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User:Kinkreet/Progeroid Syndrome

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Progeroid syndrome (PS) is a group of rare genetic disorders which mimics physiological aging at an early age. Individuals with the syndrome appear older than their chronological age. All disorders within this group are monogenic,[1] meaning they arise from mutations of a single gene. Examples of PSs include Werner syndrome (WS), Bloom syndrome (BS), Rothmund–Thomson syndrome (RTS), combined xeroderma pigmentosa-Cockayne syndrome (XP-CS), Trichothiodystrophy (TTD), restrictive dermopathy (RD), Hutchinson-Gilford progeria (HGPS) and Cockayne syndrome. Individuals with these disorders tend to have a reduced lifespan.[1] Because of its property of accelerated aging (senescence), it has been widely studied in the fields of aging, regeneration, stem cells and cancer.[1]

Most PS are segmental, meaning they do not exhibit some, but not all, of the features associated with aging; these tend to affect multiple/all tissues. Familial Alzheimer's disease and familial Parkinson's disease, an accelerated aging disease associated with aged individuals, affects only one tissue, and can be classified as an unimodal progeroid syndrome. However, progeroid syndrome usually refers to the segmental type. The most widely studied of the progeroid syndromes are Werner syndrome (WS) and Hutchinson-Gilford progeria (HGPS), as they are deemed to most resemble natural aging.[1]

Defects in DNA repair edit

The DNA damage theory of aging states that aging is a consequence of the accumulation of naturally occurring DNA damages. These damages may arise from reactive oxygen species (ROS), chemical reactions (e.g. with intercalating agents, radiation, depurination, deamination and other factors. The damage may accumulate due to excessive damage, or defects in the DNA repair mechanisms, which is the cause of the following PSs:

  • Werner syndrome (WS)
  • Bloom syndrome (BS)
  • Rothmund–Thomson syndrome (RTS)
  • Cockayne syndrome (CS)
  • Xeroderma pigmentosum (XP)
  • Trichothiodystrophy (TTD)

In particular, mutations in two classes of DNA repair proteins - RecQ protein-like helicases (RECQLs) and nucleotide excision repair (NER) proteins - have been associated with this type of progeroid syndrome.

RecQ-associated PS edit

Further information on RecQ: RecQ helicase and Helicase

RecQ is a family of conserved ATP-dependent DNA helicases required for repairing DNA, preventing deleterious recombination, and overall maintaining genomic stability.[2] There are five genes encoding RecQ in humans (RECQ1-5), and defects in RECQL2/WRN, RECQL3/BLM and RECQL4 leads to Werner syndrome, Bloom syndrome, and RTS, respectively.[2][3]

On the cellular level, cells of affected individuals exhibit chromosomal abnormalities, genomic instability, and sensitivity to mutagens. Individuals with RecQ-associated PSs shows an increased risk of developing cancer, and many have attributed this as an effect of genomic instability and increased rates of mutation.[4]

Werner syndrome edit

Main article: Werner syndrome

Werner syndrome (WS) is a rare, autosomal recessive[5] PS. It has an incidence rate of less than 1 in 100,000 per live birth[5] and there have been 1,300 reported cases[1]. The mean age of diagnosis is twenty-four, often realized when the adolescent growth spurt is not observed.[6] The median age of death is 47-48 years; the main course of death is cardiovascular disease or cancer.[1]

Affected individuals exhibit growth retardation, short stature, premature greying of hair, alopecia (hair loss), wrinkling, change in voice (weak, high-pitched), atrophy of gonads leading to reduced fertility, bilateral cataract, prematurely aged face with beaked nose, premature arteriosclerosis (thickening and loss of elasticity of arteries), calcinosis (calcium deposits in blood vessels), atherosclerosis (blockage of blood vessels), skin atrophy with scleroderma-like lesions and sparse gray hair, lipodystrophy, type 2 diabetes, osteoporosis (loss of bone mass), telangiectasia, severe ulcerations around the Achilles’ tendons and malleoli (around ankles) and malignancies.[1][5]

The WRNp protein have been shown to be associated with RAD52 (a recombination mediator protein),[7] the Ku complex,[8] components of the DNA replication complex (DNA polymerase,[9][10] human replication protein A,[11] proliferating cell nuclear antigen[12] and topoisomerase I)[12], p53,[13] and TRF2 (a telomeric repeat binding factor).[14]

Mutations which causes Werner syndrome all occurs at the regions of the gene which encodes for protein.[15] These mutations may lead to a shorter lifespan of the transcribed mRNA, which implies less WRNp protein are being synthesized, or it may lead to the truncation of the WRNp protein leading to the loss of its nuclear localization signal sequence, thus reducing or preventing its function of DNA repair.[15] 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.[16]

Individuals with Werner syndrome have a higher-than-normal somatic mutation rate, particularly deletions.[17] This increase in mutation may in turn cause more RecQ-independent aging phenotypes.

