Atrophin 1 Explained

Atrophin-1 is a protein that in humans is encoded by the ATN1 gene.^[1] The encoded protein includes a serine repeat and a region of alternating acidic and basic amino acids, as well as the variable glutamine repeat.^[2] The function of Atrophin-1 has not yet been determined.^[3] There is evidence provided by studies of Atrophin-1 in animals to suggest it acts as a transcriptional co-repressor. Atrophin-1 can be found in the nuclear and cytoplasmic compartments of neurons. It is expressed in nervous tissue.^[4]

Function

The function of Atrophin-1 has not been defined yet. It is widely hypothesized that Atrophin-1 functions as a transcriptional co-repressor. A transcriptional co-repressor is a protein that indirectly suppresses the activity of specific genes by interacting with DNA-binding proteins.

Clinical significance

The ATN1 gene has a segment of DNA called the CAG trinucleotide repeat.^[5] It is made up of cytosine, adenine, and guanine. The number of CAG repeats in the ATN1 gene in a healthy person will range from six to thirty-five repeats. CAG repeats that exceed thirty-five can cause a gain-of-function mutation in ATN1.^[6] Studies have supported the idea that mutated Atrophin-1 gathers in neurons and disrupts cell function.^[7] The sequence of the ATN1 gene contains a nuclear localizing signal (NLS) and a nuclear export signal (NES). It has been shown that a mutation of the NES in ATN1 can change where ATN1 localizes, and can cause aggregation to occur in the nucleus. This can lead to an increase in cellular toxicity.

Mutations in ATN1 are associated with a form of trinucleotide repeat disorder known as "dentatorubral-pallidoluysian atrophy" or "dentatorubropallidoluysian atrophy". Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare neurodegenerative disorder characterized by cerebellar ataxia, myoclonic epilepsy, choreoathetosis, and dementia. The disorder is related to the expansion of a trinucleotide repeat within this gene. In patients with DRPLA, truncated ATN1 has been observed forming intranuclear aggregates that cause cell death. The symptoms of this disorder can be credited to the significant reduction of brain and spinal tissue observed in those afflicted with DRPLA.^[8] There are both juvenile-onset and late adult-onset variants of DRPLA, which show differing degrees of severity of specific symptoms.

Interactions

ATN1 has been shown to interact with:

• BAIAP2,^[9]
• MAGI1,
• MAGI2,^[10]
• RERE,^[11] and
• WWP2.^[10]

