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Progeria is a specific type of progeroid syndrome, also known as Hutchinson–Gilford syndrome. A single gene mutation is responsible for progeria. The gene, known as lamin A (LMNA), makes a protein necessary for holding the Nucleus of the cell together. When this gene gets mutated an abnormal form of lamin A protein called Progerin is produced. Progeroid syndromes are a group of diseases that causes individuals to age faster than usual, leading to them appearing older than they actually are. Patients born with progeria typically live to an age of mid-teens to early twenties. Severe cardiovascular complications usually develop by puberty, resulting in death.


Signs and symptoms

Children with progeria usually develop the first symptoms during their first few months of life. The earliest symptoms may include a
failure to thrive Failure to thrive (FTT), also known as weight faltering or faltering growth, indicates insufficient weight gain or absence of appropriate physical growth in children. FTT is usually defined in terms of weight, and can be evaluated either by a low ...
and a localized
scleroderma Scleroderma is a group of autoimmune diseases that may result in changes to the skin, blood vessels, muscles, and internal organs. The disease can be either localized to the skin or involve other organs, as well. Symptoms may include areas ...
-like skin condition. As a child ages past infancy, additional conditions become apparent, usually around 18–24 months. Limited growth, full-body
alopecia Hair loss, also known as alopecia or baldness, refers to a loss of hair from part of the head or body. Typically at least the head is involved. The severity of hair loss can vary from a small area to the entire body. Inflammation or scar ...
(hair loss), and a distinctive appearance (a small face with a shallow, recessed jaw and a pinched nose) are all characteristics of progeria. Signs and symptoms of this progressive disease tend to become more marked as the child ages. Later, the condition causes wrinkled skin, kidney failure, loss of eyesight, and
atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheromatous plaque. At onset there are usually no s ...
and other
cardiovascular The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...
problems. Scleroderma, a hardening and tightening of the skin on trunk and extremities of the body, is prevalent. People diagnosed with this disorder usually have small, fragile bodies, like those of older adults. The head is usually large to the body, with a narrow, wrinkled face and a beak nose. Prominent scalp veins are noticeable (made more obvious by alopecia), as well as prominent eyes. Musculoskeletal degeneration causes loss of body fat and muscle, stiff joints, hip dislocations, and other symptoms generally absent in the non-elderly population. Individuals usually retain typical mental and motor development.


Cause

Hutchinson-Gilford syndrome (HGPS) is an extremely rare autosomal dominant
genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...
in which symptoms resembling aspects of aging are manifested at an early age. Its occurrence is usually the result of a sporadic
germline mutation A germline mutation, or germinal mutation, is any detectable variation within germ cells (cells that, when fully developed, become sperm and ova). Mutations in these cells are the only mutations that can be passed on to offspring, when either a m ...
; although HGPS is genetically dominant, people rarely live long enough to have children, preventing them from passing the disorder on in a hereditary manner. HPGS is caused by mutations that weaken the structure of the cell nucleus, making normal cell division difficult. The
histone In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn a ...
mark
H4K20me3 H4K20me is an epigenetic modification to the DNA packaging protein Histone H4. It is a mark that indicates the mono- methylation at the 20th lysine residue of the histone H4 protein. This mark can be di- and tri-methylated. It is critical for ...
is involved and caused by ''de novo'' mutations that occur in a gene that encodes
lamin A Pre-lamin A/C or lamin A/C is a protein that in humans is encoded by the ''LMNA'' gene. Lamin A/C belongs to the lamin family of proteins. Function In the setting of ZMPSTE24 deficiency, the final step of lamin processing does not occur, res ...
. Lamin A is made but is not processed properly. This poor processing creates an abnormal nuclear morphology and disorganized heterochromatin. Patients also do not have appropriate DNA repair, and they also have increased genomic instability. In normal conditions, the ''
LMNA Pre-lamin A/C or lamin A/C is a protein that in humans is encoded by the ''LMNA'' gene. Lamin A/C belongs to the lamin family of proteins. Function In the setting of ZMPSTE24 deficiency, the final step of lamin processing does not occur, re ...
'' gene codes for a structural protein called prelamin A, which undergoes a series of processing steps before attaining its final form, called lamin A.LMNA

