ATRX

{{Short description|Protein-coding gene in humans}} {{Infobox_gene}} '''Transcriptional regulator ATRX''' also known as '''ATP-dependent helicase ATRX''', '''X-linked helicase II''', or '''X-linked nuclear protein''' (XNP) is a protein that in humans is encoded by the ''ATRX'' gene.<ref name="Stayton_1994"/><ref name="Gibbons_1992"/><ref name="entrez"/>

== Function ==

Transcriptional regulator ATRX contains an ATPase / helicase domain, and thus it belongs to the SWI/SNF family of chromatin remodeling proteins. ATRX is required for deposition of the histone variant H3.3 at telomeres and other genomic repeats.<ref name="Wong_2010"/> These interactions are important for maintaining silencing at these sites.<ref name="Voon_2015"/><ref name="Elsässer_2015"/><ref name="Udugama_2015"/>

In addition, ATRX undergoes cell cycle-dependent phosphorylation, which regulates its nuclear matrix and chromatin association, and suggests its involvement in the gene regulation at interphase and chromosomal segregation in mitosis.<ref name="entrez" />

== Clinical significance ==

=== Inherited mutations ===

Inherited mutations of the ATRX gene are associated with an X-linked intellectual disability (XLMR) syndrome most often accompanied by alpha-thalassemia (ATR-X) syndrome. These mutations have been shown to cause diverse changes in the pattern of DNA methylation, which may provide a link between chromatin remodeling, DNA methylation, and gene expression in developmental processes. Multiple alternatively spliced transcript variants encoding distinct isoforms have been reported. Female carriers may demonstrate skewed X chromosome inactivation.<ref name="entrez" />

=== Somatic mutations ===

Acquired mutations in ATRX have been reported in a number of human cancers including pancreatic neuroendocrine tumours,<ref name="Heaphy_2011"/> gliomas,<ref name="Schwartzentruber_2012"/><ref name="Kannan_2012"/> osteosarcomas,<ref name="Chen_2014"/> soft-tissue sarcomas,<ref name="TCGA_2017"/> and malignant pheochromocytomas.<ref>{{cite journal|last1=Comino-Méndez|first1=I|title=ATRX driver mutation in a composite malignant pheochromocytoma|journal=Cancer Genetics|date=June 2016|volume=209 |issue=6|pages=272–7|doi=10.1016/j.cancergen.2016.04.058|pmid=27209355|hdl=10641/3656|hdl-access=free}}</ref> There is a strong correlation between ATRX mutations and an Alternative Lengthening of Telomeres (ALT) phenotype in cancers.<ref name="Heaphy_2011" />

== Interactions ==

ATRX forms a complex with DAXX which is an histone H3.3 chaperone.<ref name="Lewis_2010"/>

ATRX has been also shown to interact with EZH2.<ref name="Cardoso_1998"/>

== See also == * Alpha-thalassemia mental retardation syndrome

== References == {{reflist|33em|refs =

<ref name = "TCGA_2017">{{cite journal | vauthors = ((Cancer Genome Atlas Research Network)) | title = Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas | journal = Cell | volume = 171 | issue = 4 | pages = 950–965 | date = November 2017 | pmid = 29100075 | doi = 10.1016/j.cell.2017.10.014 | doi-access = free | pmc = 5693358 }}</ref>

<ref name = "Cardoso_1998">{{cite journal | vauthors = Cardoso C, Timsit S, Villard L, Khrestchatisky M, Fontès M, Colleaux L | title = Specific interaction between the XNP/ATR-X gene product and the SET domain of the human EZH2 protein | journal = Human Molecular Genetics | volume = 7 | issue = 4 | pages = 679–84 | date = April 1998 | pmid = 9499421 | doi = 10.1093/hmg/7.4.679 | doi-access = free }}</ref>