Further reading

• Wang L, Rajan H, Pitman JL, McKeown M, Tsai CC . Histone deacetylase-associating Atrophin proteins are nuclear receptor corepressors . Genes & Development . 20 . 5 . 525–30 . March 2006 . 16481466 . 1410805 . 10.1101/gad.1393506 .
• Onodera O, Oyake M, Takano H, Ikeuchi T, Igarashi S, Tsuji S . Molecular cloning of a full-length cDNA for dentatorubral-pallidoluysian atrophy and regional expressions of the expanded alleles in the CNS . American Journal of Human Genetics . 57 . 5 . 1050–60 . November 1995 . 7485154 . 1801383 .
• Yazawa I, Nukina N, Hashida H, Goto J, Yamada M, Kanazawa I . Abnormal gene product identified in hereditary dentatorubral-pallidoluysian atrophy (DRPLA) brain . Nature Genetics . 10 . 1 . 99–103 . May 1995 . 7647802 . 10.1038/ng0595-99 . 5850726 .
• Nagafuchi S, Yanagisawa H, Ohsaki E, Shirayama T, Tadokoro K, Inoue T, Yamada M . Structure and expression of the gene responsible for the triplet repeat disorder, dentatorubral and pallidoluysian atrophy (DRPLA) . Nature Genetics . 8 . 2 . 177–82 . October 1994 . 7842016 . 10.1038/ng1094-177 . 2590882 .
• Burke JR, Wingfield MS, Lewis KE, Roses AD, Lee JE, Hulette C, Pericak-Vance MA, Vance JM . The Haw River syndrome: dentatorubropallidoluysian atrophy (DRPLA) in an African-American family . Nature Genetics . 7 . 4 . 521–4 . August 1994 . 7951323 . 10.1038/ng0894-521 . 40759301 .
• Nagafuchi S, Yanagisawa H, Sato K, Shirayama T, Ohsaki E, Bundo M, Takeda T, Tadokoro K, Kondo I, Murayama N . Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p . Nature Genetics . 6 . 1 . 14–8 . January 1994 . 8136826 . 10.1038/ng0194-14 . 19708585 .
• Koide R, Ikeuchi T, Onodera O, Tanaka H, Igarashi S, Endo K, Takahashi H, Kondo R, Ishikawa A, Hayashi T . Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA) . Nature Genetics . 6 . 1 . 9–13 . January 1994 . 8136840 . 10.1038/ng0194-9 . 27241147 .
• Li SH, McInnis MG, Margolis RL, Antonarakis SE, Ross CA . Novel triplet repeat containing genes in human brain: cloning, expression, and length polymorphisms . Genomics . 16 . 3 . 572–9 . June 1993 . 8325628 . 10.1006/geno.1993.1232 . free .
• Ansari-Lari MA, Muzny DM, Lu J, Lu F, Lilley CE, Spanos S, Malley T, Gibbs RA . A gene-rich cluster between the CD4 and triosephosphate isomerase genes at human chromosome 12p13 . Genome Research . 6 . 4 . 314–26 . April 1996 . 8723724 . 10.1101/gr.6.4.314 . free .
• Takano T, Yamanouchi Y, Nagafuchi S, Yamada M . Assignment of the dentatorubral and pallidoluysian atrophy (DRPLA) gene to 12p 13.31 by fluorescence in situ hybridization . Genomics . 32 . 1 . 171–2 . February 1996 . 8786114 . 10.1006/geno.1996.0100 .
• Yanagisawa H, Fujii K, Nagafuchi S, Nakahori Y, Nakagome Y, Akane A, Nakamura M, Sano A, Komure O, Kondo I, Jin DK, Sørensen SA, Potter NT, Young SR, Nakamura K, Nukina N, Nagao Y, Tadokoro K, Okuyama T, Miyashita T, Inoue T, Kanazawa I, Yamada M . A unique origin and multistep process for the generation of expanded DRPLA triplet repeats . Human Molecular Genetics . 5 . 3 . 373–9 . March 1996 . 8852663 . 10.1093/hmg/5.3.373 . free .
• Margolis RL, Li SH, Young WS, Wagster MV, Stine OC, Kidwai AS, Ashworth RG, Ross CA . DRPLA gene (atrophin-1) sequence and mRNA expression in human brain . Brain Research. Molecular Brain Research . 36 . 2 . 219–26 . March 1996 . 8965642 . 10.1016/0169-328X(95)00241-J . free .
• Ansari-Lari MA, Shen Y, Muzny DM, Lee W, Gibbs RA . Large-scale sequencing in human chromosome 12p13: experimental and computational gene structure determination . Genome Research . 7 . 3 . 268–80 . March 1997 . 9074930 . 10.1101/gr.7.3.268 . free .
• Miyashita T, Okamura-Oho Y, Mito Y, Nagafuchi S, Yamada M . Dentatorubral pallidoluysian atrophy (DRPLA) protein is cleaved by caspase-3 during apoptosis . The Journal of Biological Chemistry . 272 . 46 . 29238–42 . November 1997 . 9361003 . 10.1074/jbc.272.46.29238 . free .
• Wellington CL, Ellerby LM, Hackam AS, Margolis RL, Trifiro MA, Singaraja R, McCutcheon K, Salvesen GS, Propp SS, Bromm M, Rowland KJ, Zhang T, Rasper D, Roy S, Thornberry N, Pinsky L, Kakizuka A, Ross CA, Nicholson DW, Bredesen DE, Hayden MR . Caspase cleavage of gene products associated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract . The Journal of Biological Chemistry . 273 . 15 . 9158–67 . April 1998 . 9535906 . 10.1074/jbc.273.15.9158 . free .
• Wood JD, Yuan J, Margolis RL, Colomer V, Duan K, Kushi J, Kaminsky Z, Kleiderlein JJ, Sharp AH, Ross CA . Atrophin-1, the DRPLA gene product, interacts with two families of WW domain-containing proteins . Molecular and Cellular Neurosciences . 11 . 3 . 149–60 . June 1998 . 9647693 . 10.1006/mcne.1998.0677 . 20003277 . free .
• Hayashi Y, Kakita A, Yamada M, Koide R, Igarashi S, Takano H, Ikeuchi T, Wakabayashi K, Egawa S, Tsuji S, Takahashi H . Hereditary dentatorubral-pallidoluysian atrophy: detection of widespread ubiquitinated neuronal and glial intranuclear inclusions in the brain . Acta Neuropathologica . 96 . 6 . 547–52 . December 1998 . 9845282 . 10.1007/s004010050933 . 12861680 .
• Takiyama Y, Sakoe K, Amaike M, Soutome M, Ogawa T, Nakano I, Nishizawa M . Single sperm analysis of the CAG repeats in the gene for dentatorubral-pallidoluysian atrophy (DRPLA): the instability of the CAG repeats in the DRPLA gene is prominent among the CAG repeat diseases . Human Molecular Genetics . 8 . 3 . 453–7 . March 1999 . 9949204 . 10.1093/hmg/8.3.453 . free .
• Okamura-Oho Y, Miyashita T, Ohmi K, Yamada M . Dentatorubral-pallidoluysian atrophy protein interacts through a proline-rich region near polyglutamine with the SH3 domain of an insulin receptor tyrosine kinase substrate . Human Molecular Genetics . 8 . 6 . 947–57 . June 1999 . 10332026 . 10.1093/hmg/8.6.947 . free .
• Dias Neto E, Correa RG, Verjovski-Almeida S, Briones MR, Nagai MA, da Silva W, Zago MA, Bordin S, Costa FF, Goldman GH, Carvalho AF, Matsukuma A, Baia GS, Simpson DH, Brunstein A, de Oliveira PS, Bucher P, Jongeneel CV, O'Hare MJ, Soares F, Brentani RR, Reis LF, de Souza SJ, Simpson AJ . Shotgun sequencing of the human transcriptome with ORF expressed sequence tags . Proceedings of the National Academy of Sciences of the United States of America . 97 . 7 . 3491–6 . March 2000 . 10737800 . 16267 . 10.1073/pnas.97.7.3491 . 2000PNAS...97.3491D . free .
• Yanagisawa H, Bundo M, Miyashita T, Okamura-Oho Y, Tadokoro K, Tokunaga K, Yamada M . Protein binding of a DRPLA family through arginine-glutamic acid dipeptide repeats is enhanced by extended polyglutamine . Human Molecular Genetics . 9 . 9 . 1433–42 . May 2000 . 10814707 . 10.1093/hmg/9.9.1433 . free .

