Progeroid syndromes
Progeroid syndromes are a group of rare genetic disorders that mimic physiological aging, making affected individuals appear to be older than they are. The term progeroid syndrome does not necessarily imply progeria, which is a specific type of progeroid syndrome.
Progeroid means "resembling premature aging", a definition that can apply to a broad range of diseases. Familial Alzheimer's disease and familial Parkinson's disease are two well-known accelerated-aging diseases that are more frequent in older individuals. They affect only one tissue and can be classified as unimodal progeroid syndromes. Segmental progeria, which is more frequently associated with the term progeroid syndrome, tends to affect multiple or all tissues while causing affected individuals to exhibit only some of the features associated with aging.
All disorders within this group are thought to be monogenic, meaning they arise from mutations of a single gene. Most known PS are due to genetic mutations that lead to either defects in the DNA repair mechanism or defects in lamin A/C.
Examples of PS include Werner syndrome, Bloom syndrome, Rothmund–Thomson syndrome, Cockayne syndrome, xeroderma pigmentosum, trichothiodystrophy, combined xeroderma pigmentosum-Cockayne syndrome, restrictive dermopathy, and Hutchinson–Gilford progeria syndrome. Individuals with these disorders tend to have a reduced lifespan. Progeroid syndromes have been widely studied in the fields of aging, regeneration, stem cells, and cancer. The most widely studied of the progeroid syndromes are Werner syndrome and Hutchinson–Gilford progeria, as they are seen to most resemble natural aging.
Defects in DNA repair
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, chemical reactions, radiation, depurination, and deamination.Mutations in three classes of DNA repair proteins, RecQ protein-like helicases, nucleotide excision repair proteins, and nuclear envelope proteins LMNA have been associated with the following progeroid syndromes:
- Werner syndrome
- Bloom syndrome
- Rothmund–Thomson syndrome
- Cockayne syndrome
- Xeroderma pigmentosum
- Trichothiodystrophy
RecQ-associated PS
There are five genes encoding RecQ in humans, and defects in RECQL2/WRN, RECQL3/BLM and RECQL4 lead to Werner syndrome, Bloom syndrome, and Rothmund–Thomson syndrome, respectively. On the cellular level, cells of affected individuals exhibit chromosomal abnormalities, genomic instability, and sensitivity to mutagens.
Werner syndrome
Werner syndrome is a rare autosomal recessive disorder. It has a global incidence rate of less than 1 in 100,000 live births, although incidences in Japan and Sardinia are higher, where it affects 1 in 20,000-40,000 and 1 in 50,000, respectively. As of 2006, there were approximately 1,300 reported cases of WS worldwide. Affected individuals typically grow and develop normally until puberty, when they do not experience the typical adolescent growth spurt. The mean age of diagnosis is twenty-four. The median and mean age of death are 47-48 and 54 years, respectively; the main cause of death is cardiovascular disease or cancer.Affected individuals can exhibit growth retardation, short stature, premature graying of hair, hair loss, wrinkling, prematurely aged faces, beaked noses, skin atrophy with scleroderma-like lesions, loss of fat tissues, abnormal fat deposition leading to thin legs and arms, and severe ulcerations around the Achilles tendon and malleoli. Other signs include change in voice, making it weak, hoarse, or high-pitched; atrophy of gonads, leading to reduced fertility; bilateral cataracts ; premature arteriosclerosis ; calcinosis ; atherosclerosis ; type 2 diabetes; loss of bone mass; telangiectasia; and malignancies. In fact, the prevalence of rare cancers, such as meningiomas, are increased in individuals with Werner syndrome.
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. WRN encodes the WRNp protein, a 1432 amino acid protein with a central domain resembling members of the RecQ helicases. WRNp is active in unwinding DNA, a step necessary in DNA repair and DNA replication. Since WRNp's function depends on DNA, it is only functional when localized to the nucleus.
Mutations that cause Werner syndrome only occur at the regions of the gene that encode for protein and not at non-coding regions. These mutations can have a range of effects. They may decrease the stability of the transcribed messenger RNA, 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 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. Furthermore, mutated proteins are more likely to be degraded than normal WRNp. Apart from causing defects in DNA repair, its aberrant association with p53 down-regulates the function of p53, leading to a reduction in p53-dependent apoptosis and increase the survival of these dysfunctional cells.
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 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 5 feet 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, and chronic obstructive pulmonary disease. 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 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. Individuals with BS have a loss-of-function mutation, which means that the illegitimate recombination is no longer suppressed, leading to higher rates of mutation.