One of the main causes of progeroid syndromes are
genetic mutations, which lead to defects in the cellular processes which
repair DNA. The
DNA damage theory of aging proposes that aging is a consequence of the accumulation of
naturally occurring DNA damages. The accumulated damage may arise from
reactive oxygen species (ROS), chemical reactions (e.g. with
intercalating agents),
radiation,
depurination, and
deamination. Mutations in three classes of DNA repair proteins,
RecQ protein-like helicases (RECQLs),
nucleotide excision repair (NER) proteins, and nuclear envelope proteins
LMNA (lamins) have been associated with the following progeroid syndromes: • Werner syndrome (WS) • Bloom syndrome (BS) • Rothmund–Thomson syndrome (RTS) • Cockayne syndrome (CS) • Xeroderma pigmentosum (XP) • Trichothiodystrophy (TTD)
RecQ-associated PS RecQ is a family of
conserved ATP-dependent
helicases required for repairing DNA and preventing deleterious
recombination and
genomic instability.
DNA helicases are enzymes that bind to double-stranded DNA and temporarily separate them. This unwinding is required during replication of the genome under
mitosis, but in the context of PS, it is a required step in repairing damaged DNA. Thus, DNA helicases, maintain the integrity of a cell, and defects in these helicases are linked to an increased predisposition to
cancer and aging
phenotypes. Thus, individuals with RecQ-associated PS show an increased risk of developing cancer, which is caused by genomic instability and increased rates of mutation. There are five genes encoding RecQ in humans (RECQ1-5), and defects in RECQL2/WRN, RECQL3/BLM and RECQL4 lead to Werner syndrome (WS), Bloom syndrome (BS), and Rothmund–Thomson syndrome (RTS), respectively. On the cellular level, cells of affected individuals exhibit chromosomal abnormalities, genomic instability, and sensitivity to
mutagens. It has a global incidence rate of less than 1 in 100,000 live births, As of 2006, there were approximately 1,300 reported cases of WS worldwide. The median and mean age of death are 47-48 and 54 years, respectively; the main cause of death is
cardiovascular disease or cancer. Approximately 90% of individuals with Werner Syndrome have any of a range of mutations in the eponymous gene,
WRN, the only gene currently connected to Werner syndrome. These mutations can have a range of effects. They may decrease the stability of the
transcribed messenger RNA (mRNA), which increases the rate at which they are degraded. With fewer mRNA, fewer are available to be
translated into the WRNp protein. Mutations may also lead to the truncation (shortening) of the WRNp protein, leading to the loss of its
nuclear localization signal sequence, which would normally transport it to the nucleus where it can interact with the DNA. This leads to a reduction in DNA repair. Cells of affected individuals have reduced lifespan in
culture, more chromosome breaks and
translocations and extensive deletions. These DNA damages, chromosome aberrations and mutations may in turn cause more RecQ-independent aging phenotypes.