Genes

Genetics Home Reference
Prelamin A contains a "CAAX" where C is a cysteine, A an aliphatic amino acid, and X any amino acid. This motif at the carboxyl-termini of proteins triggers three sequential enzymatic modifications. First, protein farnesyltransferase catalyzes the addition of a farnesyl moiety to the cysteine. Second, an endoprotease that recognizes the farnesylated protein catalyzes the peptide bond's cleavage between the cysteine and -aaX. In the third step, isoprenylcysteine carboxyl methyltransferase catalyzes methylation of the carboxyl-terminal farnesyl cysteine. The farnesylated and methylated protein is
transported ''Transported'' is an Australian convict melodrama film directed by W. J. Lincoln. It is considered a lost film. Plot In England, Jessie Grey is about to marry Leonard Lincoln but the evil Harold Hawk tries to force her to marry him and she w ...
through a
nuclear pore A nuclear pore is a part of a large complex of proteins, known as a nuclear pore complex that spans the nuclear envelope, which is the double membrane surrounding the eukaryotic cell nucleus. There are approximately 1,000 nuclear pore complexe ...
to the interior of the nucleus. Once in the nucleus, the protein is cleaved by a
protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...
called zinc metallopeptidase STE24 (
ZMPSTE24 ZMPSTE24 is a human gene. The protein encoded by this gene is a metallopeptidase. It is involved in the processing of lamin A. Defects in the ZMPSTE24 gene lead to similar laminopathies as defects in lamin A, because the latter is a sub ...
), which removes the last 15 amino acids, which includes the farnesylated cysteine. After cleavage by the protease, prelamin A is referred to as lamin A. In most mammalian cells, lamin A, along with lamin B1, lamin B2, and lamin C, makes up the
nuclear lamina The nuclear lamina is a dense (~30 to 100  nm thick) fibrillar network inside the nucleus of eukaryote cells. It is composed of intermediate filaments and membrane associated proteins. Besides providing mechanical support, the nuclear lamina ...
, which provides shape and stability to the inner nuclear envelope. Before the late 20th century, research on progeria yielded very little information about the syndrome. In 2003, the cause of progeria was discovered to be a
point mutation A point mutation is a genetic mutation where a single nucleotide base is changed, inserted or deleted from a DNA or RNA sequence of an organism's genome. Point mutations have a variety of effects on the downstream protein product—consequence ...
in position 1824 of the ''LMNA'' gene, which replaces a cytosine with thymine. This mutation creates a 5'
cryptic splice site Cryptic may refer to: In science: * Cryptic species complex, a group of species that are very difficult to distinguish from one another * Crypsis, the ability of animals to blend in to avoid observation * Cryptic era, earliest period of the Earth ...
within exon 11, resulting in a shorter than normal mRNA transcript. When this shorter mRNA is
translated Translation is the communication of the meaning of a source-language text by means of an equivalent target-language text. The English language draws a terminological distinction (which does not exist in every language) between ''transla ...
into protein, it produces an abnormal variant of the prelamin A protein, referred to as
progerin Progerin (UniProt# P02545-6) is a truncated version of the lamin A protein involved in the pathology of Hutchinson–Gilford progeria syndrome. Progerin is most often generated by a sporadic single point nucleotide polymorphism c.1824 C>T (GGC -> GG ...
. Progerin's farnesyl group cannot be removed because the ZMPSTE24 cleavage site is lacking from progerin, so the abnormal protein is permanently attached to the nuclear rim. One result is that the nuclear lamina does not provide the nuclear envelope with enough structural support, causing it to take on an abnormal shape. Since the support that the nuclear lamina normally provides is necessary for the organizing of
chromatin Chromatin is a complex of DNA and protein found in eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important roles in r ...
during mitosis, weakening of the nuclear lamina limits the ability of the cell to divide. However, defective cell division is unlikely to be the main defect leading to progeria, particularly because children develop normally without any signs of disease until about one year of age. Farnesylated prelamin A variants also lead to defective DNA repair, which may play a role in the development of progeria. Progerin expression also leads to defects in the establishment of fibroblast cell polarity, which is also seen in physiological aging. To date over 1,400
SNPs In genetics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a sufficiently larg ...
in the ''LMNA'' gene are known. They can manifest as changes in mRNA, splicing, or protein amino acid sequence (e.g. Arg471Cys, Arg482Gln, Arg527Leu, Arg527Cys, Ala529Val). Progerin may also play a role in normal human aging, since its production is activated in typical
senescent Senescence () or biological aging is the gradual deterioration of functional characteristics in living organisms. The word ''senescence'' can refer to either cellular senescence or to senescence of the whole organism. Organismal senescence inv ...
cells. Unlike other " accelerated aging diseases" (such as
Werner syndrome Werner syndrome (WS) or Werner's syndrome, also known as "adult progeria",James, William; Berger, Timothy; Elston, Dirk (2005). ''Andrews' Diseases of the Skin: Clinical Dermatology''. (10th ed.). Saunders. . is a rare, autosomal recessive disorder ...
, Cockayne syndrome or
xeroderma pigmentosum Xeroderma pigmentosum (XP) is a genetic disorder in which there is a decreased ability to repair DNA damage such as that caused by ultraviolet (UV) light. Symptoms may include a severe sunburn after only a few minutes in the sun, freckling in su ...
), progeria may not be directly caused by defective
DNA repair DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA da ...
. These diseases each cause changes in a few specific aspects of aging, but never in every aspect at once, so they are often called "segmental progerias". A 2003 report in ''Nature'' said that progeria may be a de novo dominant trait. It develops during
cell division Cell division is the process by which a parent cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukaryotes, there ar ...
in a newly conceived zygote or in the
gamete A gamete (; , ultimately ) is a haploid cell that fuses with another haploid cell during fertilization in organisms that reproduce sexually. Gametes are an organism's reproductive cells, also referred to as sex cells. In species that produce ...
s of one of the parents. It is caused by
mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA replication, DNA or viral repl ...
s in the ''LMNA'' (lamin A
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
)
gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
on
chromosome 1 Chromosome 1 is the designation for the largest human chromosome. Humans have two copies of chromosome 1, as they do with all of the autosomes, which are the non- sex chromosomes. Chromosome 1 spans about 249 million nucleotide base pairs, which ...
; the mutated form of lamin A is commonly known as progerin. One of the authors, Leslie Gordon, was a physician who did not know anything about progeria until her own son, Sam, was diagnosed at 22 months. Gordon and her husband, pediatrician Scott Berns, founded the Progeria Research Foundation.


