Progeroid syndromes - Knowledge (XXG)

657:(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. Type III has the mildest symptoms, first presents later in childhood, and the cause of death is often severe nervous system deterioration and respiratory tract infections. 956: 595:. 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 1224:

models with premature aging symptoms have different genetic backgrounds, they all have abnormal structures of tissues/organs as a result of defective development. Misrepair-accumulation aging theory suggests that the abnormality of tissue structure is the common point between premature aging and normal aging. Premature aging is a result of Mis-construction during development as a consequence of gene mutations, whereas normal aging is a result of accumulation of Misrepairs for the survival of an organism. Thus the process of development and that of aging are coupled by Mis-construction and Mis-re-construction (Misrepair) of the structure of an organism.

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peripheral heterochromatin, and clustering of nuclear pores", causing the nucleus to lose its shape and integrity. 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 are significantly reduced.

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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.

1176:, abnormal facial features (small mouth, small pinched nose and micrognathia), sparse or 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. 1057:

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. However, the

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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

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Hutchinson–Gilford progeria syndrome, Werner syndrome, and Cockayne syndrome are the three genetic disorders in which patients have premature aging features. Premature aging also develops on some animal models which have genetic alterations. Although the patients with these syndromes and the animal

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promote genetic stability by maintaining levels of proteins which 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 HGPS, the inability to adequately repair

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In the truncated lamin 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, leading to "lobulation of the nuclear envelope, thickening of the nuclear lamina, loss of

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WR is associated with abnormalities in bone maturation, and lipids and hormone metabolism. Affected individuals exhibit intrauterine and postnatal growth retardation, leading to short stature and an aged appearance from birth. They have physical abnormalities including a large head (macrocephaly),

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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

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condition, characterized by premature and accelerated aging (~7 times the normal rate) beginning at childhood. It affects 1 in ~4 million newborns; over 130 cases have been reported in the literature since the first described case in 1886. The mean age of diagnosis is ~3 years and the mean age of

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Lamin is required at the inner nuclear membrane to ensure the nucleus keeps its shape. Mutations in LMNA causes dysfunctional lamin, and the nucleus can no longer keeps its shape. This leads to mislocalisation of heterochromatin, which normally lie in close proximity, or with, the nuclear matrix,

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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

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Jacquinet A, Verloes A, Callewaert B, Coremans C, Coucke P, De Paepe A, Kornak U, Lebrun F, Lombret J, Pierard GE, Robinson PN, Symoens S, Van Maldergem L, Debray FG (2014). "Neonatal progeroid variant of Marfan syndrome with congenital lipodystrophy results from mutations at the 3' end of FBN1

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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. All these disorders can be caused by mutations in a single gene, XPD, or in other

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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,

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Graul-Neumann LM, Kienitz T, Robinson PN, Baasanjav S, Karow B, Gillesen-Kaesbach G, Fahsold R, Schmidt H, Hoffmann K, Passarge E (2010). "Marfan syndrome with neonatal progeroid syndrome-like lipodystrophy associated with a novel frameshift mutation at the 3-prime terminus of the FBN1-gene".

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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

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Some segmental progeroid syndromes, such as Werner syndrome (WS), Bloom syndrome (BS), Rothmund-Thomson syndromes (RTS) and combined xeroderma pigmentosa-Cockayne syndrome (XP-CS), are associated with an increased risk of developing cancer in the affected individual; two exceptions are

472:, 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 859:(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. Milder cases cause sparse and brittle hair, which is due to the lack of 4892:

Liu B, Wang J, Chan KM, Tjia WM, Deng W, Guan X, Huang JD, Li KM, Chau PY, Chen DJ, Pei D, Pendas AM, Cadiñanos J, López-Otín C, Tse HF, Hutchison C, Chen J, Cao Y, Cheah KS, Tryggvason K, Zhou Z (2005). "Genomic instability in laminopathy-based premature aging".