<ref name = "Chen_2014">{{cite journal | vauthors = Chen X, Bahrami A, Pappo A, Easton J, Dalton J, Hedlund E, Ellison D, Shurtleff S, Wu G, Wei L, Parker M, Rusch M, Nagahawatte P, Wu J, Mao S, Boggs K, Mulder H, Yergeau D, Lu C, Ding L, Edmonson M, Qu C, Wang J, Li Y, Navid F, Daw NC, Mardis ER, Wilson RK, Downing JR, Zhang J, Dyer MA | display-authors = 6 | title = Recurrent somatic structural variations contribute to tumorigenesis in pediatric osteosarcoma | journal = Cell Reports | volume = 7 | issue = 1 | pages = 104–12 | date = April 2014 | pmid = 24703847 | pmc = 4096827 | doi = 10.1016/j.celrep.2014.03.003 }}</ref>

<ref name = "Elsässer_2015">{{cite journal | vauthors = Elsässer SJ, Noh KM, Diaz N, Allis CD, Banaszynski LA | title = Histone H3.3 is required for endogenous retroviral element silencing in embryonic stem cells | journal = Nature | volume = 522 | issue = 7555 | pages = 240–4 | date = June 2015 | pmid = 25938714 | pmc = 4509593 | doi = 10.1038/nature14345 | bibcode = 2015Natur.522..240E }}</ref>

<ref name = "entrez">{{cite web | title = Entrez Gene: ATRX alpha thalassemia/mental retardation syndrome X-linked (RAD54 homolog, S. cerevisiae)| url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=546}}</ref>

<ref name = "Gibbons_1992">{{cite journal | vauthors = Gibbons RJ, Suthers GK, Wilkie AO, Buckle VJ, Higgs DR | title = X-linked alpha-thalassemia/mental retardation (ATR-X) syndrome: localization to Xq12-q21.31 by X inactivation and linkage analysis | journal = American Journal of Human Genetics | volume = 51 | issue = 5 | pages = 1136–49 | date = November 1992 | pmid = 1415255 | pmc = 1682840 }}</ref>

<ref name = "Heaphy_2011">{{cite journal | vauthors = Heaphy CM, de Wilde RF, Jiao Y, Klein AP, Edil BH, Shi C, Bettegowda C, Rodriguez FJ, Eberhart CG, Hebbar S, Offerhaus GJ, McLendon R, Rasheed BA, He Y, Yan H, Bigner DD, Oba-Shinjo SM, Marie SK, Riggins GJ, Kinzler KW, Vogelstein B, Hruban RH, Maitra A, Papadopoulos N, Meeker AK | display-authors = 6 | title = Altered telomeres in tumors with ATRX and DAXX mutations | journal = Science | volume = 333 | issue = 6041 | pages = 425 | date = July 2011 | pmid = 21719641 | pmc = 3174141 | doi = 10.1126/science.1207313 | bibcode = 2011Sci...333..425H }}</ref>

<ref name = "Kannan_2012">{{cite journal | vauthors = Kannan K, Inagaki A, Silber J, Gorovets D, Zhang J, Kastenhuber ER, Heguy A, Petrini JH, Chan TA, Huse JT | display-authors = 6 | title = Whole-exome sequencing identifies ATRX mutation as a key molecular determinant in lower-grade glioma | journal = Oncotarget | volume = 3 | issue = 10 | pages = 1194–203 | date = October 2012 | pmid = 23104868 | pmc = 3717947 | doi = 10.18632/oncotarget.689 }}</ref>

<ref name = "Lewis_2010">{{cite journal | vauthors = Lewis PW, Elsaesser SJ, Noh KM, Stadler SC, Allis CD | title = Daxx is an H3.3-specific histone chaperone and cooperates with ATRX in replication-independent chromatin assembly at telomeres | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 32 | pages = 14075–80 | date = August 2010 | pmid = 20651253 | pmc = 2922592 | doi = 10.1073/pnas.1008850107 | bibcode = 2010PNAS..10714075L | doi-access = free }}</ref>