Lamin A

Lamin A Pre-lamin A/C or lamin A/C is a protein that in humans is encoded by the ''LMNA'' gene. Lamin A/C belongs to the lamin family of proteins. Function In the setting of ZMPSTE24 deficiency, the final step of lamin processing does not occur, res ...
is a major component of a protein
scaffold Scaffolding, also called scaffold or staging, is a temporary structure used to support a work crew and materials to aid in the construction, maintenance and repair of buildings, bridges and all other man-made structures. Scaffolds are widely used ...
on the inner edge of the
nucleus Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to: *Atomic nucleus, the very dense central region of an atom * Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucl ...
called the nuclear lamina that helps organize nuclear processes such as
RNA Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
and DNA synthesis. Prelamin A contains a CAAX box at the C-terminus of the protein (where C is a cysteine and A is any
aliphatic In organic chemistry, hydrocarbons ( compounds composed solely of carbon and hydrogen) are divided into two classes: aromatic compounds and aliphatic compounds (; G. ''aleiphar'', fat, oil). Aliphatic compounds can be saturated, like hexane, ...
amino acids). This ensures that the cysteine is farnesylated and allows prelamin A to bind membranes, specifically the nuclear membrane. After prelamin A has been localized to the cell nuclear membrane, the C-terminal amino acids, including the farnesylated cysteine, are cleaved off by a specific protease. The resulting protein, now lamin A, is no longer membrane-bound and carries out functions inside the nucleus. In HGPS, the recognition site that the enzyme requires for cleavage of prelamin A to lamin A is mutated. Lamin A cannot be produced, and prelamin A builds up on the nuclear membrane, causing a characteristic nuclear
blebbing In cell biology, a bleb is a bulge of the plasma membrane of a cell, characterized by a spherical, bulky morphology. It is characterized by the decoupling of the cytoskeleton from the plasma membrane, degrading the internal structure of the cell, ...
. This results in the symptoms of progeria, although the relationship between the misshapen nucleus and the symptoms is not known. A study that compared HGPS patient cells with the skin cells from young and elderly normal human subjects found similar defects in the HGPS and elderly cells, including
down-regulation In the biological context of organisms' production of gene products, downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus. The complementary pr ...
of certain nuclear proteins, increased DNA damage, and
demethylation Demethylation is the chemical process resulting in the removal of a methyl group (CH3) from a molecule. A common way of demethylation is the replacement of a methyl group by a hydrogen atom, resulting in a net loss of one carbon and two hydrogen at ...
of
histone In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn a ...
, leading to reduced heterochromatin. Nematodes over their lifespan show progressive lamin changes comparable to HGPS in all cells but
neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. ...
s and
gamete A gamete (; , ultimately ) is a haploid cell that fuses with another haploid cell during fertilization in organisms that reproduce sexually. Gametes are an organism's reproductive cells, also referred to as sex cells. In species that produce ...
s. These studies suggest that lamin A defects are associated with normal aging.


