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Gene Review

Usp14  -  ubiquitin specific peptidase 14

Mus musculus

Synonyms: 2610005K12Rik, 2610037B11Rik, AW107924, C78769, Deubiquitinating enzyme 14, ...
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Disease relevance of Usp14


Psychiatry related information on Usp14


High impact information on Usp14

  • We previously reported that a (CTG)n expansion causes spinocerebellar ataxia type 8 (SCA8), a slowly progressive ataxia with reduced penetrance [11].
  • Mice homozygous with respect to the woozy (wz) mutation develop adult-onset ataxia with cerebellar Purkinje cell loss [12].
  • In the mouse, homozygous mutations in Reln result in the reeler phenotype, characterized by ataxia and disrupted cortical layers [13].
  • Mutations in a novel gene encoding a CRAL-TRIO domain cause human Cayman ataxia and ataxia/dystonia in the jittery mouse [14].
  • Cayman ataxia is a recessive congenital ataxia restricted to one area of Grand Cayman Island. Comparative mapping suggested that the locus on 19p13.3 associated with Cayman ataxia might be homologous to the locus on mouse chromosome 10 associated with the recessive ataxic mouse mutant jittery [14].

Chemical compound and disease context of Usp14


Biological context of Usp14

  • Cloning and chromosomal localization of mouse aquaporin 4: exclusion of a candidate mutant phenotype, ataxia [20].
  • The function of the closely linked ataxia locus is not disrupted by the transgene insertion [21].
  • The transgene-induced mutation 9257 and the spontaneous mutation twirler cause craniofacial and inner ear malformations and are located on mouse chromosome 18 near the ataxia locus ax [22].
  • The results demonstrate that ataxia and the insertional mutation TgN9257Mm are separated by less than 1 cM and are located approximately 3 cM from the centromere, while the balding locus is 7 cM more distal [23].
  • Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene, KCNA1 [3].

Anatomical context of Usp14


Associations of Usp14 with chemical compounds

  • Paraneoplastic cerebellar ataxia due to autoantibodies against a glutamate receptor [29].
  • Mutations in another protein containing a CRAL-TRIO domain, alpha-tocopherol transfer protein (TTPA), cause a vitamin E-responsive ataxia [14].
  • RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia [8].
  • Thus, a purely electrical alteration is sufficient to cause cerebellar ataxia, and SK openers such as the neuroprotective agent riluzole may reduce neuronal hyperexcitability and have therapeutic value [30].
  • In vivo sensitivity of the individual mice was evaluated by measuring brain ethanol levels at a precise behavioral end point, recovery from ataxia [31].

Physical interactions of Usp14


Regulatory relationships of Usp14

  • Grafted cerebellar cells in a mouse model of hereditary ataxia express IGF-I system genes and partially restore behavioral function [35].
  • Surprisingly, mice in which the Atm gene has been inactivated lack distinct behavioral ataxia or pronounced cerebellar degeneration, the hallmarks of the human disease [36].
  • Like DNA damaging agents, single-stranded DNA up-regulated p53 and activated the nuclear kinase ataxia telangiectasia mutant (ATM) as evidenced by phosphorylation of histone 2AX, an endogenous ATM substrate [37].
  • Cerebellar granule-cell-specific GABAA receptors attenuate benzodiazepine-induced ataxia: evidence from alpha 6-subunit-deficient mice [38].
  • Targeted disruption of the murine Nhe1 locus induces ataxia, growth retardation, and seizures [39].

