ATRX explained

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.

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. These interactions are important for maintaining silencing at these sites.

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.

Clinical significance

Inherited mutations

Inherited mutations of the ATRX gene are associated with an X-linked mental retardation (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.

Somatic mutations

Acquired mutations in ATRX have been reported in a number of human cancers including pancreatic neuroendocrine tumours, gliomas, osteosarcomas, soft-tissue sarcomas, and malignant pheochromocytomas.^[1] There is a strong correlation between ATRX mutations and an Alternative Lengthening of Telomeres (ALT) phenotype in cancers.

Interactions

ATRX forms a complex with DAXX which is an histone H3.3 chaperone.

ATRX has been also shown to interact with EZH2.

See also

• Alpha-thalassemia mental retardation syndrome

Further reading

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

External links

• 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
• OMIM entries on Alpha-Thalassemia X-Linked Mental Retardation Syndrome

Notes and References

1. Comino-Méndez. I. ATRX driver mutation in a composite malignant pheochromocytoma. Cancer Genetics. June 2016. 209 . 6. 272–7. 10.1016/j.cancergen.2016.04.058. 27209355.