Diagnosis

Skin changes, abnormal growth, and loss of hair occur. These symptoms normally start appearing by one year of age. A genetic test for LMNA mutations can confirm the diagnosis of progeria. Prior to the advent of the genetic test, misdiagnosis was common.


Treatment

In November 2020, the U.S.
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
approved
lonafarnib Lonafarnib, sold under the brand name Zokinvy, is a medication used to reduce the risk of death due to Hutchinson-Gilford progeria syndrome and for the treatment of certain processing-deficient progeroid laminopathies in people one year of age a ...
, which helps prevent buildup of defective progerin and similar proteins. A clinical trial in 2018 points to significantly lower mortality rates – treatment with lonafarnib alone compared with no treatment (3.7% vs. 33.3%) – at a median post-trial follow-up time span of 2.2 years. The drug, given orphan drug status and Pediatric Disease Priority Review Voucher, is taken twice daily in the form of capsules and may cost US$650,000 per year, making it prohibitive for the vast majority of families. It is unclear how it will be covered by health insurance in the United States. Common side effects of the drug include "nausea, vomiting, diarrhea, infections, decreased appetite, and fatigue". Other treatment options have focused on reducing complications (such as cardiovascular disease) with coronary artery bypass surgery and low-dose
acetylsalicylic acid Aspirin, also known as acetylsalicylic acid (ASA), is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and/or inflammation, and as an antithrombotic. Specific inflammatory conditions which aspirin is used to treat ...
.
Growth hormone treatment Growth hormone therapy refers to the use of growth hormone (GH) as a prescription medication—it is one form of hormone therapy. Growth hormone is a peptide hormone secreted by the pituitary gland that stimulates growth and cell reproduction. I ...
has been attempted. The use of
Morpholino A Morpholino, also known as a Morpholino oligomer and as a phosphorodiamidate Morpholino oligomer (PMO), is a type of oligomer molecule (colloquially, an oligo) used in molecular biology to modify gene expression. Its molecular structure contain ...
s has also been attempted in mice and cell cultures in order to reduce progerin production. Antisense Morpholino oligonucleotides specifically directed against the mutated exon 11–exon 12 junction in the mutated pre-mRNAs were used. A type of anticancer drug, the
farnesyltransferase inhibitor The farnesyltransferase inhibitors (FTIs) are a class of experimental cancer drugs that target protein farnesyltransferase with the downstream effect of preventing the proper functioning of the Ras (protein), which is commonly abnormally active in ...
s (FTIs), has been proposed, but their use has been mostly limited to
animal model An animal model (short for animal disease model) is a living, non-human, often genetic-engineered animal used during the research and investigation of human disease, for the purpose of better understanding the disease process without the risk of ha ...
s. A Phase II clinical trial using the FTI
lonafarnib Lonafarnib, sold under the brand name Zokinvy, is a medication used to reduce the risk of death due to Hutchinson-Gilford progeria syndrome and for the treatment of certain processing-deficient progeroid laminopathies in people one year of age a ...
began in May 2007. In studies on the cells another anti-cancer drug,
rapamycin Sirolimus, also known as rapamycin and sold under the brand name Rapamune among others, is a macrolide compound that is used to coat coronary stents, prevent organ transplant rejection, treat a rare lung disease called lymphangioleiomyomatosi ...
, caused removal of progerin from the nuclear membrane through autophagy. It has been proved that
pravastatin Pravastatin, sold under the brand name Pravachol among others, is a statin medication, used for preventing cardiovascular disease in those at high risk and treating abnormal lipids. It should be used together with diet changes, exercise, and w ...
and
zoledronate Zoledronic acid, also known as zoledronate and sold under the brand name Zometa by Novartis among others, is a medication used to treat a number of bone diseases. These include osteoporosis, high blood calcium due to cancer, bone breakdown due ...
are effective drugs when it comes to the blocking of farnesyl group production. Farnesyltransferase inhibitors (FTIs) are drugs that inhibit the activity of an enzyme needed to make a link between
progerin Progerin (UniProt# P02545-6) is a truncated version of the lamin A protein involved in the pathology of Hutchinson–Gilford progeria syndrome. Progerin is most often generated by a sporadic single point nucleotide polymorphism c.1824 C>T (GGC -> GG ...
proteins and farnesyl groups. This link generates the permanent attachment of the progerin to the nuclear rim. In progeria, cellular damage can occur because that attachment occurs, and the nucleus is not in a normal state. Lonafarnib is an FTI, which means it can avoid this link, so progerin can not remain attached to the nucleus rim, and it now has a more normal state. Studies of
sirolimus Sirolimus, also known as rapamycin and sold under the brand name Rapamune among others, is a macrolide compound that is used to coat coronary stents, prevent organ transplant rejection, treat a rare lung disease called lymphangioleiomyomatosi ...
, an
mTOR Inhibitor mTOR inhibitors are a class of drugs that inhibit the mechanistic target of rapamycin (mTOR), which is a serine/threonine-specific protein kinase that belongs to the family of phosphatidylinositol-3 kinase (PI3K) related kinases (PIKKs). mTOR re ...
, demonstrate that it can minimize the phenotypic effects of progeria fibroblasts. Other observed consequences of its use are abolishing nuclear
blebbing In cell biology, a bleb is a bulge of the plasma membrane of a cell, characterized by a spherical, bulky morphology. It is characterized by the decoupling of the cytoskeleton from the plasma membrane, degrading the internal structure of the cell, ...
, degradation of progerin in affected cells, and reducing insoluble progerin aggregates formation. These results have been observed only ''in vitro'' and are not the results of any clinical trial, although it is believed that the treatment might benefit HGPS patients. A possible cure for progeria, by genetic editing, has been successfully tested on mice and might be tested on humans in the near future.