Other interactions of Usp14


Analytical, diagnostic and therapeutic context of Usp14


  1. Atypical mouse cerebellar development is caused by ectopic expression of the forkhead box transcription factor HNF-3beta. Zhou, H., Hughes, D.E., Major, M.L., Yoo, K., Pesold, C., Costa, R.H. Gene Expr. (2001) [Pubmed]
  2. RORalpha-Mediated Purkinje Cell Development Determines Disease Severity in Adult SCA1 Mice. Serra, H.G., Duvick, L., Zu, T., Carlson, K., Stevens, S., Jorgensen, N., Lysholm, A., Burright, E., Zoghbi, H.Y., Clark, H.B., Andresen, J.M., Orr, H.T. Cell (2006) [Pubmed]
  3. Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene, KCNA1. Browne, D.L., Gancher, S.T., Nutt, J.G., Brunt, E.R., Smith, E.A., Kramer, P., Litt, M. Nat. Genet. (1994) [Pubmed]
  4. Pharmacologic rescue of lethal seizures in mice deficient in succinate semialdehyde dehydrogenase. Hogema, B.M., Gupta, M., Senephansiri, H., Burlingame, T.G., Taylor, M., Jakobs, C., Schutgens, R.B., Froestl, W., Snead, O.C., Diaz-Arrastia, R., Bottiglieri, T., Grompe, M., Gibson, K.M. Nat. Genet. (2001) [Pubmed]
  5. Targeted deletion of the gene encoding iron regulatory protein-2 causes misregulation of iron metabolism and neurodegenerative disease in mice. LaVaute, T., Smith, S., Cooperman, S., Iwai, K., Land, W., Meyron-Holtz, E., Drake, S.K., Miller, G., Abu-Asab, M., Tsokos, M., Switzer, R., Grinberg, A., Love, P., Tresser, N., Rouault, T.A. Nat. Genet. (2001) [Pubmed]
  6. Imprinted expression of the murine Angelman syndrome gene, Ube3a, in hippocampal and Purkinje neurons. Albrecht, U., Sutcliffe, J.S., Cattanach, B.M., Beechey, C.V., Armstrong, D., Eichele, G., Beaudet, A.L. Nat. Genet. (1997) [Pubmed]
  7. Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis, tapeto-retinal degeneration and hepatic fibrosis. Olbrich, H., Fliegauf, M., Hoefele, J., Kispert, A., Otto, E., Volz, A., Wolf, M.T., Sasmaz, G., Trauer, U., Reinhardt, R., Sudbrak, R., Antignac, C., Gretz, N., Walz, G., Schermer, B., Benzing, T., Hildebrandt, F., Omran, H. Nat. Genet. (2003) [Pubmed]
  8. RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia. Xia, H., Mao, Q., Eliason, S.L., Harper, S.Q., Martins, I.H., Orr, H.T., Paulson, H.L., Yang, L., Kotin, R.M., Davidson, B.L. Nat. Med. (2004) [Pubmed]
  9. Assessment of genetic susceptibility to ethanol intoxication in mice. Rustay, N.R., Wahlsten, D., Crabbe, J.C. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  10. Gerstmann-Sträussler-Scheinker disease and the Indiana kindred. Ghetti, B., Dlouhy, S.R., Giaccone, G., Bugiani, O., Frangione, B., Farlow, M.R., Tagliavini, F. Brain Pathol. (1995) [Pubmed]
  11. Bidirectional expression of CUG and CAG expansion transcripts and intranuclear polyglutamine inclusions in spinocerebellar ataxia type 8. Moseley, M.L., Zu, T., Ikeda, Y., Gao, W., Mosemiller, A.K., Daughters, R.S., Chen, G., Weatherspoon, M.R., Clark, H.B., Ebner, T.J., Day, J.W., Ranum, L.P. Nat. Genet. (2006) [Pubmed]
  12. Protein accumulation and neurodegeneration in the woozy mutant mouse is caused by disruption of SIL1, a cochaperone of BiP. Zhao, L., Longo-Guess, C., Harris, B.S., Lee, J.W., Ackerman, S.L. Nat. Genet. (2005) [Pubmed]
  13. Interaction of reelin signaling and Lis1 in brain development. Assadi, A.H., Zhang, G., Beffert, U., McNeil, R.S., Renfro, A.L., Niu, S., Quattrocchi, C.C., Antalffy, B.A., Sheldon, M., Armstrong, D.D., Wynshaw-Boris, A., Herz, J., D'Arcangelo, G., Clark, G.D. Nat. Genet. (2003) [Pubmed]
  14. Mutations in a novel gene encoding a CRAL-TRIO domain cause human Cayman ataxia and ataxia/dystonia in the jittery mouse. Bomar, J.M., Benke, P.J., Slattery, E.L., Puttagunta, R., Taylor, L.P., Seong, E., Nystuen, A., Chen, W., Albin, R.L., Patel, P.D., Kittles, R.A., Sheffield, V.C., Burmeister, M. Nat. Genet. (2003) [Pubmed]
