Atrophin 1

Atrophin-1 is a protein that in humans is encoded by the ATN1 gene.[5] The encoded protein includes a serine repeat and a region of alternating acidic and basic amino acids, as well as the variable glutamine repeat.[6] The function of Atrophin-1 has not yet been determined.[7] There is evidence provided by studies of Atrophin-1 in animals to suggest it acts as a transcriptional co-repressor.[7] Atrophin-1 can be found in the nuclear and cytoplasmic compartments of neurons.[7] It is expressed in nervous tissue.[8]

ATN1
Identifiers
AliasesATN1, B37, D12S755E, DRPLA, HRS, NOD, atrophin 1, CHEDDA
External IDsOMIM: 607462 MGI: 104725 HomoloGene: 1461 GeneCards: ATN1
Orthologs
SpeciesHumanMouse
Entrez

1822

13498

Ensembl

ENSG00000111676

ENSMUSG00000004263

UniProt

P54259

O35126

RefSeq (mRNA)

NM_001940
NM_001007026

NM_007881

RefSeq (protein)

NP_001007027
NP_001931

NP_031907

Location (UCSC)Chr 12: 6.92 – 6.94 MbChr 6: 124.72 – 124.73 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Function

The function of Atrophin-1 has not been defined yet. It is widely hypothesized that Atrophin-1 functions as a transcriptional co-repressor.[9] A transcriptional co-repressor is a protein that indirectly suppresses the activity of specific genes by interacting with DNA-binding proteins.[9]

Clinical significance

The ATN1 gene has a segment of DNA called the CAG trinucleotide repeat.[9] It is made up of cytosine, adenine, and guanine.[9] The number of CAG repeats in the ATN1 gene in a healthy person will range from six to thirty-five repeats.[9] CAG repeats that exceed thirty-five can cause a gain-of-function mutation in ATN1.[10] Studies have supported the idea that mutated Atrophin-1 gathers in neurons and disrupts cell function.[11] The sequence of the ATN1 gene contains a nuclear localizing signal (NLS) and a nuclear export signal (NES).[11] 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.[11] This can lead to an increase in cellular toxicity.[11]

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.[5] The disorder is related to the expansion of a trinucleotide repeat within this gene.[5] In patients with DRPLA, truncated ATN1 has been observed forming intranuclear aggregates that cause cell death.[11] The symptoms of this disorder can be credited to the significant reduction of brain and spinal tissue observed in those afflicted with DRPLA.[12] There are both juvenile-onset and late adult-onset variants of DRPLA, which show differing degrees of severity of specific symptoms.[12]

Interactions

ATN1 has been shown to interact with:

References
  1. GRCh38: Ensembl release 89: ENSG00000111676 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000004263 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. "ATN1 atrophin 1 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2017-03-12.
  6. "Entrez Gene: ATN1 atrophin 1".
  7. Wood JD, Nucifora FC, Duan K, Zhang C, Wang J, Kim Y, Schilling G, Sacchi N, Liu JM, Ross CA (September 2000). "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. doi:10.1083/jcb.150.5.939. PMC 2175251. PMID 10973986.
  8. Shen Y, Peterson AS (February 2009). "Atrophins' emerging roles in development and neurodegenerative disease". Cellular and Molecular Life Sciences. 66 (3): 437–46. doi:10.1007/s00018-008-8403-9. PMID 18953689. S2CID 11380927.
  9. "ATN1 gene". Genetics Home Reference. Retrieved 2017-02-21.
  10. Shen Y, Lee G, Choe Y, Zoltewicz JS, Peterson AS (February 2007). "Functional architecture of atrophins". The Journal of Biological Chemistry. 282 (7): 5037–44. doi:10.1074/jbc.M610274200. PMID 17150957.
  11. Suzuki Y, Yazawa I (April 2011). "Pathological accumulation of atrophin-1 in dentatorubralpallidoluysian atrophy". International Journal of Clinical and Experimental Pathology. 4 (4): 378–84. PMC 3093063. PMID 21577324.
  12. "Dentatorubral-Pallidoluysian Atrophy, DRPLA". themedicalbiochemistrypage.org. Retrieved 2017-02-21.
  13. Okamura-Oho Y, Miyashita T, Ohmi K, Yamada M (June 1999). "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. doi:10.1093/hmg/8.6.947. PMID 10332026.
  14. Wood JD, Yuan J, Margolis RL, Colomer V, Duan K, Kushi J, Kaminsky Z, Kleiderlein JJ, Sharp AH, Ross CA (June 1998). "Atrophin-1, the DRPLA gene product, interacts with two families of WW domain-containing proteins". Molecular and Cellular Neurosciences. 11 (3): 149–60. doi:10.1006/mcne.1998.0677. PMID 9647693. S2CID 20003277.
  15. Yanagisawa H, Bundo M, Miyashita T, Okamura-Oho Y, Tadokoro K, Tokunaga K, Yamada M (May 2000). "Protein binding of a DRPLA family through arginine-glutamic acid dipeptide repeats is enhanced by extended polyglutamine". Human Molecular Genetics. 9 (9): 1433–42. doi:10.1093/hmg/9.9.1433. PMID 10814707.

Further reading
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