Content deleted Content added
Citation bot (talk | contribs) Add: s2cid. | Use this bot. Report bugs. | Suggested by AManWithNoPlan | #UCB_CommandLine 240/2145 |
m Dating maintenance tags: {{Cn}} |
||
| (31 intermediate revisions by 12 users not shown) | |||
Line 3:
'''Progeroid syndromes''' ('''PS''') are a group of rare [[genetic disorder]]s that mimic [[Physiology|physiological]] [[senescence|aging]], making affected individuals appear to be older than they are.<ref>{{Cite journal | last1 = Sinha | first1 = Jitendra Kumar | last2 = Ghosh | first2 = Shampa | last3 = Raghunath | first3 = Manchala | title = Progeria: a rare genetic premature ageing disorder | journal = Indian J Med Res | volume = 139 | issue = 5 | pages = 667–74 |date= May 2014 | pmid = 25027075 | pmc=4140030 }}</ref><ref>{{Cite journal | last1 = Gordon | first1 = Leslie B. | last2 = Cao | first2 = Kan | last3 = Collins | first3 = Francis S. | title = Progeria: Translational insights from cell biology | journal = J Cell Biol | volume = 199 | issue = 1 | pages = 9–13 | date= 2012 | doi = 10.1083/jcb.201207072 | pmid=23027899 | pmc=3461511}}</ref> The term ''progeroid syndrome'' does not necessarily imply [[progeria]] ([[Progeria|Hutchinson–Gilford progeria syndrome]]), which is a specific type of progeroid syndrome.
''Progeroid'' means "resembling premature aging
All disorders within this group are thought to be [[Monogenic (genetics)|monogenic]],<ref name="Navarro">{{cite journal|pmid=16987878|year=2006|last1=Navarro|first1=CL|last2=Cau|first2=P|last3=Lévy|first3=N|title=Molecular bases of progeroid syndromes|volume=15 Spec No 2|pages=R151–61|doi=10.1093/hmg/ddl214|journal=Human Molecular Genetics|doi-access=free}}</ref> meaning they arise from [[mutation]]s 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 [[LMNA|lamin A/C]].
Line 10:
==Defects in DNA repair==
One of the main causes of progeroid syndromes
Mutations in three classes of DNA repair proteins, [[RECQL|RecQ protein-like helicases]] (RECQLs), [[nucleotide excision repair]] (NER) proteins, and nuclear envelope proteins [[LMNA]] (lamins) have been associated with the following progeroid syndromes:{{cn|date=May 2022}}
Line 22:
===RecQ-associated PS===
{{Further|topic=RecQ|RecQ helicase|Helicase}}
[[RecQ helicase|''RecQ'']]''
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.<ref name="Pmid" /><ref>{{cite journal|doi=10.1007/s00018-007-7121-z|title=Molecular genetics of RecQ helicase disorders|year=2007|last1=Hanada|first1=K.|last2=Hickson|first2=I. D.|journal=Cellular and Molecular Life Sciences|volume=64|issue=17|pages=2306–22|pmid=17571213|s2cid=29287970|pmc=11136437}}</ref> On the cellular level, cells of affected individuals exhibit chromosomal abnormalities, genomic instability, and sensitivity to [[mutagen]]s.<ref name="Ouyang" />
====Werner syndrome====
[[File:Autosomal recessive - en.svg|thumb|250px|Werner syndrome is inherited in an autosomal recessive manner, which means '''''both''''' parents must contribute a dysfunctional allele for an individual to develop the disease.]]
{{Main|Werner syndrome}}
''Werner syndrome'' (WS) is a rare [[autosomal recessive]] disorder.<ref name="Doiscience">{{cite journal|doi=10.1126/science.1079161|title=Aging and Genome Maintenance: Lessons from the Mouse?|year=2003|last1=Hasty|first1=P.|journal=Science|volume=299|issue=5611|pages=1355–9|pmid=12610296|last2=Campisi|first2=J|last3=Hoeijmakers|first3=J|last4=Van Steeg|first4=H|last5=Vijg|first5=J|s2cid=840477}}</ref><ref name="Doing">{{cite journal|doi=10.1038/ng0997-100|title=The Werner syndrome protein is a DNA helicase|year=1997|last1=Gray|first1=Matthew D.|last2=Shen|first2=Jiang-Cheng|last3=Kamath-Loeb|first3=Ashwini S.|last4=Blank|first4=A.|last5=Sopher|first5=Bryce L.|last6=Martin|first6=George M.|author-link6=George M Martin|last7=Oshima|first7=Junko|author-link7=Junko Oshima|last8=Loeb|first8=Lawrence A.|journal=Nature Genetics|volume=17|pages=100–3|pmid=9288107|issue=1|s2cid=20587915}}</ref> It has a global incidence rate of less than 1 in 100,000 live births,<ref name="Doiscience" /> although incidences in Japan and Sardinia are higher, where it affects 1 in 20,000-40,000 and 1 in 50,000, respectively.<ref name="ghr_a">{{cite web|title=Werner syndrome|url=http://ghr.nlm.nih.gov/condition/werner-syndrome|work=Genetics Home Reference|access-date=18 March 2013}}</ref><ref>{{cite journal|pmid=17478382|year=2007|last1=Masala|first1=MV|last2=Scapaticci|first2=S|last3=Olivieri|first3=C|last4=Pirodda|first4=C|last5=Montesu|first5=MA|last6=Cuccuru|first6=MA|last7=Pruneddu|first7=S|last8=Danesino|first8=C|last9=Cerimele|first9=D | display-authors=8 |title=Epidemiology and clinical aspects of Werner's syndrome in North Sardinia: Description of a cluster|volume=17|issue=3|pages=213–6|doi=10.1684/ejd.2007.0155|journal=European Journal of Dermatology|doi-broken-date=