  15. Spectrin mutations cause spinocerebellar ataxia type 5. Ikeda, Y., Dick, K.A., Weatherspoon, M.R., Gincel, D., Armbrust, K.R., Dalton, J.C., Stevanin, G., Dürr, A., Zühlke, C., Bürk, K., Clark, H.B., Brice, A., Rothstein, J.D., Schut, L.J., Day, J.W., Ranum, L.P. Nat. Genet. (2006) [Pubmed]
  16. Ataxia telangiectasia mutant protein activates c-Abl tyrosine kinase in response to ionizing radiation. Baskaran, R., Wood, L.D., Whitaker, L.L., Canman, C.E., Morgan, S.E., Xu, Y., Barlow, C., Baltimore, D., Wynshaw-Boris, A., Kastan, M.B., Wang, J.Y. Nature (1997) [Pubmed]
  17. Animal models of multiple system atrophy. Stefanova, N., Tison, F., Reindl, M., Poewe, W., Wenning, G.K. Trends Neurosci. (2005) [Pubmed]
  18. Mitochondrial disease in superoxide dismutase 2 mutant mice. Melov, S., Coskun, P., Patel, M., Tuinstra, R., Cottrell, B., Jun, A.S., Zastawny, T.H., Dizdaroglu, M., Goodman, S.I., Huang, T.T., Miziorko, H., Epstein, C.J., Wallace, D.C. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  19. Aberrant recombination involving the granzyme locus occurs in Atm-/- T-cell lymphomas. Winrow, C.J., Pankratz, D.G., Vibat, C.R., Bowen, T.J., Callahan, M.A., Warren, A.J., Hilbush, B.S., Wynshaw-Boris, A., Hasel, K.W., Weaver, Z., Lockhart, D.J., Barlow, C. Hum. Mol. Genet. (2005) [Pubmed]
  20. Cloning and chromosomal localization of mouse aquaporin 4: exclusion of a candidate mutant phenotype, ataxia. Turtzo, L.C., Lee, M.D., Lu, M., Smith, B.L., Copeland, N.G., Gilbert, D.J., Jenkins, N.A., Agre, P. Genomics (1997) [Pubmed]
  21. Insertional mutation on mouse chromosome 18 with vestibular and craniofacial abnormalities. Ting, C.N., Kohrman, D., Burgess, D.L., Boyle, A., Altschuler, R.A., Gholizadeh, G., Samuelson, L.C., Jang, W., Meisler, M.H. Genetics (1994) [Pubmed]
  22. Localization of the homolog of a mouse craniofacial mutant to human chromosome 18q11 and evaluation of linkage to human CLP and CPO. Griffith, A.J., Burgess, D.L., Kohrman, D.C., Yu, J., Blaschak, J., Blanton, S.H., Boehnke, M., Hecht, J.T., Overhauser, J., Meisler, M.H. Genomics (1996) [Pubmed]
  23. Location of the 9257 and ataxia mutations on mouse chromosome 18. Griffith, A.J., Radice, G.L., Burgess, D.L., Kohrman, D.C., Hansen, G.M., Justice, M.J., Johnson, K.R., Davisson, M.T., Meisler, M.H. Mamm. Genome (1996) [Pubmed]
  24. Loss of Usp14 results in reduced levels of ubiquitin in ataxia mice. Anderson, C., Crimmins, S., Wilson, J.A., Korbel, G.A., Ploegh, H.L., Wilson, S.M. J. Neurochem. (2005) [Pubmed]
  25. Synaptic defects in ataxia mice result from a mutation in Usp14, encoding a ubiquitin-specific protease. Wilson, S.M., Bhattacharyya, B., Rachel, R.A., Coppola, V., Tessarollo, L., Householder, D.B., Fletcher, C.F., Miller, R.J., Copeland, N.G., Jenkins, N.A. Nat. Genet. (2002) [Pubmed]
  26. Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice. Klement, I.A., Skinner, P.J., Kaytor, M.D., Yi, H., Hersch, S.M., Clark, H.B., Zoghbi, H.Y., Orr, H.T. Cell (1998) [Pubmed]
  27. Sensory ataxia and muscle spindle agenesis in mice lacking the transcription factor Egr3. Tourtellotte, W.G., Milbrandt, J. Nat. Genet. (1998) [Pubmed]
  28. Myelination in the absence of galactocerebroside and sulfatide: normal structure with abnormal function and regional instability. Coetzee, T., Fujita, N., Dupree, J., Shi, R., Blight, A., Suzuki, K., Suzuki, K., Popko, B. Cell (1996) [Pubmed]
  29. Paraneoplastic cerebellar ataxia due to autoantibodies against a glutamate receptor. Sillevis Smitt, P., Kinoshita, A., De Leeuw, B., Moll, W., Coesmans, M., Jaarsma, D., Henzen-Logmans, S., Vecht, C., De Zeeuw, C., Sekiyama, N., Nakanishi, S., Shigemoto, R. N. Engl. J. Med. (2000) [Pubmed]
  30. Enhanced neuronal excitability in the absence of neurodegeneration induces cerebellar ataxia. Shakkottai, V.G., Chou, C.H., Oddo, S., Sailer, C.A., Knaus, H.G., Gutman, G.A., Barish, M.E., LaFerla, F.M., Chandy, K.G. J. Clin. Invest. (2004) [Pubmed]