The prevalence of rare cancers, such as meningiomas, are increased in individuals with Werner syndrome.[18]

Bloom syndrome edit

autosomal recessive

NER protein-associated PS edit

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). Defects in the NER pathway have been linked to progeroid syndromes. In NER, the damaged strand of DNA is removed but the undamaged strand remains, and is used as a template for polymerase to act on to complete the complementary sequence. Finally, the completion of the dsDNA is carried out by DNA ligase. There are two subpathways for NER, which differs only in their mechanism for recognition - global genomic NER (GG-NER) and transcription coupled NER (TC-NER).

Individuals with defects in this DNA repair pathway often have developmental defects and exhibit neurodegeneration, and can develop CS, XP and TTD, often in combination of each other, such as in combined xeroderma pigmentosa-Cockayne syndrome (XP-CS).[19] Variants on 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 affected individuals have increased risk of cancer.[20]

All these disorders can be caused by mutations in a single gene - XPD[21][22][23][24] as well as other genes.[25]

Cockayne syndrome edit

Cockayne syndrome (CS) is a rare autosomal recessive PS. There are two types of CS - CSA and CSB. CSA is caused by mutations in the cross-complementing gene 8 (ERCC8) gene which encodes for the CSA protein. CSB is caused by mutations in the ERCC6 gene, which encodes the CSB protein.[26] Both these proteins are involved in transcription coupled NER (TC-NER). They also ubiquitinate RNA polymerase II, halting its progress and allowing TC-NER mechanism to be carried out.[27] The ubiquitinated RNAP II then dissociates and is degraded via the proteasome.[28]

Individuals with CS exhibit severe growth retardation and neurodevelopmental abnormalities, and often exhibit lipoatrophy, atrophic skin, dental caries, sparse hair, calcium deposits in nuerons, microcephaly, cataracts, sensorineural hearing loss, pigmentary retinopathy, cutaneous photosensitivity (sensitivity to the light), but do not have a higher risk of cancer. The mean age of death is ~12 years,[29] although the two forms differ significantly. Individuals with the CSA form of the disorder usually presents between ages 1 and 3, and have lifespan of between 20 and 40 years; CSB individuals have symptoms present at birth, and live to ~6-7 years.[20] The cause of death is often severe nervous system deterioration and respiratory tract infections.[30]

Xeroderma pigmentosum edit

Trichothiodystrophy edit

Defects in Lamin A/C edit

Further information on other diseases caused by defects in lamin: Laminopathy

Hutchinson–Gilford progeria syndrome (HGPS) and restrictive dermopathy (RD) are two PS caused by a defect in lamin A/C, which is encoded by the LMNA gene.[31][32] Lamin A is a major nuclear component that determines the shape and integrity of the nucleus, by acting as a scaffolding protein that forms a filamentous meshwork underlying the inner nuclear envelope, the membrane that surrounds the nucleus.

Structure or post-translational modification

Hutchinson–Gilford progeria syndrome edit

Main article: Progeria

Hutchinson–Gilford progeria syndrome is an extremely rare developmental autosomal dominant condition, affecting 1 in ~4 million newborns; over 130 cases have been reported in the literature since the first described case in 1886.[33]

Individuals with HGPS typically appear normal at birth, but their growth is severely retarded, resulting in short stature, a very low body weight and delayed tooth eruption. Their facial/cranial proportions and facial features are abnormal, characterized by larger-than-normal eyes, a thin, beaked nose, thin lips, small chin and jaw (micrognathia), protruding ears, scalp hair, eyebrows, and lashes, alopecia (hair loss), large head (macrocephaly), large fontanelle and generally appearing aged. Other features include skeletal alterations (osteolysis, osteoporosis), amyotrophy (wasting of muscle), lipodystrophy and skin atrophy (loss of subcutaneous tissue and fat) with sclerodermatous focal lesions, severe atherosclerosis and prominent scalp veins.[34] However, the level of cognitive function, motor skills, and risk of developing cancer is not affected significantly.[35]