Affected individuals can exhibit growth retardation, short stature, premature graying of hair, [[alopecia|hair loss]], [[wrinkle|wrinkling]], prematurely aged faces, [[Aquiline nose|beaked nose]]s, skin [[atrophy]] (wasting away) with [[scleroderma]]-like [[lesion]]s, [[lipodystrophy|loss of fat tissues]], abnormal fat deposition leading to thin legs and arms, and severe [[ulcer]]ations around the [[Achilles tendon]] and [[Malleolus|malleoli]]. Other signs include change in voice, making it weak, hoarse, or high-pitched; atrophy of [[gonad]]s, leading to reduced [[fertility]]; bilateral [[cataract]]s (clouding of lens); premature [[arteriosclerosis]] (thickening and loss of elasticity of arteries); [[calcinosis]] (calcium deposits in blood vessels); [[atherosclerosis]] (blockage of blood vessels); [[type 2 diabetes]]; [[osteoporosis|loss of bone mass]]; [[telangiectasia]]; and [[malignancy|malignancies]].<ref name="Navarro" /><ref name="Doiscience" /> In fact, the prevalence of rare cancers, such as [[meningioma]]s, are increased in individuals with Werner syndrome.<ref>{{cite journal|pmid=8722214|year=1996|last1=Goto|first1=M|last2=Miller|first2=RW|last3=Ishikawa|first3=Y|last4=Sugano|first4=H|title=Excess of rare cancers in Werner syndrome (adult progeria)|volume=5|issue=4|pages=239–46|journal=Cancer Epidemiology, Biomarkers & Prevention}}</ref>
Approximately 90% of individuals with Werner Syndrome have any of a range of mutations in the eponymous gene, [[Werner syndrome ATP-dependent helicase|WRN]], the only gene currently connected to Werner syndrome.<ref name="ncbi" /> 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]].<ref name="Doing" /><ref name="ghr_a" /> Since WRNp's function depends on DNA, it is only functional when localized to the nucleus.{{cn|date=November 2024}}
Mutations that cause Werner syndrome only occur at the regions of the gene that encode for protein and not at [[Noncoding DNA|non-coding]] regions.<ref name="Pmid_b">{{cite journal|pmid=16673358|year=2006|last1=Huang|first1=S|last2=Lee|first2=L|last3=Hanson|first3=NB|last4=Lenaerts|first4=C|last5=Hoehn|first5=H|last6=Poot|first6=M|last7=Rubin|first7=CD|last8=Chen|first8=DF|last9=Yang|first9=CC | display-authors=8 |title=The spectrum of WRN mutations in Werner syndrome patients|volume=27|issue=6|pages=558–67|doi=10.1002/humu.20337|pmc=1868417|journal=Human Mutation}}</ref> These mutations can have a range of effects. They may decrease the stability of the [[Transcription (genetics)|transcribed]] [[messenger RNA]] (mRNA), which increases the rate at which they are degraded. With fewer mRNA, fewer are available to be [[Translation (biology)|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 sequence|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.<ref name="Pmid_b" /> Furthermore, mutated proteins are more likely to be degraded than normal WRNp.<ref name="ghr_a" /> 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.<ref>{{cite journal|pmid=10364153|year=1999|last1=Spillare|first1=EA|last2=Robles|first2=AI|last3=Wang|first3=XW|last4=Shen|first4=JC|last5=Yu|first5=CE|last6=Schellenberg|first6=GD|last7=Harris|first7=CC|title=P53-mediated apoptosis is attenuated in Werner syndrome cells|volume=13|issue=11|pages=1355–60|pmc=316776|journal=Genes & Development|doi=10.1101/gad.13.11.1355}}</ref>
Line 48:
Other characteristics of BS include [[Learning disability|learning disabilities]], an increased risk of [[diabetes]], [[Gastroesophageal reflux disease|gastroesophageal reflux]] (GER), and [[chronic obstructive pulmonary disease]] (COPD). GER may also lead to recurrent [[Upper respiratory tract infection|infections of the upper respiratory tract]], [[Otitis|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.{{cn|date=May 2022}}