Bloom syndrome Bloom syndrome (BS) is a very rare autosomal recessive disorder. Incidence rates are unknown, although it is known to be higher in people of
Ashkenazi Jewish background, presenting in around 1 in 50,000. Approximately one-third of individuals who have BS are of Ashkenazi Jewish descent. There is no evidence from the Bloom's Syndrome Registry or from the peer-reviewed medical literature that BS is a progeroid condition associated with advanced aging. It is, however, associated with early-onset cancer and adult-type diabetes and also with Werner syndrome, which is a progeroid syndrome, through mutation in the RecQ helicases. These associations have led to the speculation that BS could be associated with aging. Unfortunately, the average lifespan of persons with Bloom syndrome is 27 years; consequently, there is insufficient information to completely rule out the possibility that BS is associated with some features of aging. People with BS start their life with a low weight and length when they are born. Even as adults, they typically remain under tall. Individuals with BS are characterized by low weight and height and abnormal facial features, particularly a long, narrow face with a small lower jaw, a large nose and prominent ears. Most also develop
photosensitivity, which causes the blood vessels to be
dilated and leads to reddening of the skin, usually presented as a "butterfly-shaped patch of reddened skin across the nose and cheeks". Other characteristics of BS include
learning disabilities, an increased risk of
diabetes,
gastroesophageal reflux (GER), and
chronic obstructive pulmonary disease (COPD). GER may also lead to recurrent
infections of the upper respiratory tract,
ears, and lungs during infancy. BS causes
infertility in males and reduced fertility and early-onset
menopause in females. In line with any RecQ-associated PS, people with BS have an increased risk of developing cancer, often more than one type. BS is caused by mutations in the BLM gene, which encodes for the
Bloom syndrome protein, a RecQ helicase. These mutations may be
frameshift,
missense,
non-sense, or mutations of other kinds and are likely to cause deletions in the gene product. Apart from helicase activity that is common to all RecQ helices, it also acts to prevent inappropriate
homologous recombination. During replication of the genome, the two copies of DNA, called
sister chromatids, are held together through a structure called the
centromere. During this time, the homologous (corresponding) copies are in close physical proximity to each other, allowing them to 'cross' and exchange genetic information, a process called
homologous recombination. Defective homologous recombination can cause mutation and genetic instability. Such defective recombination can introduce gaps and breaks within the genome and disrupt the function of genes, possibly causing growth retardation, aging and elevated risk of cancer. It introduces gaps and breaks within the genome and disrupts the function of genes, often causing retardation of growth, aging and elevated risks of cancers. The Bloom syndrome protein interacts with other proteins, such as topoisomerase IIIα and RMI2, and suppresses illegitimate recombination events between sequences that are divergent from strict homology, thus maintaining genome stability.
NER protein-associated PS Nucleotide excision repair is a DNA repair mechanism. There are three excision repair pathways: nucleotide excision repair (NER),
base excision repair (BER), and
DNA mismatch repair (MMR). In NER, the damaged DNA strand is removed and the undamaged strand is kept as a template for the formation of a complementary sequence with DNA polymerase.
DNA ligase joins the strands together to form dsDNA. There are two subpathways for NER, which differ only in their mechanism for recognition: global genomic NER (GG-NER) and transcription coupled NER (TC-NER). Defects in the NER pathway have been linked to progeroid syndromes. There are 28 genes in this pathway. Individuals with defects in these genes often have developmental defects and exhibit
neurodegeneration. They can also develop CS, XP, and TTD, often in combination with each other, as with combined xeroderma pigmentosa-Cockayne syndrome (XP-CS). Variants of these diseases, such as
DeSanctis–Cacchione syndrome and Cerebro-oculo-facio-skeletal (COFS) syndrome, can also be caused by defects in the NER pathway. However, unlike RecQ-associated PS, not all individuals affected by these diseases have increased risk of cancer. or in other genes.
Cockayne syndrome Cockayne syndrome (CS) is a rare autosomal recessive PS. There are three types of CS, distinguished by severity and age of onset. It occurs at a rate of about 1 in 300,000-500,000 in the United States and Europe. The mean age of death is ~12 years, although the different forms differ significantly. Individuals with the type I (or classical) form of the disorder usually first show symptoms between one and three years and have lifespans of between 20 and 40 years. Type II Cockayne syndrome (CSB) is more severe: symptoms present at birth and individuals live to approximately 6–7 years of age. Individuals with CS appear prematurely aged and exhibit severe growth retardation leading to short stature. They have a
small head (less than the -3 standard deviation), fail to gain weight and
failure to thrive. They also have extreme
cutaneous photosensitivity (sensitivity to sunlight), neurodevelopmental abnormalities, and deafness, and often exhibit lipoatrophy, atrophic skin, severe
tooth decay, sparse hair, calcium deposits in neurons, cataracts, sensorineural hearing loss,
pigmentary retinopathy, and bone abnormalities. However, they do not have a higher risk of cancer. Type I and II are known to be caused by mutation of a specific gene. CSA is caused by mutations in the
cross-complementing gene 8 (
ERCC8), which encodes for the CSA protein. These mutations are thought to cause alternate splicing of the pre-mRNA which leads to an abnormal protein. CSB is caused by mutations in the
ERCC6 gene, which encodes the CSB protein. CSA and CSB are involved in transcription-coupled NER (TC-NER), which is involved in repairing DNA; they
ubiquitinate
RNA polymerase II, halting its progress thus allowing the TC-NER mechanism to be carried out. The ubiquitinated RNAP II then dissociates and is degraded via the
proteasome. Mutations in ERCC8, ERCC6, or both mean DNA is no longer repaired through TC-NER, and the accumulation of mutations leads to cell death, which may contribute to the symptoms of Cockayne syndrome.
Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder, affecting about one per million in the United States and
autochthonic Europe populations There have been 830 published cases from 1874 to 1982. The disorder presents at infancy or early childhood. Xeroderma pigmentosum mostly affects the eye and skin. Individuals with XP have extreme sensitivity to light in the
ultraviolet range starting from one to two years of age, When the eye is exposed to sunlight, it becomes irritated and
bloodshot, and the
cornea becomes cloudy. Around 30% of affected individuals also develop neurological abnormalities, including
deafness, poor coordination, decreased intellectual abilities, difficulty swallowing and talking, and seizures; these effects tend to become progressively worse over time. All affected individuals have a 1000-fold higher risk of developing
skin cancer: half of the affected population develop skin cancer by age 10, usually at areas most exposed to sunlight (e.g. face, head, or neck). The risk for other cancers such as
brain tumors,
lung cancer and
eye cancers also increase. There are eight types of XP (XP-A through XP-G), plus a variant type (XP-V), all categorized based on the genetic cause. XP can be caused by mutations in any of these genes:
DDB2,
ERCC2,
ERCC3,
ERCC4,
ERCC5,
XPA,
XPC. These genes are all involved in the NER repair pathway that repairs damaged DNA. The variant form, XP-V, is caused by mutations in the
POLH gene, which unlike the rest does not code for components of the NER pathway but produces a DNA polymerase that allows accurate
translesion synthesis of DNA damage resulting from UV radiation; its mutation leads to an overall increase in UV-dependent mutation, which ultimately causes the symptoms of XP.
Trichothiodystrophy Trichothiodystrophy (TTD) is a rare autosomal recessive disease whose symptoms span across multiple systems and can vary greatly in severity. The incidence rate of TTD is estimated to be 1.2 per million in Western Europe. an element that is part of the matrix proteins that give hair its strength. More severe cases cause delayed development, significant intellectual disability, and recurrent infection; the most severe cases see death at infancy or early childhood. TTD also affects the mother of the affected child during pregnancy, when she may experience
pregnancy-induced high blood pressure and develop
HELLP syndrome. The baby has a high risk of being born
prematurely and will have a low
birth weight. After birth, the child's normal growth is retarded, resulting in a short stature. Other symptoms include
scaly skin, abnormalities of the fingernails and toenails, clouding of the lens of the eye from birth (
congenital cataracts), poor co-ordination, and
ocular and skeletal abnormalities. Half of affected individuals also experience photosensitivity to UV light. which is involved in transcription and DNA damage repair. Mutations in one of these genes cause reduction of gene transcription, which may be involved in development (including
placental development), and thus may explain retardation in intellectual abilities, in some cases; A form of TTD without photosensitivity also exists, although its mechanism is unclear. The
MPLKIP gene has been associated with this form of TTD, although it accounts for only 20% of all known cases of the non-photosensitive form of TTD, and the function of its gene product is also unclear. Mutations in the
TTDN1 gene explain another 10% of non-photosensitive TTD. The function of the gene product of
TTDN1 is unknown, but the sex organs of individuals with this form of TTD often produce no hormones, a condition known as
hypogonadism. ==Defects in Lamin A/C==