  31. Ethanol disordering of spin-labeled mouse brain membranes: correlation with genetically determined ethanol sensitivity of mice. Goldstein, D.B., Chin, J.H., Lyon, R.C. Proc. Natl. Acad. Sci. U.S.A. (1982) [Pubmed]
  32. Nova regulates GABA(A) receptor gamma2 alternative splicing via a distal downstream UCAU-rich intronic splicing enhancer. Dredge, B.K., Darnell, R.B. Mol. Cell. Biol. (2003) [Pubmed]
  33. Ataxia and paroxysmal dyskinesia in mice lacking axonally transported FGF14. Wang, Q., Bardgett, M.E., Wong, M., Wozniak, D.F., Lou, J., McNeil, B.D., Chen, C., Nardi, A., Reid, D.C., Yamada, K., Ornitz, D.M. Neuron (2002) [Pubmed]
  34. Inositol 1,4,5-trisphosphate receptors and protein kinase C in olivopontocerebellar atrophy. Desaiah, D., Vig, P.J., Subramony, S.H., Currier, R.D. Brain Res. (1991) [Pubmed]
  35. Grafted cerebellar cells in a mouse model of hereditary ataxia express IGF-I system genes and partially restore behavioral function. Zhang, W., Lee, W.H., Triarhou, L.C. Nat. Med. (1996) [Pubmed]
  36. Selective loss of dopaminergic nigro-striatal neurons in brains of Atm-deficient mice. Eilam, R., Peter, Y., Elson, A., Rotman, G., Shiloh, Y., Groner, Y., Segal, M. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  37. Single-stranded DNA induces ataxia telangiectasia mutant (ATM)/p53-dependent DNA damage and apoptotic signals. Nur-E-Kamal, A., Li, T.K., Zhang, A., Qi, H., Hars, E.S., Liu, L.F. J. Biol. Chem. (2003) [Pubmed]
  38. Cerebellar granule-cell-specific GABAA receptors attenuate benzodiazepine-induced ataxia: evidence from alpha 6-subunit-deficient mice. Korpi, E.R., Koikkalainen, P., Vekovischeva, O.Y., Mäkelä, R., Kleinz, R., Uusi-Oukari, M., Wisden, W. Eur. J. Neurosci. (1999) [Pubmed]
  39. Targeted disruption of the murine Nhe1 locus induces ataxia, growth retardation, and seizures. Bell, S.M., Schreiner, C.M., Schultheis, P.J., Miller, M.L., Evans, R.L., Vorhees, C.V., Shull, G.E., Scott, W.J. Am. J. Physiol. (1999) [Pubmed]
  40. A targeted mutation in Cacng4 exacerbates spike-wave seizures in stargazer (Cacng2) mice. Letts, V.A., Mahaffey, C.L., Beyer, B., Frankel, W.N. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  41. Mediation of Af4 protein function in the cerebellum by Siah proteins. Oliver, P.L., Bitoun, E., Clark, J., Jones, E.L., Davies, K.E. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  42. Atm-deficient mice: a paradigm of ataxia telangiectasia. Barlow, C., Hirotsune, S., Paylor, R., Liyanage, M., Eckhaus, M., Collins, F., Shiloh, Y., Crawley, J.N., Ried, T., Tagle, D., Wynshaw-Boris, A. Cell (1996) [Pubmed]
  43. Multicolour spectral karyotyping of mouse chromosomes. Liyanage, M., Coleman, A., du Manoir, S., Veldman, T., McCormack, S., Dickson, R.B., Barlow, C., Wynshaw-Boris, A., Janz, S., Wienberg, J., Ferguson-Smith, M.A., Schröck, E., Ried, T. Nat. Genet. (1996) [Pubmed]
  44. The reconstruction of cerebellar circuits. Sotelo, C., Alvarado-Mallart, R.M. Trends Neurosci. (1991) [Pubmed]
  45. Targeted disruption of the Epm2a gene causes formation of Lafora inclusion bodies, neurodegeneration, ataxia, myoclonus epilepsy and impaired behavioral response in mice. Ganesh, S., Delgado-Escueta, A.V., Sakamoto, T., Avila, M.R., Machado-Salas, J., Hoshii, Y., Akagi, T., Gomi, H., Suzuki, T., Amano, K., Agarwala, K.L., Hasegawa, Y., Bai, D.S., Ishihara, T., Hashikawa, T., Itohara, S., Cornford, E.M., Niki, H., Yamakawa, K. Hum. Mol. Genet. (2002) [Pubmed]
  46. Transgenic mice with an expanded CAG repeat controlled by the human AR promoter show polyglutamine nuclear inclusions and neuronal dysfunction without neuronal cell death. Adachi, H., Kume, A., Li, M., Nakagomi, Y., Niwa, H., Do, J., Sang, C., Kobayashi, Y., Doyu, M., Sobue, G. Hum. Mol. Genet. (2001) [Pubmed]
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