Chorein is the protein encoded by gene VPS13A which is altered in chorea-acanthocytosis (ChAc). It belongs to the VPS13 protein family which, in mammals, has three other members: VPS13B, VPS13C and VPS13D. These proteins are similar to Vps13p, a yeast protein shown to be involved in intra-cellular trafficking of a number of transmembrane proteins. Chorein and its homologous human proteins lack domains or motifs of known function. This, together with their large size, makes the functional characterisation of these proteins a difficult task. Nevertheless, we have undertaken this task following a molecular and cellular biology approach. We have cloned the cDNA for the human VPS13 genes and used them for transfection of mammalian cell lines. We present here an overview of the results obtained. We also analyse the data available for similar proteins and the information provided by mutational screening in ChAc patients in the context of the implications in protein function.
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References
Baralle D, Baralle M (2005) Splicing in action: assessing disease causing sequence changes. J Med Genet 42:737–748.
Brickner JH, Fuller RS (1997) SOI1 encodes a novel, conserved protein that promotes TGN-endosomal cycling of Kex2p and other membrane proteins by modulating the function of two TGN localization signals. J Cell Biol 139:23–36.
Buratti E, Baralle M, Baralle FE (2006) Defective splicing, disease and therapy: searching for master checkpoints in exon definition. Nucleic Acids Res 34:3494–3510.
Caceres JF, Kornblihtt AR (2002) Alternative splicing: multiple control mechanisms and involvement in human disease. Trends Genet 18:186–193.
Cartegni L, Chew SL, Krainer AR (2002) Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nat Rev Genet 3:285–298.
Coates PJ, Hall PA (2003) The yeast two-hybrid system for identifying protein-protein interactions. J Pathol 199:4–7.
D’Andrea LD, Regan L (2003) TPR proteins: the versatile helix. Trends Biochem Sci 28:655–662.
Danek A, Walker RH (2005) Neuroacanthocytosis. Curr Opin Neurol 18:386–392.
Danek A, Jung HH, Melone MA, Rampoldi L, Broccoli V, Walker RH (2005) Neuroacanthocytosis: new developments in a neglected group of dementing disorders. J Neurol Sci 229–230:171–186.
den Dunnen JT, Antonarakis SE (2000) Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion. Hum Mutat 15:7–12.
Dobson-Stone C (2004) Molecular genetics of chorea-acanthocytosis. Thesis, University of Oxford, Oxford.
Dobson-Stone C, Danek A, Rampoldi L, Hardie RJ, Chalmers RM, Wood NW, Bohlega S, Dotti MT, Federico A, Shizuka M, Tanaka M, Watanabe M, Ikeda Y, Brin M, Goldfarb LG, Karp BI, Mohiddin S, Fananapazir L, Storch A, Fryer AE, Maddison P, Sibon I, Trevisol-Bittencourt PC, Singer C, Caballero IR, Aasly JO, Schmierer K, Dengler R, Hiersemenzel LP, Zeviani M, Meiner V, Lossos A, Johnson S, Mercado FC, Sorrentino G, Dupre N, Rouleau GA, Volkmann J, Arpa J, Lees A, Geraud G, Chouinard S, Nemeth A, Monaco AP (2002) Mutational spectrum of the CHAC gene in patients with chorea-acanthocytosis. Eur J Hum Genet 10:773–781.
Dobson-Stone C, Rampoldi L, Monaco AP (2004) The spectrum of mutations and possible function of the CHAC gene. In: Danek A (ed) Neuroacanthocytosis syndromes. Springer, Dordrecht, pp 169–175.
Dobson-Stone C, Velayos-Baeza A, Filippone LA, Westbury S, Storch A, Erdmann T, Wroe SJ, Leenders KL, Lang AE, Dotti MT, Federico A, Mohiddin SA, Fananapazir L, Daniels G, Danek A, Monaco AP (2004) Chorein detection for the diagnosis of chorea-acanthocytosis. Ann Neurol 56:299–302.