917:, the first two of which are also linked to xeroderma pigmentosum. However, patients with TTD do not show a higher risk of developing skin cancer, in contrast to patients with XP. The three genes associated with TTD encode for XPB, XPD and p8/TTDA of the 4799:

Mazereeuw-Hautier, J; Wilson, LC; Mohammed, S; Smallwood, D; Shackleton, S; Atherton, DJ; Harper, JI (2007). "Hutchinson–Gilford progeria syndrome: Clinical findings in three patients carrying the G608G mutation in LMNA and review of the literature".

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Kleijer, WJ; Laugel, V; Berneburg, M; Nardo, T; Fawcett, H; Gratchev, A; Jaspers, NG; Sarasin, A; et al. (2008). "Incidence of DNA repair deficiency disorders in western Europe: Xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy".

863:, 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. 446:, 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 70:

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

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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. At least 16 Other mutations in lamin A/C, or defects in the

771:, 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 3636:

Xeroderma pigmentosa is a rare, autosomal recessive disease caused by a defective UV-specific endonuclease. Patients with mutations are unable to repair DNA damage caused by sunlight and have been described as "children of the

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Masala, MV; Scapaticci, S; Olivieri, C; Pirodda, C; Montesu, MA; Cuccuru, MA; Pruneddu, S; Danesino, C; et al. (2007). "Epidemiology and clinical aspects of Werner's syndrome in North Sardinia: Description of a cluster".

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Romere C, Duerrschmid C, Bournat J, Constable P, Jain M, Xia F, Saha PK, Del Solar M, Zhu B, York B, Sarkar P, Rendon DA, Gaber MW, LeMaire SA, Coselli JS, Milewicz DM, Sutton VR, Butte NF, Moore DD, Chopra AR (April 2016).

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Takenouchi T, Hida M, Sakamoto Y, Torii C, Kosaki R, Takahashi T, Kosaki K (2013). "Severe congenital lipodystrophy and a progeroid appearance: Mutation in the penultimate exon of FBN1 causing a recognizable phenotype".

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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

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Yang, LY; Jiang, H; Rangel, KM (2003). "RNA polymerase II stalled on a DNA template during transcription elongation is ubiquitinated and the ubiquitination facilitates displacement of the elongation complex".

287:, 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 743:

Europe populations but with a higher incidence rate in Japan, North Africa, and the Middle East. There have been 830 published cases from 1874 to 1982. The disorder presents at infancy or early childhood.

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is about a boy who was born with the appearance of a 70-year-old and who ages backwards. This short story is thought to be inspired by progeria. The description of the fictitious Smallweed family in the

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Amor-Guéret, M; Dubois-d'Enghien, C; Laugé, A; Onclercq-Delic, R; Barakat, A; Chadli, E; Bousfiha, AA; Benjelloun, M; et al. (2008). "Three new BLM gene mutations associated with Bloom syndrome".

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Oshima J, Martin GM, Hisama FM. Werner Syndrome. 2002 Dec 2 . In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™ . Seattle (WA): University of Washington, Seattle; 1993-. Available from:

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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).

710:. 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. 921:(TFIIH) complex, 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 4450:

Jansen, T; Romiti, R (2000). "Progeria infantum (Hutchinson–Gilford syndrome) associated with scleroderma-like lesions and acro-osteolysis: A case report and brief review of the literature".

1210: 1526:, an extremely rare genetic disorder which is unique from other PS because of the absence of any cardiovascular abnormalities (which lead to premature death in cases where they are present) 631:

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

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who has a syndrome that resembles progeria, although the exact nature is unclear; it is now thought to be a form of neonatal progeroid syndrome. Velásquez is an advocate of anti-bullying.

579:, 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 5919:

Maloney, W. J. (2009). "Hutchinson–Gilford Progeria Syndrome: Its Presentation in F. Scott Fitzgerald's Short Story 'The Curious Case of Benjamin Button' and Its Oral Manifestations".

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death is ~13 years. The cause of death is usually myocardial infarction, caused by the severe hardening of the arteries (arteriosclerosis). There is currently no treatment available.