BS is caused by mutations in the BLM gene, which encodes for the [[Bloom syndrome protein]], a RecQ helicase.<ref>{{cite journal|pmid=16246145|year=2005|last1=Cheok|first1=CF|last2=Bachrati|first2=CZ|last3=Chan|first3=KL|last4=Ralf|first4=C|last5=Wu|first5=L|last6=Hickson|first6=ID|title=Roles of the Bloom's syndrome helicase in the maintenance of genome stability|volume=33|issue=Pt 6|pages=1456–9|doi=10.1042/BST20051456|journal=Biochemical Society Transactions|url=http://eprints.lincoln.ac.uk/8888/1/BiochSocTrans33.1456.pdf}}</ref> These mutations may be [[Frameshift mutation|frameshift]], [[Missense mutation|missense]], [[Nonsense mutation|non-sense]], or mutations of other kinds and are likely to cause deletions in the gene product.<ref name="Pmid_a">{{cite journal|pmid=17407155|year=2007|last1=German|first1=J|last2=Sanz|first2=MM|last3=Ciocci|first3=S|last4=Ye|first4=TZ|last5=Ellis|first5=NA|title=Syndrome-causing mutations of the BLM gene in persons in the Bloom's Syndrome Registry|volume=28|issue=8|pages=743–53|doi=10.1002/humu.20501|journal=Human Mutation|s2cid=44382072|doi-access=free}}</ref><ref>{{cite journal|pmid=18471088|year=2008|last1=Amor-Guéret|first1=M|last2=Dubois-d'Enghien|first2=C|last3=Laugé|first3=A|last4=Onclercq-Delic|first4=R|last5=Barakat|first5=A|last6=Chadli|first6=E|last7=Bousfiha|first7=AA|last8=Benjelloun|first8=M|last9=Flori|first9=E | display-authors=8 |title=Three new BLM gene mutations associated with Bloom syndrome|volume=12|issue=2|pages=257–61|doi=10.1089/gte.2007.0119|journal=Genetic Testing}}</ref> 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 [[Sister chromatid exchange|homologous recombination]]. Defective homologous recombination can cause mutation and genetic instability.<ref name=Wang>{{cite journal |vauthors=Wang Y, Li S, Smith K, Waldman BC, Waldman AS |title=Intrachromosomal recombination between highly diverged DNA sequences is enabled in human cells deficient in Bloom helicase |journal=DNA Repair (Amst.) |volume=41 |pages=73–84 |year=2016 |pmid=27100209 |doi=10.1016/j.dnarep.2016.03.005 |doi-access=free }}</ref> 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,<ref>{{cite journal|pmid=18923082|year=2008|last1=Xu|first1=D|last2=Guo|first2=R|last3=Sobeck|first3=A|last4=Bachrati|first4=CZ|last5=Yang|first5=J|last6=Enomoto|first6=T|last7=Brown|first7=GW|last8=Hoatlin|first8=ME|last9=Hickson|first9=ID | display-authors=8 |title=RMI, a new OB-fold complex essential for Bloom syndrome protein to maintain genome stability|volume=22|issue=20|pages=2843–55|doi=10.1101/gad.1708608|pmc=2569887|journal=Genes & Development}}</ref><ref>{{cite journal|pmid=18923083|year=2008|last1=Singh|first1=TR|last2=Ali|first2=AM|last3=Busygina|first3=V|last4=Raynard|first4=S|last5=Fan|first5=Q|last6=Du|first6=CH|last7=Andreassen|first7=PR|last8=Sung|first8=P|last9=Meetei|first9=AR | display-authors=8 |title=BLAP18/RMI2, a novel OB-fold-containing protein, is an essential component of the Bloom helicase-double Holliday junction dissolvasome|volume=22|issue=20|pages=2856–68|doi=10.1101/gad.1725108|pmc=2569884|journal=Genes & Development}}</ref><ref>{{cite journal|pmid=18923071|year=2008|last1=Liu|first1=Y|last2=West|first2=SC|title=More complexity to the Bloom's syndrome complex|volume=22|issue=20|pages=2737–42|doi=10.1101/gad.1732808|pmc=2751278|journal=Genes & Development}}</ref> and suppresses illegitimate recombination events between sequences that are divergent from strict homology, thus maintaining genome stability.<ref name=Wang /> Individuals with BS have a [[Mutation#By effect on function|loss-of-function mutation]], 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).<ref>{{cite journal|pmid=2911598|year=1989|last1=Langlois|first1=RG|last2=Bigbee|first2=WL|last3=Jensen|first3=RH|last4=German|first4=J|title=Evidence for increased in vivo mutation and somatic recombination in Bloom's syndrome|volume=86|issue=2|pages=670–4|pmc=286535|journal=Proceedings of the National Academy of Sciences of the United States of America|bibcode=1989PNAS...86..670L|doi=10.1073/pnas.86.2.670|doi-access=free}}</ref><ref>{{cite journal|pmid=8063614|pmc=5919530|year=1994|last1=Kusunoki|first1=Y|last2=Hayashi|first2=T|last3=Hirai|first3=Y|last4=Kushiro|first4=J|last5=Tatsumi|first5=K|last6=Kurihara|first6=T|last7=Zghal|first7=M|last8=Kamoun|first8=MR|last9=Takebe|first9=H | display-authors=8 |title=Increased rate of spontaneous mitotic recombination in T lymphocytes from a Bloom's syndrome patient using a flow-cytometric assay at HLA-A locus|volume=85|issue=6|pages=610–8|journal=Japanese Journal of Cancer Research|doi=10.1111/j.1349-7006.1994.tb02403.x}}</ref>
===NER protein-associated PS===
Line 54:
''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).{{citation needed|date=November 2020}}