Prognosis

As there is no known cure, few people with progeria exceed 13 years of age. At least 90 percent of patients die from complications of atherosclerosis, such as heart attack or stroke. Mental development is not adversely affected; in fact, intelligence tends to be average to above average. With respect to the features of aging that progeria appears to manifest, the development of symptoms is comparable to aging at a rate eight to ten times faster than normal. With respect to those that progeria does not exhibit, patients show no neurodegeneration or
cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
predisposition. They also do not develop conditions that are commonly associated with accumulation of damage, such as
cataracts A cataract is a cloudy area in the lens of the eye that leads to a decrease in vision. Cataracts often develop slowly and can affect one or both eyes. Symptoms may include faded colors, blurry or double vision, halos around light, trouble w ...
(caused by UV exposure) and
osteoarthritis Osteoarthritis (OA) is a type of degenerative joint disease that results from breakdown of joint cartilage and underlying bone which affects 1 in 7 adults in the United States. It is believed to be the fourth leading cause of disability in the w ...
. Although there may not be any successful treatments for progeria itself, there are treatments for the problems it causes, such as arthritic, respiratory, and cardiovascular problems. People with progeria have normal reproductive development, and there are known cases of women with progeria who delivered healthy offspring.


Epidemiology

A study from the Netherlands has shown an incidence of 1 in 20 million births. According to the Progeria Research Foundation, as of September 2020, there are 179 known cases in the world, in 53 countries; 18 of the cases were identified in the United States. Hundreds of cases have been reported in medical history since 1886. However, the
Progeria Research Foundation The Progeria Research Foundation (PRF) is a non-profit organization dedicated to developing treatments and, ultimately, a cure for progeria, a congenital disorder. The Foundation was established in 1999 by the family and friends of Sam Berns, a chi ...
believes there may be as many as 150 undiagnosed cases worldwide. There have been only two cases in which a healthy person was known to carry the LMNA mutation that causes progeria. One family from India had four of six children with progeria.