<ref name = "Schwartzentruber_2012">{{cite journal | vauthors = Schwartzentruber J, Korshunov A, Liu XY, Jones DT, Pfaff E, Jacob K, Sturm D, Fontebasso AM, Quang DA, Tönjes M, Hovestadt V, Albrecht S, Kool M, Nantel A, Konermann C, Lindroth A, Jäger N, Rausch T, Ryzhova M, Korbel JO, Hielscher T, Hauser P, Garami M, Klekner A, Bognar L, Ebinger M, Schuhmann MU, Scheurlen W, Pekrun A, Frühwald MC, Roggendorf W, Kramm C, Dürken M, Atkinson J, Lepage P, Montpetit A, Zakrzewska M, Zakrzewski K, Liberski PP, Dong Z, Siegel P, Kulozik AE, Zapatka M, Guha A, Malkin D, Felsberg J, Reifenberger G, von Deimling A, Ichimura K, Collins VP, Witt H, Milde T, Witt O, Zhang C, Castelo-Branco P, Lichter P, Faury D, Tabori U, Plass C, Majewski J, Pfister SM, Jabado N | display-authors = 6 | title = Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma | journal = Nature | volume = 482 | issue = 7384 | pages = 226–31 | date = January 2012 | pmid = 22286061 | doi = 10.1038/nature10833 | bibcode = 2012Natur.482..226S | s2cid = 4312169 }}</ref>

<ref name = "Stayton_1994">{{cite journal | vauthors = Stayton CL, Dabovic B, Gulisano M, Gecz J, Broccoli V, Giovanazzi S, Bossolasco M, Monaco L, Rastan S, Boncinelli E | display-authors = 6 | title = Cloning and characterization of a new human Xq13 gene, encoding a putative helicase | journal = Human Molecular Genetics | volume = 3 | issue = 11 | pages = 1957–64 | date = November 1994 | pmid = 7874112 | doi = 10.1093/hmg/3.11.1957 }}</ref>

<ref name = "Udugama_2015">{{cite journal | vauthors = Udugama M, M Chang FT, Chan FL, Tang MC, Pickett HA, R McGhie JD, Mayne L, Collas P, Mann JR, Wong LH | display-authors = 6 | title = Histone variant H3.3 provides the heterochromatic H3 lysine 9 tri-methylation mark at telomeres | journal = Nucleic Acids Research | volume = 43 | issue = 21 | pages = 10227–37 | date = December 2015 | pmid = 26304540 | pmc = 4666390 | doi = 10.1093/nar/gkv847 }}</ref>

<ref name = "Voon_2015">{{cite journal | vauthors = Voon HP, Hughes JR, Rode C, De La Rosa-Velázquez IA, Jenuwein T, Feil R, Higgs DR, Gibbons RJ | display-authors = 6 | title = ATRX Plays a Key Role in Maintaining Silencing at Interstitial Heterochromatic Loci and Imprinted Genes | journal = Cell Reports | volume = 11 | issue = 3 | pages = 405–18 | date = April 2015 | pmid = 25865896 | pmc = 4410944 | doi = 10.1016/j.celrep.2015.03.036 }}</ref>

<ref name = "Wong_2010">{{cite journal | vauthors = Wong LH, McGhie JD, Sim M, Anderson MA, Ahn S, Hannan RD, George AJ, Morgan KA, Mann JR, Choo KH | display-authors = 6 | title = ATRX interacts with H3.3 in maintaining telomere structural integrity in pluripotent embryonic stem cells | journal = Genome Research | volume = 20 | issue = 3 | pages = 351–60 | date = March 2010 | pmid = 20110566 | pmc = 2840985 | doi = 10.1101/gr.101477.109 }}</ref>