Dobson-Stone C, Velayos-Baeza A, Jansen A, Andermann F, Dubeau F, Robert F, Summers A, Lang AE, Chouinard S, Danek A, Andermann E, Monaco AP (2005) Identification of a VPS13A founder mutation in French Canadian families with chorea-acanthocytosis. Neurogenetics 6:151–158.
Falk MJ, Feiler HS, Neilson DE, Maxwell K, Lee JV, Segall SK, Robin NH, Wilhelmsen KC, Traskelin AL, Kolehmainen J, Lehesjoki AE, Wiznitzer M, Warman ML (2004) Cohen syndrome in the Ohio Amish. Am J Med Genet 128A:23–28.
Faustino NA, Cooper TA (2003) Pre-mRNA splicing and human disease. Genes Dev 17:419–437.
Garcia-Mata R, Gao YS, Sztul E (2002) Hassles with taking out the garbage: aggravating aggresomes. Traffic 3:388–396.
Hennies HC, Rauch A, Seifert W, Schumi C, Moser E, Al-Taji E, Tariverdian G, Chrzanowska KH, Krajewska-Walasek M, Rajab A, Giugliani R, Neumann TE, Eckl KM, Karbasiyan M, Reis A, Horn D (2004) Allelic heterogeneity in the COH1 gene explains clinical variability in Cohen syndrome. Am J Hum Genet 75:138–145.
Ho M, Chelly J, Carter N, Danek A, Crocker P, Monaco AP (1994) Isolation of the gene for McLeod syndrome that encodes a novel membrane transport protein. Cell 77:869–880.
Kolehmainen J, Black GC, Saarinen A, Chandler K, Clayton-Smith J, Traskelin AL, Perveen R, Kivitie-Kallio S, Norio R, Warburg M, Fryns JP, de la Chapelle A, Lehesjoki AE (2003) Cohen syndrome is caused by mutations in a novel gene, COH1, encoding a transmembrane protein with a presumed role in vesicle-mediated sorting and intracellular protein transport. Am J Hum Genet 72:1359–1369.
Kolehmainen J, Wilkinson R, Lehesjoki AE, Chandler K, Kivitie-Kallio S, Clayton-Smith J, Traskelin AL, Waris L, Saarinen A, Khan J, Gross-Tsur V, Traboulsi EI, Warburg M, Fryns JP, Norio R, Black GC, Manson FD (2004) Delineation of Cohen syndrome following a large-scale genotype-phenotype screen. Am J Hum Genet 75:122–127.
Lejeune F, Maquat LE (2005) Mechanistic links between nonsense-mediated mRNA decay and pre-mRNA splicing in mammalian cells. Curr Opin Cell Biol 17:309–315.
Mochida GH, Rajab A, Eyaid W, Lu A, Al-Nouri D, Kosaki K, Noruzinia M, Sarda P, Ishihara J, Bodell A, Apse K, Walsh CA (2004) Broader geographical spectrum of Cohen syndrome due to COH1 mutations. J Med Genet 41:e87.
Parrish JR, Gulyas KD, Finley RL Jr (2006) Yeast two-hybrid contributions to interactome mapping. Curr Opin Biotechnol 17:387–393.
Rampoldi L, Dobson-Stone C, Rubio JP, Danek A, Chalmers RM, Wood NW, Verellen C, Ferrer X, Malandrini A, Fabrizi GM, Brown R, Vance J, Pericak-Vance M, Rudolf G, Carre S, Alonso E, Manfredi M, Nemeth AH, Monaco AP (2001) A conserved sorting-associated protein is mutant in chorea-acanthocytosis. Nat Genet 28:119–120.
Rampoldi L, Danek A, Monaco AP (2002) Clinical features and molecular bases of neuroacanthocytosis. J Mol Med 80:475–491.
Redman CM, Russo D, Lee S (1999) Kell, Kx and the McLeod syndrome. Baillieres Best Pract Res Clin Haematol 12:621–635.