591:. 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 693:), 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 635:. 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 1246:, is an autosomal recessive progeroid syndrome. More than 30 cases have been reported. Most affected individuals die by seven months of age, but some do survive into their teens. 2062: 6394: 790:

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:

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Kraemer, KH; Lee, MM; Andrews, AD; Lambert, WC (1994). "The role of sunlight and DNA repair in melanoma and nonmelanoma skin cancer. The xeroderma pigmentosum paradigm".

775:: 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 1383: 5405: 1092:; this farnesylation is important in targeting lamin to the nuclear envelope, where it maintains its integrity. Normally, lamin A is recognized by ZMPSTE24 (FACE1, a 2997:

Graham, John M.; Anyane-Yeboa, Kwame; Raams, Anja; Appeldoorn, Esther; Kleijer, Wim J.; Garritsen, Victor H.; Busch, David; Edersheim, Terri G.; et al. (2001).

599:, which means that the illegitimate recombination is no longer suppressed, leading to higher rates of mutation (~10-100 times above normal, depending on cell type). 528:

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

3097:"Two individuals with features of both xeroderma pigmentosum and trichothiodystrophy highlight the complexity of the clinical outcomes of mutations in the XPD gene" 4843:

Redwood AB, Perkins SM, Vanderwaal RP, Feng Z, Biehl KJ, Gonzalez-Suarez I, Morgado-Palacin L, Shi W, Sage J, Roti-Roti JL, Stewart CL, Zhang J, Gonzalo S (2011).

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Ouyang, KJ; Woo, LL; Ellis, NA (2008). "Homologous recombination and maintenance of genome integrity: Cancer and aging through the prism of human RecQ helicases".

624:(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. 6224: 295:. Thus, individuals with RecQ-associated PS show an increased risk of developing cancer, which is caused by genomic instability and increased rates of mutation. 3419:

Komatsu, A; Suzuki, S; Inagaki, T; Yamashita, K; Hashizume, K (2004). "A kindred with Cockayne syndrome caused by multiple splicing variants of the CSA gene".

925:), and thus may explain retardation in intellectual abilities, in some cases; these mutations also lead to reduction in DNA repair, causing photosensitivity. 842:

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.

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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

5861: 2999:"Cerebro-Oculo-Facio-Skeletal Syndrome with a Nucleotide Excision–Repair Defect and a Mutated XPD Gene, with Prenatal Diagnosis in a Triplet Pregnancy" 5384:

Wang-Michelitsch, Jicun; Michelitsch, Thomas (2015). "Premature aging as a consequence of Misconstruction of tissues and organs during development".

2872:"Increased rate of spontaneous mitotic recombination in T lymphocytes from a Bloom's syndrome patient using a flow-cytometric assay at HLA-A locus" 955: 5806: 4939:

Navarro, C. L.; De Sandre-Giovannoli, A; Bernard, R; Boccaccio, I; Boyer, A; Geneviève, D; Hadj-Rabia, S; Gaudy-Marqueste, C; et al. (2004).

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photosensitivity (sensitivity to sunlight), neurodevelopmental abnormalities, and deafness, and often exhibit lipoatrophy, atrophic skin, severe

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Salk, D; Au, K; Hoehn, H; Martin, GM (1981). "Cytogenetics of Werner's syndrome cultured skin fibroblasts: Variegated translocation mosaicism".

2081:"Werner's syndrome a review of its symptomatology, natural history, pathologic features, genetics and relationship to the natural aging process" 706:, halting its progress thus allowing the TC-NER mechanism to be carried out. The ubiquitinated RNAP II then dissociates and is degraded via the 3608: 443: 141:(HGPS). Individuals with these disorders tend to have a reduced lifespan. Progeroid syndromes have been widely studied in the fields of aging, 2263:

Martin, GM; Sprague, CA; Epstein, CJ (1970). "Replicative life-span of cultivated human cells. Effects of donor's age, tissue, and genotype".