}}

== Further reading == {{refbegin|33em}} * {{cite journal | vauthors = Mulley JC, Kerr B, Stevenson R, Lubs H | title = Nomenclature guidelines for X-linked mental retardation | journal = American Journal of Medical Genetics | volume = 43 | issue = 1–2 | pages = 383–91 | year = 1992 | pmid = 1605216 | doi = 10.1002/ajmg.1320430159 }} * {{cite journal | vauthors = Tang P, Park DJ, Marshall Graves JA, Harley VR | title = ATRX and sex differentiation | journal = Trends in Endocrinology and Metabolism | volume = 15 | issue = 7 | pages = 339–44 | date = September 2004 | pmid = 15350606 | doi = 10.1016/j.tem.2004.07.006 | s2cid = 22192941 }} * {{cite journal | vauthors = Forget BG | title = De novo and acquired forms of alpha thalassemia | journal = Current Hematology Reports | volume = 5 | issue = 1 | pages = 11–4 | date = March 2006 | pmid = 16537041 }} * {{cite journal | vauthors = Adès LC, Kerr B, Turner G, Wise G | title = Smith-Fineman-Myers syndrome in two brothers | journal = American Journal of Medical Genetics | volume = 40 | issue = 4 | pages = 467–70 | date = September 1991 | pmid = 1684092 | doi = 10.1002/ajmg.1320400419 }} * {{cite journal | vauthors = Sutherland GR, Gedeon AK, Haan EA, Woodroffe P, Mulley JC |authorlink1=Grant Robert Sutherland | title = Linkage studies with the gene for an X-linked syndrome of mental retardation, microcephaly and spastic diplegia (MRX2) | journal = American Journal of Medical Genetics | volume = 30 | issue = 1–2 | pages = 493–508 | year = 1988 | pmid = 3177467 | doi = 10.1002/ajmg.1320300152 }} * {{cite journal | vauthors = Shapiro MB, Senapathy P | title = RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression | journal = Nucleic Acids Research | volume = 15 | issue = 17 | pages = 7155–74 | date = September 1987 | pmid = 3658675 | pmc = 306199 | doi = 10.1093/nar/15.17.7155 }} * {{cite journal | vauthors = Gibbons RJ, Picketts DJ, Villard L, Higgs DR | title = Mutations in a putative global transcriptional regulator cause X-linked mental retardation with alpha-thalassemia (ATR-X syndrome) | journal = Cell | volume = 80 | issue = 6 | pages = 837–45 | date = March 1995 | pmid = 7697714 | doi = 10.1016/0092-8674(95)90287-2 | doi-access = free }} * {{cite journal | vauthors = Wang LH, Collins A, Lawrence S, Keats BJ, Morton NE | title = Integration of gene maps: chromosome X | journal = Genomics | volume = 22 | issue = 3 | pages = 590–604 | date = August 1994 | pmid = 8001970 | doi = 10.1006/geno.1994.1432 }} * {{cite journal | vauthors = Gecz J, Pollard H, Consalez G, Villard L, Stayton C, Millasseau P, Khrestchatisky M, Fontes M | title = Cloning and expression of the murine homologue of a putative human X-linked nuclear protein gene closely linked to PGK1 in Xq13.3 | journal = Human Molecular Genetics | volume = 3 | issue = 1 | pages = 39–44 | date = January 1994 | pmid = 8162050 | doi = 10.1093/hmg/3.1.39 }} * {{cite journal | vauthors = Villard L, Gecz J, Mattéi JF, Fontés M, Saugier-Veber P, Munnich A, Lyonnet S | title = XNP mutation in a large family with Juberg-Marsidi syndrome | journal = Nature Genetics | volume = 12 | issue = 4 | pages = 359–60 | date = April 1996 | pmid = 8630485 | doi = 10.1038/ng0496-359 | s2cid = 33759894 }} * {{cite journal | vauthors = Bonaldo MF, Lennon G, Soares MB | title = Normalization and subtraction: two approaches to facilitate gene