Research


Mouse model

A mouse
model A model is an informative representation of an object, person or system. The term originally denoted the plans of a building in late 16th-century English, and derived via French and Italian ultimately from Latin ''modulus'', a measure. Models c ...
of progeria exists, though in the mouse, the
LMNA Pre-lamin A/C or lamin A/C is a protein that in humans is encoded by the ''LMNA'' gene. Lamin A/C belongs to the lamin family of proteins. Function In the setting of ZMPSTE24 deficiency, the final step of lamin processing does not occur, re ...
prelamin A is not mutated. Instead,
ZMPSTE24 ZMPSTE24 is a human gene. The protein encoded by this gene is a metallopeptidase. It is involved in the processing of lamin A. Defects in the ZMPSTE24 gene lead to similar laminopathies as defects in lamin A, because the latter is a sub ...
, the specific protease that is required to remove the C-terminus of prelamin A, is missing. Both cases result in the buildup of farnesylated prelamin A on the nuclear membrane and in the characteristic nuclear LMNA blebbing.


DNA repair

Repair of DNA double-strand breaks can occur by either of two processes,
non-homologous end joining Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. NHEJ is referred to as "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homology direc ...
(NHEJ) or
homologous recombination Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in cellular organisms but may ...
(HR). A-type
lamin Lamins, also known as nuclear lamins are fibrous proteins in type V intermediate filaments, providing structural function and transcriptional regulation in the cell nucleus. Nuclear lamins interact with inner nuclear membrane proteins to form t ...
s promote genetic stability by maintaining levels of proteins that have key roles in NHEJ and HR. Mouse cells deficient for maturation of prelamin A show increased DNA damage and chromosome aberrations and have increased sensitivity to DNA damaging agents. In progeria, the inability to adequately repair DNA damages due to defective A-type lamin may cause aspects of premature aging (also see
DNA damage theory of aging The DNA damage theory of aging proposes that aging is a consequence of unrepaired accumulation of naturally occurring DNA damage. Damage in this context is a DNA alteration that has an abnormal structure. Although both mitochondrial and nuclear D ...
).


Epigenetic clock analysis of human HGPS

Fibroblast samples from children with progeria syndrome exhibit accelerated epigenetic aging effects according to the epigenetic clock for skin and blood samples.


History

Progeria was first described in 1886 by
Jonathan Hutchinson Sir Jonathan Hutchinson (23 July 1828 – 23 June 1913), was an English surgeon, ophthalmologist, dermatologist, venereologist, and pathologist. Life He was born in Selby, Yorkshire, of Quaker parents and educated in the local school. Then he ...
. It was also described independently in 1897 by Hastings Gilford. The condition was later named Hutchinson–Gilford progeria syndrome. Scientists are interested in progeria partly because it might reveal clues about the normal process of aging.


Etymology

The word ''progeria'' comes from the Greek words "pro" ( πρό), meaning "before" or "premature", and "gēras" ( γῆρας), meaning "old age".