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,<ref>{{cite journal|pmid=19809470|year=2009|last1=Cleaver|first1=JE|last2=Lam|first2=ET|last3=Revet|first3=I|title=Disorders of nucleotide excision repair: The genetic and molecular basis of heterogeneity|volume=10|issue=11|pages=756–68|doi=10.1038/nrg2663|journal=Nature Reviews Genetics|s2cid=2211460}}</ref> often in combination with each other, as with combined xeroderma pigmentosa-Cockayne syndrome (XP-CS).<ref>{{cite journal|pmid=14726016|year=2003|last1=Lehmann|first1=AR|title=DNA repair-deficient diseases, xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy|volume=85|issue=11|pages=1101–11|journal=Biochimie|doi=10.1016/j.biochi.2003.09.010}}</ref> 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.<ref name="Navarro" /> All these disorders can be caused by mutations in a single gene, XPD,<ref>{{cite journal|doi=10.1086/321295|pmid=11443545|title=Cerebro-Oculo-Facio-Skeletal Syndrome with a Nucleotide Excision–Repair Defect and a Mutated XPD Gene, with Prenatal Diagnosis in a Triplet Pregnancy|year=2001|last1=Graham|first1=John M.|last2=Anyane-Yeboa|first2=Kwame|last3=Raams|first3=Anja|last4=Appeldoorn|first4=Esther|last5=Kleijer|first5=Wim J.|last6=Garritsen|first6=Victor H.|last7=Busch|first7=David|last8=Edersheim|first8=Terri G.|last9=Jaspers|first9=Nicolaas G.J. | display-authors=8 |journal=The American Journal of Human Genetics|volume=69|issue=2|pages=291–300|pmc=1235303}}</ref><ref>{{cite journal|pmid=10447254|year=1999|last1=Cleaver|first1=JE|last2=Thompson|first2=LH|last3=Richardson|first3=AS|last4=States|first4=JC|title=A summary of mutations in the UV-sensitive disorders: Xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy|volume=14|issue=1|pages=9–22|doi=10.1002/(SICI)1098-1004(1999)14:1<9::AID-HUMU2>3.0.CO;2-6|journal=Human Mutation|s2cid=24148589 |doi-access=free}}</ref><ref>{{cite journal|doi=10.1093/hmg/10.22.2539|title=Two individuals with features of both xeroderma pigmentosum and trichothiodystrophy highlight the complexity of the clinical outcomes of mutations in the XPD gene|year=2001|last1=Broughton|first1=B. C.|journal=Human Molecular Genetics|volume=10|issue=22|pages=2539–47|pmid=11709541|last2=Berneburg|first2=M|last3=Fawcett|first3=H|last4=Taylor|first4=EM|last5=Arlett|first5=CF|last6=Nardo|first6=T|last7=Stefanini|first7=M|last8=Menefee|first8=E|last9=Price|first9=VH | display-authors=8 |doi-access=free}}</ref><ref>{{cite journal|pmid=11156600|year=2001|last1=Lehmann|first1=AR|title=The xeroderma pigmentosum group D (XPD) gene: One gene, two functions, three diseases|volume=15|issue=1|pages=15–23|journal=Genes & Development|doi=10.1101/gad.859501|doi-access=free}}</ref> or in other genes.<ref>{{cite journal|doi=10.1016/j.mrfmmm.2005.04.004|title=Transcription-coupled repair and premature ageing|year=2005|last1=Andressoo|first1=J.O.|last2=Hoeijmakers|first2=J.H.J.|journal=Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis|volume=577|pages=179–94|pmid=16009385|issue=1–2|bibcode=2005MRFMM.577..179A }}</ref>
====Cockayne syndrome====
{{Main|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.<ref name="Pmid_f">{{cite journal|pmid=18329345|year=2008|last1=Kleijer|first1=WJ|last2=Laugel|first2=V|last3=Berneburg|first3=M|last4=Nardo|first4=T|last5=Fawcett|first5=H|last6=Gratchev|first6=A|last7=Jaspers|first7=NG|last8=Sarasin|first8=A|last9=Stefanini|first9=M | display-authors=8 |title=Incidence of DNA repair deficiency disorders in western Europe: Xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy|volume=7|issue=5|pages=744–50|doi=10.1016/j.dnarep.2008.01.014|journal=DNA Repair}}</ref>
<ref name="ghr_b">{{cite web|title=Cockayne syndrome|url=http://ghr.nlm.nih.gov/condition/cockayne-syndrome|work=Genetics Home Reference|publisher=NIH|access-date=19 March 2013}}</ref> The mean age of death is ~12 years,<ref>{{cite journal|pmid=1308368|year=1992|last1=Nance|first1=MA|last2=Berry|first2=SA|title=Cockayne syndrome: Review of 140 cases|volume=42|issue=1|pages=68–84|doi=10.1002/ajmg.1320420115|journal=American Journal of Medical Genetics}}</ref> 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.<ref name="Navarro" /> Type III has the mildest symptoms, first presents later in childhood,<ref name="ghr_b" /> and the cause of death is often severe nervous system deterioration and respiratory tract infections.<ref>{{cite journal|pmid=16009385|year=2005|last1=Andressoo|first1=JO|last2=Hoeijmakers|first2=JH|title=Transcription-coupled repair and premature ageing|volume=577|issue=1–2|pages=179–94|doi=10.1016/j.mrfmmm.2005.04.004|journal=Mutation Research|bibcode=2005MRFMM.577..179A }}</ref>