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gene, which encodes the CSB protein. CSA and CSB are involved in transcription-coupled NER (TC-NER), which is involved in repairing DNA; they

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are enzymes that bind to double-stranded DNA and temporarily separate them. This unwinding is required during replication of the genome under

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Park, CJ; Choi, BS (2006). "The protein shuffle. Sequential interactions among components of the human nucleotide excision repair pathway".

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Puzianowska-Kuznicka, M; Kuznicki, J (2005). "Genetic alterations in accelerated ageing syndromes. Do they play a role in natural ageing?".

1237: 153:. The most widely studied of the progeroid syndromes are Werner syndrome and Hutchinson–Gilford progeria, as they are seen to most resemble 491:

and extensive deletions. These DNA damages, chromosome aberrations and mutations may in turn cause more RecQ-independent aging phenotypes.

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Wang, Jicun; Michelitsch, Thomas; Wunderlin, Arne; Mahadeva, Ravi (2009). "Aging as a consequence of Misrepair –a novel theory of aging".

4941:"Lamin a and ZMPSTE24 (FACE-1) defects cause nuclear disorganization and identify restrictive dermopathy as a lethal neonatal laminopathy" 4715:

Broers, JL; Ramaekers, FC; Bonne, G; Yaou, RB; Hutchison, CJ (2006). "Nuclear lamins: Laminopathies and their role in premature ageing".

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Kraemer, KH; Lee, MM; Scotto, J (1987). "Xeroderma pigmentosum. Cutaneous, ocular, and neurologic abnormalities in 830 published cases".

832:. 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 5768: 4758:

Verstraeten, VL; Broers, JL; Van Steensel, MA; Zinn-Justin, S; Ramaekers, FC; Steijlen, PM; Kamps, M; Kuijpers, HJ; et al. (2006).

2715:"BLAP18/RMI2, a novel OB-fold-containing protein, is an essential component of the Bloom helicase-double Holliday junction dissolvasome" 1205: 1192:, the term is a misnomer since they do not exhibit accelerated aging. The condition is caused by mutations near the 3'-terminus of the 1073:

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

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in females. In line with any RecQ-associated PS, people with BS have an increased risk of developing cancer, often more than one type.

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tends to affect multiple or all tissues while causing affected individuals to exhibit only some of the features associated with aging.

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Kaneko, H; Fukao, T; Kondo, N (2004). "The function of RecQ helicase gene family (especially BLM) in DNA recombination and joining".

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Cleaver, JE; Lam, ET; Revet, I (2009). "Disorders of nucleotide excision repair: The genetic and molecular basis of heterogeneity".

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background, presenting in around 1 in 50,000. Approximately one-third of individuals who have BS are of Ashkenazi Jewish descent.

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Okur, Mustafa N.; Fang, Evandro F.; Fivenson, Elayne M.; Tiwari, Vinod; Croteau, Deborah L.; Bohr, Vilhelm A. (December 2020).

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De Sandre-Giovannoli, A.; Bernard, R; Cau, P; Navarro, C; Amiel, J; Boccaccio, I; Lyonnet, S; Stewart, CL; et al. (2003).

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Stefanini, M; Botta, E; Lanzafame, M; Orioli, D (2010). "Trichothiodystrophy: From basic mechanisms to clinical implications".

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gene, which unlike the rest does not code for components of the NER pathway but produces a DNA polymerase that allows accurate

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Mallory, Susan B.; Krafchik, Bernice R.; Bender, Matthew M.; Potocki, Lorraine; Metry, Denise W. (2003). "Cockayne Syndrome".

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De Sandre-Giovannoli, A; Bernard, R; Cau, P; Navarro, C; Amiel, J; Boccaccio, I; Lyonnet, S; Stewart, CL; et al. (2003).

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Hasty, P.; Campisi, J; Hoeijmakers, J; Van Steeg, H; Vijg, J (2003). "Aging and Genome Maintenance: Lessons from the Mouse?".