Society and culture


Notable cases

Yan Hui Yan Hui (–481 BC) was a Chinese philosopher. He was the favorite disciple of Confucius and one of the most revered figures of Confucianism. He is venerated in Confucian temples as one of the Four Sages. Names Yan Hui is also known by his c ...
, a student of
Confucius Confucius ( ; zh, s=, p=Kǒng Fūzǐ, "Master Kǒng"; or commonly zh, s=, p=Kǒngzǐ, labels=no; – ) was a Chinese philosopher and politician of the Spring and Autumn period who is traditionally considered the paragon of Chinese sages. C ...
, aged rapidly and died at a young age, appearing as an old man by his late 20s. He may be one of the earliest potential examples of progeria in history. In 1987, fifteen-year-old
Mickey Hays Mickey Hays (June 30, 1972 – June 30, 1992) was an American actor with progeria, a rare genetic condition whose symptoms resemble accelerated aging. He starred in the 1986 Weird Western science fiction film '' The Aurora Encounter'', where he ...
, who had progeria, appeared along with
Jack Elam William Scott "Jack" Elam (November 13, 1920 – October 20, 2003) was an American film and television actor best known for his numerous roles as villains in Western films and, later in his career, comedies (sometimes spoofing his villainou ...
in the documentary ''I Am Not a Freak''. Elam and Hays first met during the filming of the 1986 film ''
The Aurora Encounter ''The Aurora Encounter'' is a 1986 American Weird Western film directed by Jim McCullough Sr., written by Melody Brooke and Jim McCullough, Jr., and starring Jack Elam, Mickey Hays, Peter Brown, Carol Bagdasarian, and Dottie West. Its plot fol ...
'', in which Hays was cast as an alien. The friendship that developed lasted until Hays died in 1992, on his 20th birthday. Elam said, "You know I've met a lot of people, but I've never met anybody that got next to me like Mickey."
Harold Kushner Harold Samuel Kushner (born April 3, 1935) is a prominent American rabbi and author. He is a member of the Rabbinical Assembly of Conservative Judaism and served as the congregational rabbi of Temple Israel of Natick, in Natick, Massachusetts, ...
's 1978 book '' When Bad Things Happen to Good People'', which explores God and the
problem of evil The problem of evil is the question of how to reconcile the existence of evil and suffering with an omnipotent, omnibenevolent, and omniscient God.The Stanford Encyclopedia of Philosophy,The Problem of Evil, Michael TooleyThe Internet Encycl ...
, was written in response to his 14-year-old son's death due to progeria. Margaret Casey, a 29-year-old progeria patient who was then believed to be the oldest survivor of the premature aging disease, died on Sunday, May 26, 1985. Casey, a freelance artist, was admitted to
Yale-New Haven Hospital Yale New Haven Hospital (YNHH) is a 1,541-bed hospital located in New Haven, Connecticut. It is owned and operated by the Yale New Haven Health System. YNHH includes the 168-bed Smilow Cancer Hospital at Yale New Haven, the 201-bed Yale New Have ...
on the night of May 25 with respiratory problems, which caused her death.
Sam Berns Sampson Gordon Berns (October 23, 1996 – January 10, 2014) was an American activist with progeria, an extremely rare and fatal disease that causes the body to age rapidly. Sam helped raise awareness about the disease and he was the subject of ...
was an American activist with the disease. He was the subject of the HBO documentary ''
Life According to Sam ''Life According to Sam'' is an HBO original documentary film directed by Sean Fine and Andrea Nix Fine. Premiering in January 2013 at the Sundance Film Festival, the documentary discloses the impact that progeria had on the lives of Sam Berns and ...
''. Berns also gave a TEDx talk titled My Philosophy for a Happy Life on December 13, 2013.
Hayley Okines Hayley Leanne Okines (3 December 1997 – 2 April 2015) was an English author and activist who was a sufferer of the extremely rare aging disease progeria. She was known for spreading awareness of the condition. Although the average life e ...
was an English progeria patient who spread awareness of the condition. Rania was a French progeria patient who died on October 16, 2020, at the age of 16. She was a popular creator on the social media platforms
TikTok TikTok, known in China as Douyin (), is a short-form video hosting service owned by the Chinese company ByteDance. It hosts user-submitted videos, which can range in duration from 15 seconds to 10 minutes. TikTok is an international version o ...
, Instagram and
YouTube YouTube is a global online video sharing and social media platform headquartered in San Bruno, California. It was launched on February 14, 2005, by Steve Chen, Chad Hurley, and Jawed Karim. It is owned by Google, and is the second mo ...
with 871,000 followers on TikTok, 700,000 on Instagram and 320,000 on YouTube. Leon Botha, the South African painter and DJ who was known, among other things, for his work with the hip-hop duo
Die Antwoord Die Antwoord (, Afrikaans for "The Answer") is a South African alternative hip hop group formed in Cape Town in 2008. The group comprises rappers Watkin Tudor "Ninja" Jones and Anri "Yolandi Visser" du Toit, a male/female duo, and producers ...
, lived with progeria. He died in 2011, aged 26. Tiffany Wedekind of Columbus, Ohio, is believed to be the oldest survivor of progeria at 44 years old as of September 2022. Alexandra Peraut is a Catalan girl with progeria, she has inspired the book ''Una nena entre vint milions'' ('A girl in 20 million'), a children's book to explain progeria to youngsters. Adalia Rose Williams, born December 10, 2006, was an American girl with progeria, who was a notable YouTuber and vlogger who shared her everyday life on social media. She died on January 12, 2022, at the age of 15.


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* * {{Progeroid syndromes Genodermatoses Progeroid syndromes Rare diseases Senescence