Redman CM, Russo DCW, Pu JJ, Lee S (2004) The Kell blood group protein, its relation to XK and its function as an endothelin-3-converting enzyme. In: Danek A (ed) Neuroacanthocytosis syndromes. Springer, Dordrecht, pp 197–203.
Saiki S, Sakai K, Kitagawa Y, Saiki M, Kataoka S, Hirose G (2003) Mutation in the CHAC gene in a family of autosomal dominant chorea-acanthocytosis. Neurology 61:1614–1616.
Scamuffa N, Calvo F, Chretien M, Seidah NG, Khatib AM (2006) Proprotein convertases: lessons from knockouts. FASEB J 20:1954–1963.
Seidah NG, Chretien M (1999) Proprotein and prohormone convertases: a family of subtilases generating diverse bioactive polypeptides. Brain Res 848:45–62.
Seifert W, Holder-Espinasse M, Spranger S, Hoeltzenbein M, Rossier E, Dollfus H, Lacombe D, Verloes A, Chrzanowska KH, Maegawa GH, Chitayat D, Kotzot D, Huhle D, Meinecke P, Albrecht B, Mathijssen I, Leheup B, Raile K, Hennies HC, Horn D (2006) Mutational spectrum of COH1 and clinical heterogeneity in Cohen syndrome. J Med Genet 43:e22.
Stamm S, Ben-Ari S, Rafalska I, Tang Y, Zhang Z, Toiber D, Thanaraj TA, Soreq H (2005) Function of alternative splicing. Gene 344:1–20.
Stege JT, Laub MT, Loomis WF (1999) tip genes act in parallel pathways of early Dictyostelium development. Dev Genet 25:64–77.
Steiner DF (1998) The proprotein convertases. Curr Opin Chem Biol 2:31–39.
Taylor NA, Van De Ven WJ, Creemers JW (2003) Curbing activation: proprotein convertases in homeostasis and pathology. FASEB J 17:1215–1227.
Thomas G (2002) Furin at the cutting edge: from protein traffic to embryogenesis and disease. Nat Rev Mol Cell Biol 3:753–766.
Tomemori Y, Ichiba M, Kusumoto A, Mizuno E, Sato D, Muroya S, Nakamura M, Kawaguchi H, Yoshida H, Ueno S, Nakao K, Nakamura K, Aiba A, Katsuki M, Sano A (2005) A gene-targeted mouse model for chorea-acanthocytosis. J Neurochem 92:759–766.
Ueno S, Maruki Y, Nakamura M, Tomemori Y, Kamae K, Tanabe H, Yamashita Y, Matsuda S, Kaneko S, Sano A (2001) The gene encoding a newly discovered protein, chorein, is mutated in chorea-acanthocytosis. Nat Genet 28:121–122.
Velayos-Baeza A, Vettori A, Copley RR, Dobson-Stone C, Monaco AP (2004) Analysis of the human VPS13 gene family. Genomics 84:536–549.
Walker RH, Danek A, Dobson-Stone C, Guerrini R, Jung HH, Lafontaine AL, Rampoldi L, Tison F, Andermann E (2006) Developments in neuroacanthocytosis: expanding the spectrum of choreatic syndromes. Mov Disord 21:1794–1805.
Walker RH, Liu Q, Ichiba M, Muroya S, Nakamura M, Sano A, Kennedy CA, Sclar G (2006) Self-mutilation in chorea-acanthocytosis: manifestation of movement disorder or psychopathology? Mov Disord 21:2268–2269.
Walker RH, Jung HH, Dobson-Stone C, Rampoldi L, Sano A, Tison F, Danek A (2007) Neurologic phenotypes associated with acanthocytosis. Neurology 68:92–98.
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Velayos-Baeza, A., Lévecque, C., Dobson-Stone, C., Monaco, A.P. (2008). The Function of Chorein. In: Walker, R.H., Saiki, S., Danek, A. (eds) Neuroacanthocytosis Syndromes II. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-71693-8_7
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