508:(BS) is a very rare autosomal recessive disorder. Incidence rates are unknown, although it is known to be higher in people of 468:

into the WRNp protein. Mutations may also lead to the truncation (shortening) of the WRNp protein, leading to the loss of its

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Broughton, B. C.; Berneburg, M; Fawcett, H; Taylor, EM; Arlett, CF; Nardo, T; Stefanini, M; Menefee, E; et al. (2001).

2625:"Intrachromosomal recombination between highly diverged DNA sequences is enabled in human cells deficient in Bloom helicase" 1326:

Alterations in lipid and carbohydrate metabolism, a triplet-repeat disorder (myotonic dystrophy) and an idiopathic disorder

110: 4599:"Accumulation of mutant lamin a causes progressive changes in nuclear architecture in Hutchinson–Gilford progeria syndrome" 6190: 3940:

Itin, PH; Sarasin, A; Pittelkow, MR (2001). "Trichothiodystrophy: Update on the sulfur-deficient brittle hair syndromes".

3886:"Trichothiodystrophy: A systematic review of 112 published cases characterises a wide spectrum of clinical manifestations" 1315: 469: 3048:"A summary of mutations in the UV-sensitive disorders: Xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy" 2450:. Bethesda, Maryland: U.S. National Library of Medicine, a division of the National Institutes of Health. 27 October 2014 6427: 6210: 5596:

Karikkineth, Ajoy C.; Scheibye-Knudsen, Morten; Fivenson, Elayne; Croteau, Deborah L.; Bohr, Vilhelm A. (January 2017).

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Goldman, RD; Shumaker, DK; Erdos, MR; Eriksson, M; Goldman, AE; Gordon, LB; Gruenbaum, Y; Khuon, S; et al. (2004).

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Individuals with CS appear prematurely aged and exhibit severe growth retardation leading to short stature. They have a

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Lehmann, AR (2003). "DNA repair-deficient diseases, xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy".

5897: 1520:, a rare autosomal recessive genetic disorder caused by defect(s) in the Double Holliday junction DNA repair mechanism 1440: 1189: 1089: 6349: 4051:

Moslehi, R; Signore, C; Tamura, D; Mills, JL; Digiovanna, JJ; Tucker, MA; Troendle, J; Ueda, T; et al. (2010).

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is unknown, but the sex organs of individuals with this form of TTD often produce no hormones, a condition known as

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Xeroderma pigmentosum mostly affects the eye and skin. Individuals with XP have extreme sensitivity to light in the

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Pasquier, L; Laugel, V; Lazaro, L; Dollfus, H; Journel, H; Edery, P; Goldenberg, A; Martin, D; et al. (2006).

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Kusunoki, Y; Hayashi, T; Hirai, Y; Kushiro, J; Tatsumi, K; Kurihara, T; Zghal, M; Kamoun, MR; et al. (1994).

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Goto, M; Miller, RW; Ishikawa, Y; Sugano, H (1996). "Excess of rare cancers in Werner syndrome (adult progeria)".

5875: 4658:"Blocking protein farnesyltransferase improves nuclear shape in fibroblasts from humans with progeroid syndromes" 1764:

Goode, EL; Ulrich, CM; Potter, JD (2002). "Polymorphisms in DNA repair genes and associations with cancer risk".

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of skin, dry skin and pigmentation after exposure. When the eye is exposed to sunlight, it becomes irritated and

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Eriksson, M; Brown, WT; Gordon, LB; Glynn, MW; Singer, J; Scott, L; Erdos, MR; Robbins, CM; et al. (2003).