Individuals with CS appear prematurely aged and exhibit severe growth retardation leading to short stature. They have a [[microcephaly|small head]] (less than the -3 standard deviation),<ref>{{cite journal|pmid=16428367|year=2006|last1=Pasquier|first1=L|last2=Laugel|first2=V|last3=Lazaro|first3=L|last4=Dollfus|first4=H|last5=Journel|first5=H|last6=Edery|first6=P|last7=Goldenberg|first7=A|last8=Martin|first8=D|last9=Heron|first9=D | display-authors=8 |title=Wide clinical variability among 13 new Cockayne syndrome cases confirmed by biochemical assays|volume=91|issue=2|pages=178–82|doi=10.1136/adc.2005.080473|pmc=2082700|journal=Archives of Disease in Childhood}}</ref> 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 [[dental caries|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.{{citation needed|date=November 2020}}
Line 68:
[[File:Xeroderma pigmentosum 02.jpg|thumb|An eight-year-old girl from [[Guatemala]] with xeroderma pigmentosum. Children with XP are often colloquially referred to as Children of the Night.<ref>{{cite book|title=Medical Biochemistry at a Glance |url=https://books.google.com/books?id=4d7wHD428MwC&q=Xeroderma+pigmentosa+Children+of+the+Night&pg=PT313|access-date=17 June 2011|date=28 November 2011|publisher=[[John Wiley & Sons]]|isbn=978-1118292402|quote=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 night."}}</ref>]]
{{Main|Xeroderma pigmentosum}}
''Xeroderma pigmentosum'' (XP) is a rare autosomal recessive disorder, affecting about one per million in the United States and [[wikt:autochthonic|autochthonic]] Europe populations<ref name="Pmid_f" /> but with a higher incidence rate in Japan, North Africa, and the Middle East.<ref>{{cite web|title=Xeroderma pigmentosum|url=http://ghr.nlm.nih.gov/condition/xeroderma-pigmentosum|work=Genetics Home Reference|publisher=NIH|access-date=20 March 2013}}</ref> There have been 830 published cases from 1874 to 1982.<ref name="Pmid_g">{{cite journal|pmid=3545087|year=1987|last1=Kraemer|first1=KH|last2=Lee|first2=MM|last3=Scotto|first3=J|title=Xeroderma pigmentosum. Cutaneous, ocular, and neurologic abnormalities in 830 published cases|volume=123|issue=2|pages=241–50|journal=Archives of Dermatology|doi=10.1001/archderm.123.2.241}}</ref> The disorder presents at infancy or early childhood.{{cn|date=November 2024}}
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,<ref name="Pmid_g" /> and causes [[sunburn]], [[freckle|freckling]] of skin, dry skin and pigmentation after exposure.<ref>{{cite book|pmid=19181106
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]]'', ''[[XPB|ERCC3]]'', ''[[ERCC4]]'', ''[[ERCC5]]'', ''[[XPA]]'', ''[[XPC (gene)|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 ''[[DNA polymerase eta|POLH]]'' gene, which unlike the rest does not code for components of the NER pathway but produces a DNA polymerase that allows accurate [[DNA repair#Translesion synthesis|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.{{citation needed|date=November 2020}}
Line 76:
====Trichothiodystrophy====
{{Main|Trichothiodystrophy}}
''Trichothiodystrophy'' (TTD) is a rare autosomal recessive disease whose symptoms span across multiple systems<ref name="Pmid_h">{{cite journal|pmid=18603627|year=2008|last1=Faghri|first1=S|last2=Tamura|first2=D|last3=Kraemer|first3=KH|last4=Digiovanna|first4=JJ|title=Trichothiodystrophy: A systematic review of 112 published cases characterises a wide spectrum of clinical manifestations|volume=45|issue=10|pages=609–21|doi=10.1136/jmg.2008.058743|pmc=3459585|journal=Journal of Medical Genetics}}</ref> and can vary greatly in severity. The incidence rate of TTD is estimated to be 1.2 per million in Western Europe.<ref name="Pmid_f" /> Milder cases cause sparse and brittle hair, which is due to the lack of [[sulfur]],<ref name="Pmid_i">{{cite journal|pmid=11369901|year=2001|last1=Itin|first1=PH|last2=Sarasin|first2=A|last3=Pittelkow|first3=MR|title=Trichothiodystrophy: Update on the sulfur-deficient brittle hair syndromes|volume=44|issue=6|pages=891–920; quiz 921–4|doi=10.1067/mjd.2001.114294|journal=Journal of the American Academy of Dermatology|s2cid=26006150
TTD also affects the mother of the affected child during pregnancy, when she may experience [[Pre-eclampsia|pregnancy-induced high blood pressure]] and develop [[HELLP syndrome]]. The baby has a high risk of being born [[Preterm birth|prematurely]] and will have a low [[birth weight]]. After birth, the child's normal growth is retarded, resulting in a short stature.