discovery | journal = Genome Research | volume = 6 | issue = 9 | pages = 791–806 | date = September 1996 | pmid = 8889548 | doi = 10.1101/gr.6.9.791 | doi-access = free }} * {{cite journal | vauthors = Picketts DJ, Higgs DR, Bachoo S, Blake DJ, Quarrell OW, Gibbons RJ | title = ATRX encodes a novel member of the SNF2 family of proteins: mutations point to a common mechanism underlying the ATR-X syndrome | journal = Human Molecular Genetics | volume = 5 | issue = 12 | pages = 1899–907 | date = December 1996 | pmid = 8968741 | doi = 10.1093/hmg/5.12.1899 | doi-access = free }} * {{cite journal | vauthors = Villard L, Lacombe D, Fontés M | title = A point mutation in the XNP gene, associated with an ATR-X phenotype without alpha-thalassemia | journal = European Journal of Human Genetics | volume = 4 | issue = 6 | pages = 316–20 | year = 1997 | pmid = 9043863 | doi = 10.1159/000472225| s2cid = 43618843 }} * {{cite journal | vauthors = Villard L, Lossi AM, Cardoso C, Proud V, Chiaroni P, Colleaux L, Schwartz C, Fontés M | title = Determination of the genomic structure of the XNP/ATRX gene encoding a potential zinc finger helicase | journal = Genomics | volume = 43 | issue = 2 | pages = 149–55 | date = July 1997 | pmid = 9244431 | doi = 10.1006/geno.1997.4793 }} * {{cite journal | vauthors = Golub EI, Kovalenko OV, Gupta RC, Ward DC, Radding CM | title = Interaction of human recombination proteins Rad51 and Rad54 | journal = Nucleic Acids Research | volume = 25 | issue = 20 | pages = 4106–10 | date = October 1997 | pmid = 9321665 | pmc = 147015 | doi = 10.1093/nar/25.20.4106 }} * {{cite journal | vauthors = Gibbons RJ, Bachoo S, Picketts DJ, Aftimos S, Asenbauer B, Bergoffen J, Berry SA, Dahl N, Fryer A, Keppler K, Kurosawa K, Levin ML, Masuno M, Neri G, Pierpont ME, Slaney SF, Higgs DR | title = Mutations in transcriptional regulator ATRX establish the functional significance of a PHD-like domain | journal = Nature Genetics | volume = 17 | issue = 2 | pages = 146–8 | date = October 1997 | pmid = 9326931 | doi = 10.1038/ng1097-146 | s2cid = 12470300 }} * {{cite journal | vauthors = Cardoso C, Timsit S, Villard L, Khrestchatisky M, Fontès M, Colleaux L | title = Specific interaction between the XNP/ATR-X gene product and the SET domain of the human EZH2 protein | journal = Human Molecular Genetics | volume = 7 | issue = 4 | pages = 679–84 | date = April 1998 | pmid = 9499421 | doi = 10.1093/hmg/7.4.679 | doi-access = free }} * {{cite journal | vauthors = Bérubé NG, Mangelsdorf M, Jagla M, Vanderluit J, Garrick D, Gibbons RJ, Higgs DR, Slack RS, Picketts DJ | title = The chromatin-remodeling protein ATRX is critical for neuronal survival during corticogenesis | journal = The Journal of Clinical Investigation | volume = 115 | issue = 2 | pages = 258–67 | date = February 2005 | pmid = 15668733 | pmc = 544602 | doi = 10.1172/JCI22329 }} {{refend}}

== External links == * [https://www.ncbi.nlm.nih.gov/books/NBK1449/ GeneReviews/NCBI/NIH/UW entry on Alpha-Thalassemia X-Linked Mental Retardation Syndrome; ATRX Syndrome; Alpha Thalassemia/Mental Retardation, X-Linked; XLMR-Hypotonic Face Syndrome] * [https://www.omim.org/search?index=entry&start=1&limit=10&search=300032+301040+300032+301040&sort=score+desc&field=number OMIM entries on Alpha-Thalassemia X-Linked Mental Retardation Syndrome] * {{UCSC gene info|ATRX}} * {{UCSC gene info|RAD54L}}