1511: 1476: 1429:, more characters get this same fictional progeroid syndrome, which by then is called Chaos Child Syndrome. In 1306:

for progeroid syndromes, early observations have detected abnormalities within overall mitochondrial function,

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typically exhibit congenital lipodystrophy and a neonatal progeroid appearance. Sometimes identified as having

1120: 580: 458: 4053:"Adverse effects of trichothiodystrophy DNA repair and transcription gene disorder on human fetal development" 453:

Mutations that cause Werner syndrome only occur at the regions of the gene that encode for protein and not at

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Approximately 90% of individuals with Werner Syndrome have any of a range of mutations in the eponymous gene,

3756:"Xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome: A complex genotype–phenotype relationship" 6432: 182: 5712:"Potential therapeutic effects of the MTOR inhibitors for preventing ageing and progeria-related disorders" 3464:"UV-induced ubiquitination of RNA polymerase II: A novel modification deficient in Cockayne syndrome cells" 6369: 6323: 4760:"Compound heterozygosity for mutations in LMNA causes a progeria syndrome without prelamin a accumulation" 4381: 2713:

Singh, TR; Ali, AM; Busygina, V; Raynard, S; Fan, Q; Du, CH; Andreassen, PR; Sung, P; et al. (2008).

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Wang-Michelitsch, Jicun; Michelitsch, Thomas (2015). "Aging as a process of accumulation of Misrepairs".

5246:"Fibulin-5/DANCE has an elastogenic organizer activity that is abrogated by proteolytic cleavage in vivo" 4322: 2664:

Xu, D; Guo, R; Sobeck, A; Bachrati, CZ; Yang, J; Enomoto, T; Brown, GW; Hoatlin, ME; et al. (2008).

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with xeroderma pigmentosum. Children with XP are often colloquially referred to as Children of the Night.

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level of cognitive function, motor skills, and risk of developing cancer is not affected significantly.

731: 465: 464:(mRNA), which increases the rate at which they are degraded. With fewer mRNA, fewer are available to be 272: 126: 118: 2165:

Huang, S; Lee, L; Hanson, NB; Lenaerts, C; Hoehn, H; Poot, M; Rubin, CD; Chen, DF; et al. (2006).

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gene, have been shown to cause HGPS and other progeria-like symptoms, although these are less studied.

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and skeletal abnormalities. Half of affected individuals also experience photosensitivity to UV light.

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Type I and II are known to be caused by mutation of a specific gene. CSA is caused by mutations in the

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is a DNA repair mechanism. There are three excision repair pathways: nucleotide excision repair (NER),

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means "resembling premature aging", a definition that can apply to a broad range of diseases. Familial

5129:"De novo heterozygous FBN1 mutations in the extreme C-terminal region cause progeroid fibrillinopathy" 767:

becomes cloudy. Around 30% of affected individuals also develop neurological abnormalities, including

739:(XP) is a rare autosomal recessive disorder, affecting about one per million in the United States and 4669: 4610: 4259: 3614: 3534: 3475: 3336: 3186: 2824: 2397: 2338: 1946: 1502:, a rare progressive congenital disorder of the skin and bone marrow in some ways resembling progeria 1436: 1353: 617: 79: 4386: 6447: 6344: 6296: 5862:"Lizzie Velasquez, Born Without Adipose Tissue: 'Maybe You Should Stop Staring And Start Learning'" 1379: 1349: 1307: 1278: 1149:(RD), also called tight skin contracture syndrome, is a rare, lethal autosomal recessive perinatal 851: 621: 568: 529: 336: 186: 5655:"Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD+ signaling" 3177:

Andressoo, J.O.; Hoeijmakers, J.H.J. (2005). "Transcription-coupled repair and premature ageing".

1950: 6162: 6082: 5993: 5944: 5385: 5364: 5343: 5166: 5056: 5009: 4918: 4825: 4740: 4576: 4524: 4475: 4407: 4303: 4221: 4169: 3965: 3863: 3444: 3077: 2944: 2567: 1978: 1924: 1876: 1819: 1311: 1263: 1033: 834: 760: 276: 261: 3372:"Wide clinical variability among 13 new Cockayne syndrome cases confirmed by biochemical assays" 1725:"DNA helicase deficiencies associated with cancer predisposition and premature ageing disorders" 2495: 355:

Affected individuals can exhibit growth retardation, short stature, premature graying of hair,