Line 87:
==Defects in Lamin A/C==
[[File:A range of putative disease-causing mechanisms for the case of HGPS.jpg|thumb|500px|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, nuclear blebbing and misregulation of gene expression.]]
{{further|topic=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.<ref name="Doiscience_a">{{cite journal|doi=10.1126/science.1084125|title=Lamin a Truncation in Hutchinson–Gilford Progeria|year=2003|last1=De Sandre-Giovannoli|first1=A.|journal=Science|volume=300|issue=5628|pages=2055|pmid=12702809|last2=Bernard|first2=R|last3=Cau|first3=P|last4=Navarro|first4=C|last5=Amiel|first5=J|last6=Boccaccio|first6=I|last7=Lyonnet|first7=S|last8=Stewart|first8=CL|last9=Munnich|first9=A |s2cid=33927803| display-authors=8 |doi-access=free}}</ref><ref name="Pmid_d">{{cite journal|pmid=12714972|year=2003|last1=Eriksson|first1=M|last2=Brown|first2=WT|last3=Gordon|first3=LB|last4=Glynn|first4=MW|last5=Singer|first5=J|last6=Scott|first6=L|last7=Erdos|first7=MR|last8=Robbins|first8=CM|last9=Moses|first9=TY | display-authors=8 |title=Recurrent de novo point mutations in lamin a cause Hutchinson–Gilford progeria syndrome|volume=423|issue=6937|pages=293–8|doi=10.1038/nature01629|journal=Nature|pmc=10540076 |bibcode = 2003Natur.423..293E |hdl=2027.42/62684|s2cid=4420150|hdl-access=free}}</ref> Lamin A is a major nuclear component that determines the shape and integrity of the [[Cell nucleus|nucleus]], by acting as a [[scaffold protein]] that forms a filamentous meshwork underlying the inner [[nuclear envelope]], the membrane that surrounds the nucleus.{{cn|date=November 2024}}
===Hutchinson–Gilford progeria syndrome===
[[File:Hutchinson-Gilford Progeria Syndrome.png|thumb|Girl with HGPS (''left''). This condition is caused by dysfunctional [[lamin]] which is unable to maintain the nuclear shape (''normal at top, abnormal at bottom'').]]
{{main|Progeria}}
''Hutchinson–Gilford progeria syndrome'' is an extremely rare developmental [[autosomal dominant]] condition, characterized by premature and accelerated aging (~7 times the normal rate)<ref>{{cite web|last=Collins|first=Francis|title=We need better drugs -- now|url=http://www.ted.com/talks/francis_collins_we_need_better_drugs_now.html|publisher=TED.com|access-date=22 March 2013}}</ref> 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.<ref name="ghr">{{cite web|title=Hutchinson–Gilford progeria syndrome|url=http://ghr.nlm.nih.gov/condition/hutchinson-gilford-progeria-syndrome|work=Genetics Home Reference|access-date=16 March 2013}}</ref> 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).<ref>{{cite journal|pmid=16838330|year=2006|last1=Hennekam|first1=RC|title=Hutchinson–Gilford progeria syndrome: Review of the phenotype|volume=140|issue=23|pages=2603–24|doi=10.1002/ajmg.a.31346|journal=American Journal of Medical Genetics Part A|citeseerx=10.1.1.333.3746|s2cid=15692098}}</ref> There is currently no treatment available.<ref>{{cite web|title=Progeria|url=https://www.nlm.nih.gov/medlineplus/ency/article/001657.htm|work=MedlinePlus|access-date=16 March 2013}}</ref>
Line 99:
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]], [[macrocephaly|large head]], 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.<ref>{{cite journal|pmid=10990576|year=2000|last1=Jansen|first1=T|last2=Romiti|first2=R|title=Progeria infantum (Hutchinson–Gilford syndrome) associated with scleroderma-like lesions and acro-osteolysis: A case report and brief review of the literature|volume=17|issue=4|pages=282–5|journal=Pediatric Dermatology|doi=10.1046/j.1525-1470.2000.01775.x|s2cid=20739447}}</ref> However, the level of cognitive function, motor skills, and risk of developing cancer is not affected significantly.<ref name="ghr" />
HGPS is caused by sporadic mutations (not inherited from parent) in the ''LMNA'' gene, which encodes for lamin A.<ref name="Doiscience_a" /><ref name="Pmid_d" /> Specifically, most HGPS are caused by a dominant, ''de novo'', point mutation p.G608G (GGC > GGT).<ref name="Pmid_d" /> 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.<ref name="Pmid_d" /> This results in a truncated lamin A precursor (a.k.a. [[progerin]] or LaminAΔ50).<ref>{{cite journal|pmid=12702809|year=2003|last1=De Sandre-Giovannoli|first1=A|last2=Bernard|first2=R|last3=Cau|first3=P|last4=Navarro|first4=C|last5=Amiel|first5=J|last6=Boccaccio|first6=I|last7=Lyonnet|first7=S|last8=Stewart|first8=CL|last9=Munnich|first9=A | display-authors=8 |title=Lamin a truncation in Hutchinson–Gilford progeria|volume=300|issue=5628|pages=2055|doi=10.1126/science.1084125|journal=Science|s2cid=33927803|doi-access=free}}</ref>