HGPS is caused by sporadic mutations (not inherited from parent) in the LMNA gene, which encodes for lamin A.[36][37] Specifically, most HGPS are caused by a dominant, de novo, point mutation p.G608G (GGC > GGT).[38] This mutation causes a splice site within exon 11 of the pre-mRNA to come into action, leading to the last 150 base pairs of that exon, and consequently, the 50 amino acids near the C-terminus, being deleted.[39] This results in a truncated prelamin A precursor (a.k.a. progerin or LaminAΔ50).[40]

Normally, lamin A is recognized by ZMPSTE24 (FACE1, a metalloprotease) and cleaved. After being translated, a farnesol is added to prelamin A using protein farnesyltransferase; this farnesylation is important in targeting lamin to the nuclear envelope, where it maintains its integrity.

In the truncated prelamin A precursor, this cleavage is not possible and the prelamin A cannot mature. When the truncated prelamin A is localized to the nuclear envelope, it will not be processed and accumulates,[41] leading to "lobulation of the nuclear envelope, thickening of the nuclear lamina, loss of peripheral heterochromatin, and clustering of nuclear pores", causing the nucleus to lose its shape and integrity.[42] The prelamin A also maintains the farnesyl and a methyl moiety on its C-terminal cysteine residue, ensuring their continued localization at the membrane. When this farnesylation is prevented using farnesyltransferase inhibitor (FTI), the abnormalities in nuclear shape significantly reduced.[43][44]

HGPS is considered autosomal dominant, which means only one of the two copies of the LMNA gene needs to be mutated to produce this phenotype. As the phenotype is caused by an accumulation of the truncated prelamin A, only mutation in one of the two genes is sufficient.[45] At least 16 Other mutations in lamin A/C,[46][47] or defects in the ZMPSTE24 gene,[48] have been shown to cause HGPS and other progeria-like symptoms, although these are less studied.

The mean age of diagnosis is ~3 years and the mean age of death is ~13 years. The cause of death is usually myocardial infarction, caused by the severe hardening of the arteries (arteriosclerosis).[49] There is currently no treatment available.[50]

Restrictive dermopathy edit

Main article: Restrictive dermopathy

Restrictive dermopathy (RD), also called tight skin contracture syndrome, is a rare, lethal autosomal recessive perinatal genodermatosis.[51] Like HGPS, RD can be caused by defects in lamin. Mutations in the LMNA gene leading to the truncated prelamin A precursor being produced, insertions in the ZMPSTE24 giving rise to a premature stop codon, are all known causes of RD.[52]

Individuals with RD exhibits growth retardation starting in the uterus, tight and rigid skin with erosions, prominent superficial vasculature and epidermal hyperkeratosis, facial features (small mouth, small pinched nose and micrognathia), sparse/absent eyelashes and eyebrows, mineralization defects of the skull, thin dysplastic clavicles, pulmonary hypoplasia and multiple joint contractures. Most affected individuals die in the uterus or are stillbirths, and liveborns usually die within a week.

Unknown causes edit

Wiedemann-Rautenstrauch syndrome edit

Wiedemann-Rautenstrauch (WR) syndrome, also known as neonatal progeroid syndrome,[53] is a autosomal recessive progeroid syndrome. There has more than 30 cases reported.[54]

WR is associated with abnormalities in bone maturation, and lipids and hormone metabolism.[55] Affected individuals have an aged appearance from birth, loss of fat under the skin, abnormal hair pattern (hypotrichosis), large head (macrocephaly), severe growth retardation and dysmorphism.

Most affected individuals die by seven months of age, but some do survive into their teens.

The cause WR is unknown, although defects in DNA repair have been implemented.[56]

See also edit

References edit

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Further reading edit

External links edit


Category:Syndromes Category:Rare diseases Category:Aging-associated diseases Category:Genetic disorders Category:Mid-importance Genetics articles Category:Diseases and disorders Category:Health Category:Medicine Category:Medical genetics Category:Senescence Category:Aging

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