signaling and functional cascade of events of hormones are checked in the prevalent and existing models of ageing and longevity diet restriction , it has been observed that there is a significant shift from the normal parameters.
This shift can be due to pituitary or any organ related faults, defect in the micronutrient like vitamin D, etc. These kinds of animal models should be checked for their genomic, proteomic and biochemical status to look into the details of the common or shared and probably faulty pathways.
The field of gerontology gained importance relatively late when compared to other areas of research. However, presently a lot of effort is being put in by researchers in this area to delay the normal ageing process and the trauma that follows the common physical, psychological, and social implications associated with it.
The inheritance pattern of HGPS is known but it appears mostly as a sporadic disorder. Hence to address it efficiently it will be worthwhile to study the causal cellular and molecular mechanisms that accelerate the ageing process leading to rapid progression of the disease. National Center for Biotechnology Information , U.
Indian J Med Res. Author information Article notes Copyright and License information Disclaimer. Reprint requests : Dr. Received Dec This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3. This article has been cited by other articles in PMC.
Abstract Progeria is characterized by clinical features that mimic premature ageing. Keywords: Accelerated ageing, clinical trial, experimental models, farnesylation, Hutchinson-Gilford progeria syndrome, lamin A, LMNA gene, lonafarnib, longevity. Introduction Progeroid syndromes PSs are a group of fatal, severe and rare genetic disorders characterized by various clinical features and phenotypes of physiological ageing prematurely.
Epidemiology, prevalence and common symptoms of HGPS As of now, the prevalence of this syndrome is one in 4 - 8 million new births 2. Table Summary of gene mutations leading to various progeroid syndromes with their clinical symptoms. Open in a separate window. Experimental models of progeria In order to develop a better understanding of the pathogenesis and progression of PSs and design potential therapies, effort has been put in by scientists globally to develop animal models of the same.
Current status of diagnosis, drugs and medication Although the pursuit for finding an effective treatment for HGPS is still on, yet there is still no diagnostic kit available for early detection of the same. Conclusion The field of gerontology gained importance relatively late when compared to other areas of research. Footnotes Equal contribution by the authors. References 1. Kamenisch Y, Berneburg M.
J Investig Dermatol Symp Proc. HGPS and related premature aging disorders: from genomic identification to the first therapeutic approaches. Mech Ageing Dev. Hennekam RC. Hutchinson-Gilford progeria syndrome: review of the phenotype.
Am J Med Genet A. An association of Hutchinson-Gilford progeria and malignancy. Positional cloning of the Werner's syndrome gene. Usually within the first year of life, growth of a child with progeria slows markedly, but motor development and intelligence remain normal. Progeria is usually detected in infancy or early childhood, often at regular checkups, when a baby first shows the characteristic signs of premature aging.
If you notice changes in your child that could be signs and symptoms of progeria, or you have any concerns about your child's growth or development, make an appointment with your child's doctor.
A single gene mutation is responsible for progeria. The gene, known as lamin A LMNA , makes a protein necessary for holding the center nucleus of a cell together.
When this gene has a defect mutation , an abnormal form of the lamin A protein called progerin is produced and makes cells unstable. This appears to lead to progeria's aging process. Unlike many genetic mutations, progeria is rarely passed down in families. The gene mutation is a rare, chance occurrence in the majority of cases. There are other progeroid syndromes that do run in families. These inherited syndromes cause rapid aging and a shortened life span:. There are no known factors, such as lifestyle or environmental issues, which increase the risk of having progeria or of giving birth to a child with progeria.
Progeria is extremely rare. For parents who have had one child with progeria, the chances of having a second child with progeria are about 2 to 3 percent. Children with progeria usually develop severe hardening of the arteries atherosclerosis. This is a condition in which the walls of the arteries — blood vessels that carry nutrients and oxygen from the heart to the rest of the body — stiffen and thicken, often restricting blood flow.
Other health problems frequently associated with aging — such as arthritis, cataracts and increased cancer risk — typically do not develop as part of the course of progeria. Frequency This condition is very rare; it is reported to occur in 1 in 4 million newborns worldwide. Inheritance 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.
Research Studies from ClinicalTrials. Lamin a truncation in Hutchinson-Gilford progeria. Epub Apr Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Genetics of aging, progeria and lamin disorders. Curr Opin Genet Dev. Epub Jul 6. Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome. Epub Jun 7. A-type lamins and Hutchinson-Gilford progeria syndrome: pathogenesis and therapy.
Front Biosci Schol Ed. Hutchinson-Gilford Progeria Syndrome.
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