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. Normally, lamin A is recognized by ZMPSTE24 (FACE1, a [[metalloprotease]]) and cleaved, removing the farnesol and a few other amino acids.{{cn|date=November 2024}}
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,<ref name="DoijbcR">{{cite journal|doi=10.1074/jbc.R600033200|title=Prelamin a Farnesylation and Progeroid Syndromes|year=2006|last1=Young|first1=S. G.|last2=Meta|first2=M.|last3=Yang|first3=S. H.|last4=Fong|first4=L. G.|journal=Journal of Biological Chemistry|volume=281|issue=52|pages=39741–5|pmid=17090536|s2cid=27614400|doi-access=free}}</ref> 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.<ref name="Pmid_e">{{cite journal|pmid=15184648|year=2004|last1=Goldman|first1=RD|last2=Shumaker|first2=DK|last3=Erdos|first3=MR|last4=Eriksson|first4=M|last5=Goldman|first5=AE|last6=Gordon|first6=LB|last7=Gruenbaum|first7=Y|last8=Khuon|first8=S|last9=Mendez|first9=M | display-authors=8 |title=Accumulation of mutant lamin a causes progressive changes in nuclear architecture in Hutchinson–Gilford progeria syndrome|volume=101|issue=24|pages=8963–8|doi=10.1073/pnas.0402943101|pmc=428455|journal=Proceedings of the National Academy of Sciences of the United States of America|bibcode = 2004PNAS..101.8963G |doi-access=free}}</ref> 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.<ref name="DoijbcR" /><ref>{{cite journal|doi=10.1073/pnas.0505767102|title=Blocking protein farnesyltransferase improves nuclear shape in fibroblasts from humans with progeroid syndromes|year=2005|last1=Toth|first1=J. I.|journal=Proceedings of the National Academy of Sciences|volume=102|issue=36|pages=12873–12878|bibcode = 2005PNAS..10212873T|pmid=16129834|pmc=1193538|doi-access=free}}</ref>
HGPS is considered autosomal dominant, which means that 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.<ref name="Pmid_e" /> At least 16 Other mutations in lamin A/C,<ref>{{cite journal|pmid=16816143|year=2006|last1=Broers|first1=JL|last2=Ramaekers|first2=FC|last3=Bonne|first3=G|last4=Yaou|first4=RB|last5=Hutchison|first5=CJ|title=Nuclear lamins: Laminopathies and their role in premature ageing|volume=86|issue=3|pages=967–1008|doi=10.1152/physrev.00047.2005|journal=Physiological Reviews|s2cid=5609417
Repair of DNA double-strand breaks can occur by one of two processes, [[non-homologous end joining]] (NHEJ) or [[homologous recombination]] (HR). A-type [[lamin]]s promote genetic stability by maintaining levels of proteins which have key roles in NHEJ and HR.<ref name="pmid21701264">{{cite journal |vauthors=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 |title=A dual role for A-type lamins in DNA double-strand break repair |journal=Cell Cycle |volume=10 |issue=15 |pages=2549–60 |year=2011 |pmid=21701264 |pmc=3180193 |doi=10.4161/cc.10.15.16531 }}</ref> Mouse cells deficient for maturation of prelamin A show increased DNA damage and chromosome aberrations and have increased sensitivity to DNA damaging agents.<ref name="pmid15980864">{{cite journal |vauthors=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 |title=Genomic instability in laminopathy-based premature aging |journal=Nat. Med. |volume=11 |issue=7 |pages=780–5 |year=2005 |pmid=15980864 |doi=10.1038/nm1266 |s2cid=11798376 }}</ref> In HGPS, the inability to adequately repair DNA damages due to defective A-type lamin may cause aspects of premature aging (see [[DNA damage theory of aging]]).{{cn|date=November 2024}}
===Restrictive dermopathy===
Line 131:
====Rothmund–Thomson syndrome====
Classified as an [[autosomal recessive]] defect, but the [[pathology]] has still yet to be well researched.{{cn|date=November 2024}}
==Cancer==
Line 137:
==Animal models==