6384: 6379: 6286: 6154: 6125: 6074: 6045: 5985: 5936: 5749: 5731: 5692: 5674: 5635: 5617: 5578: 5543: 5494: 5324: 5275: 5202: 5158: 5109: 5048: 5001: 4962: 4910: 4874: 4817: 4781: 4732: 4697: 4638: 4568: 4516: 4467: 4425: 4399: 4295: 4213: 4161: 4117: 4082: 4033: 3957: 3915: 3855: 3820: 3785: 3736: 3726: 3695: 3618: 3590: 3562: 3503: 3436: 3401: 3352: 3309: 3243: 3202: 3159: 3118: 3069: 3028: 2979: 2936: 2901: 2852: 2793: 2744: 2695: 2666:"RMI, a new OB-fold complex essential for Bloom syndrome protein to maintain genome stability" 2646: 2602: 2559: 2518: 2425: 2366: 2307: 2272: 2245: 2196: 2144: 2102: 2044: 1970: 1916: 1868: 1811: 1773: 1746: 1705: 1667: 1615: 1566: 1346:

famed for her efforts in spreading awareness of the condition. She was featured in the media.

703: 665: 649: 632: 584: 576: 572: 166: 130: 114: 5776: 4940: 3523:"Transcription-coupled and DNA damage-dependent ubiquitination of RNA polymerase II in vitro" 889:, abnormalities of the fingernails and toenails, clouding of the lens of the eye from birth ( 457:

regions. These mutations can have a range of effects. They may decrease the stability of the

450:. Since WRNp's function depends on DNA, it is only functional when localized to the nucleus. 6146: 6115: 6107: 6066: 6035: 6027: 5975: 5928: 5739: 5723: 5682: 5666: 5625: 5609: 5570: 5533: 5525: 5484: 5476: 5314: 5306: 5265: 5257: 5194: 5148: 5140: 5099: 5091: 5040: 4993: 4952: 4902: 4864: 4856: 4809: 4771: 4724: 4687: 4677: 4628: 4618: 4558: 4506: 4459: 4391: 4285: 4275: 4267: 4203: 4151: 4109: 4072: 4064: 4023: 4012:"Trichothiodystrophy view from the molecular basis of DNA repair/transcription factor TFIIH" 3992: 3949: 3905: 3897: 3847: 3812: 3775: 3767: 3718: 3687: 3552: 3542: 3493: 3483: 3428: 3391: 3383: 3344: 3327:

Andressoo, JO; Hoeijmakers, JH (2005). "Transcription-coupled repair and premature ageing".

3301: 3235: 3194: 3149: 3108: 3059: 3018: 3010: 2971: 2928: 2891: 2883: 2842: 2832: 2783: 2775: 2734: 2726: 2685: 2677: 2636: 2594: 2549: 2510: 2415: 2405: 2356: 2346: 2299: 2235: 2227: 2186: 2178: 2092: 2036: 1962: 1908: 1858: 1850: 1803: 1736: 1697: 1657: 1605: 1597: 1556: 1466: 1461: 1157:

gene, which lead to the production of truncated prelamin A precursor, and insertions in the

992: 988: 866:

TTD also affects the mother of the affected child during pregnancy, when she may experience

408: 34: 3838:

Cleaver, JE (2005). "Cancer in xeroderma pigmentosum and related disorders of DNA repair".

2214:

Spillare, EA; Robles, AI; Wang, XW; Shen, JC; Yu, CE; Schellenberg, GD; Harris, CC (1999).

1945:

Gray, Matthew D.; Shen, Jiang-Cheng; Kamath-Loeb, Ashwini S.; Blank, A.; Sopher, Bryce L.;

928:

A form of TTD without photosensitivity also exists, although its mechanism is unclear. The

395:. Other signs include change in voice, making it weak, hoarse, or high-pitched; atrophy of 6258: 1431: 1414: 1390: 1103:

HGPS is considered autosomal dominant, which means that only one of the two copies of the

1093: 983:

gene. Lamin A is a major nuclear component that determines the shape and integrity of the

718: 447: 420: 416: 388: 327: 312: 102: 4248:"Recurrent de novo point mutations in lamin a cause Hutchinson–Gilford progeria syndrome" 3649: 6096:"Roles of RECQ helicases in recombination based DNA repair, genomic stability and aging" 4673: 4614: 4290: 4263: 4247: 3754:

Kraemer, KH; Patronas, NJ; Schiffmann, R; Brooks, BP; Tamura, D; Digiovanna, JJ (2007).