External links

• GeneReviews/NCBI/NIH/UW entry on DRPLA

Notes and References

1. Web site: ATN1 atrophin 1 [Homo sapiens (human)] - Gene - NCBI]. www.ncbi.nlm.nih.gov. 2017-03-12.
2. Web site: Entrez Gene: ATN1 atrophin 1.
3. Wood JD, Nucifora FC, Duan K, Zhang C, Wang J, Kim Y, Schilling G, Sacchi N, Liu JM, Ross CA . Atrophin-1, the dentato-rubral and pallido-luysian atrophy gene product, interacts with ETO/MTG8 in the nuclear matrix and represses transcription . The Journal of Cell Biology . 150 . 5 . 939–48 . September 2000 . 10973986 . 10.1083/jcb.150.5.939 . 2175251.
4. Shen Y, Peterson AS . Atrophins' emerging roles in development and neurodegenerative disease . Cellular and Molecular Life Sciences . 66 . 3 . 437–46 . February 2009 . 10.1007/s00018-008-8403-9 . 18953689 . 11380927 . 11131516 .
5. Web site: ATN1 gene. Genetics Home Reference . 2017-02-21 .
6. Shen Y, Lee G, Choe Y, Zoltewicz JS, Peterson AS . Functional architecture of atrophins . en . The Journal of Biological Chemistry . 282 . 7 . 5037–44 . February 2007 . 17150957 . 10.1074/jbc.M610274200 . free .
7. Suzuki Y, Yazawa I . Pathological accumulation of atrophin-1 in dentatorubralpallidoluysian atrophy . International Journal of Clinical and Experimental Pathology . 4 . 4 . 378–84 . April 2011 . 21577324 . 3093063 .
8. Web site: Dentatorubral-Pallidoluysian Atrophy, DRPLA. themedicalbiochemistrypage.org. 2017-02-21.
9. Okamura-Oho Y, Miyashita T, Ohmi K, Yamada M . Dentatorubral-pallidoluysian atrophy protein interacts through a proline-rich region near polyglutamine with the SH3 domain of an insulin receptor tyrosine kinase substrate . Human Molecular Genetics . 8 . 6 . 947–57 . June 1999 . 10332026 . 10.1093/hmg/8.6.947 . free .
10. Wood JD, Yuan J, Margolis RL, Colomer V, Duan K, Kushi J, Kaminsky Z, Kleiderlein JJ, Sharp AH, Ross CA . Atrophin-1, the DRPLA gene product, interacts with two families of WW domain-containing proteins . Molecular and Cellular Neurosciences . 11 . 3 . 149–60 . June 1998 . 9647693 . 10.1006/mcne.1998.0677 . 20003277 . free .
11. Yanagisawa H, Bundo M, Miyashita T, Okamura-Oho Y, Tadokoro K, Tokunaga K, Yamada M . Protein binding of a DRPLA family through arginine-glutamic acid dipeptide repeats is enhanced by extended polyglutamine . Human Molecular Genetics . 9 . 9 . 1433–42 . May 2000 . 10814707 . 10.1093/hmg/9.9.1433 . free .