Within [[animal models]] for progeroid syndromes, early observations have detected abnormalities within overall mitochondrial function,<ref>{{Cite journal |last1=Karikkineth |first1=Ajoy C. |last2=Scheibye-Knudsen |first2=Morten |last3=Fivenson |first3=Elayne |last4=Croteau |first4=Deborah L. |last5=Bohr |first5=Vilhelm A. |date=January 2017 |title=Cockayne syndrome: Clinical features, model systems and pathways |journal=Ageing Research Reviews |volume=33 |pages=3–17 |doi=10.1016/j.arr.2016.08.002 |issn=1872-9649 |pmc=5195851 |pmid=27507608}}</ref><ref>{{Cite journal |last1=Okur |first1=Mustafa N. |last2=Fang |first2=Evandro F. |last3=Fivenson |first3=Elayne M. |last4=Tiwari |first4=Vinod |last5=Croteau |first5=Deborah L. |last6=Bohr |first6=Vilhelm A. |date=December 2020 |title=Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD+ signaling |journal=Aging Cell |volume=19 |issue=12 |pages=e13268 |doi=10.1111/acel.13268 |issn=1474-9726 |pmc=7744955 |pmid=33166073}}</ref> [[signal transduction]] between [[membrane receptors]],<ref>{{Cite journal |last1=Evangelisti |first1=Camilla |last2=Cenni |first2=Vittoria |last3=Lattanzi |first3=Giovanna |date=November 2016 |title=Potential therapeutic effects of the MTOR inhibitors for preventing ageing and progeria-related disorders |journal=British Journal of Clinical Pharmacology |volume=82 |issue=5 |pages=1229–1244 |doi=10.1111/bcp.12928 |issn=1365-2125 |pmc=5061804 |pmid=26952863}}</ref> and [[Regulation of gene expression|nuclear regulatory proteins]].
==Other==
Line 150:
Jesper Sørensen is widely recognized in Denmark as the only child in [[Denmark]] and [[Scandinavia]] with progeria (as of 2008).<ref>{{cite web|title=Drengen i den gamle krop|url=http://programmer.tv2.dk/article.php/id-18266721:drengen-i-den-gamle-krop.html|access-date=22 March 2013|date=2008-11-20}}</ref> His fame came about after a documentary in 2008 on [[TV 2 (Denmark)|TV 2]] about Sørensen.<ref>{{cite web|title=Seerne er vilde med Jesper|url=http://programmer.tv2.dk/articlenew.php/id-50757961:seerne-er-vilde-med-jesper.html|access-date=22 March 2013|date=2012-05-30}}</ref>
===Literature and Theatre===
[[F. Scott Fitzgerald]]'s 1922 short story [[The Curious Case of Benjamin Button (short story)|''The Curious Case of Benjamin Button'']] 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.<ref>{{cite journal|doi=10.1177/0022034509348765|title=Hutchinson–Gilford Progeria Syndrome: Its Presentation in F. Scott Fitzgerald's Short Story 'The Curious Case of Benjamin Button' and Its Oral Manifestations|year=2009|last1=Maloney|first1=W. J.|journal=Journal of Dental Research|volume=88|issue=10|pages=873–6|pmid=19783794|s2cid=40615631}}</ref> The description of the fictitious Smallweed family in the [[Charles Dickens]]' ''[[Bleak House]]'' suggests the characters had progeria.<ref>{{cite journal|doi=10.1212/WNL.0b013e3181ec7f6c|title=Reflections for August: Description of a Family with Progeria by Charles Dickens|year=2010|last1=Singh|first1=V.|journal=Neurology|volume=75|issue=6|pages=571|pmid=20697111|s2cid=219232325|doi-access=free}}</ref> Christopher Snow, the main character in [[Dean Koontz]]'s ''[[Moonlight Bay Trilogy]]'', has xeroderma pigmentosum, as does Luke from the 2002 novel ''Going Out'' by [[Scarlett Thomas]]. In the visual novel ''[[Chaos;Head]]'', the character Shogun eventually dies of a progeroid syndrome, and in its sequel ''[[Chaos;Child]]'', more characters get this same fictional progeroid syndrome, which by then is called Chaos Child Syndrome. In ''[[Kimberly Akimbo]]'', a 2000 play by [[David Lindsay-Abaire]], and its [[Tony Award for Best Musical]]-winning [[Kimberly Akimbo (musical)|adaptation of the same name]], the main character, Kimberly Levaco, has an unnamed progeria-like condition.{{citation needed|date=November 2020}}
===Film===
''[[Paa (film)|Paa]]'', a 2009 Indian comedy-drama film, features a protagonist, Auro ([[Amitabh Bachchan]]), who has progeria. ''[[Jack (1996 film)|Jack]]'' is a 1996 American comedy-drama film, in which the titular character (portrayed by [[Robin Williams]]) has Werner syndrome. ''[[Midnight Sun (2006 film)|Taiyou no Uta]]'', a 2006 Japanese film, features Kaoru Amane (portrayed by [[Yui (singer)|Yui]]), a 16-year-old girl has xeroderma pigmentosum.{{cn|date=November 2024}}
==See also==
Line 185:
[[Category:Rare syndromes]]
[[Category:Aging-associated diseases]]
[[Category:Genetic
[[Category:Senescence]]
| |||