3538: 3479: 3340: 3190: 2828: 2538:"Syndrome-causing mutations of the BLM gene in persons in the Bloom's Syndrome Registry" 2401: 2342: 1863: 1838: 939:

gene explain another 10% of non-photosensitive TTD. The function of the gene product of

322:

parents must contribute a dysfunctional allele for an individual to develop the disease.

6364: 6263: 6120: 6095: 5744: 5711: 5687: 5654: 5630: 5597: 5538: 5513: 5489: 5464: 5319: 5294: 5270: 5245: 5153: 5128: 5104: 5079: 4869: 4844: 4692: 4657: 4138:

Morice-Picard, F; Cario-André, M; Rezvani, H; Lacombe, D; Sarasin, A; Taïeb, A (2009).

4077: 4052: 3910: 3885: 3780: 3771: 3755: 3396: 3371: 3138:"The xeroderma pigmentosum group D (XPD) gene: One gene, two functions, three diseases" 3023: 2998: 2896: 2887: 2871: 2813:"Evidence for increased in vivo mutation and somatic recombination in Bloom's syndrome" 2788: 2763: 2739: 2714: 2690: 2665: 2191: 2166: 1610: 1585: 1561: 1544: 1505: 1471: 1368: 1150: 871: 509: 500: 428: 122: 106: 6040: 6015: 4633: 4598: 4372:

Hennekam, RC (2006). "Hutchinson–Gilford progeria syndrome: Review of the phenotype".

3557: 3522: 3462:

Bregman, DB; Halaban, R; Van Gool, AJ; Henning, KA; Friedberg, EC; Warren, SL (1996).

2847: 2812: 2361: 2326: 2240: 2215: 1701: 6421: 6389: 6250: 6150: 6070: 5997: 4813: 4463: 4068: 3498: 3463: 3266: 2420: 2385: 2097: 2080: 1339: 1303: 1259: 1201: 1169: 875: 867: 673: 461: 454: 380: 364: 254: 245: 6166: 6086: 5948: 5170: 5060: 5013: 4922: 4829: 4580: 4528: 4479: 4411: 4225: 4173: 3969: 3448: 3081: 2571: 1982: 1880: 1128:

DNA damages due to defective A-type lamin may cause aspects of premature aging (see

882:. After birth, the child's normal growth is retarded, resulting in a short stature. 740: 5465:"Wiedemann–Rautenstrauch neonatal progeroid syndrome: Report of three new patients" 4744: 4307: 3867: 2948: 2386:"The Bloom's syndrome gene product promotes branch migration of holliday junctions" 2001: 1823: 1481: 1470:

is a 1996 American comedy-drama film, in which the titular character (portrayed by

1069:, point mutation p.G608G (GGC > GGT). This mutation causes a splice site within 1065:

gene, which encodes for lamin A. Specifically, most HGPS are caused by a dominant,

1050: 1042: 984: 944: 879: 685: 676:, sparse hair, calcium deposits in neurons, cataracts, sensorineural hearing loss, 661: 525: 484: 424: 194: 5964:"Reflections for August: Description of a Family with Progeria by Charles Dickens" 2469: 2443: 1928: 1423:, the character Shogun eventually dies of a progeroid syndrome, and in its sequel 5980: 5963: 5574: 4113: 3348: 3239: 3198: 2975: 2641: 2624: 1269:

The cause of WR is unknown, although defects in DNA repair have been implicated.

3816: 3722: 1425: 1400: 1395: 1364: 1255: 1194: 967: 780: 776: 772: 748: 553: 372: 198: 90:. Most known PS are due to genetic mutations that lead to either defects in the 5198: 5095: 4728: 4603: