title: ZFYVE27 (SPG33), a novel spastin-binding protein, is mutated in hereditary spastic paraplegia.
abstract: Spastin, the most commonly mutated protein in the autosomal dominant form of hereditary spastic paraplegia (AD-HSP) has been suggested to be involved in vesicular cargo trafficking; however, a comprehensive function of spastin has not yet been elucidated. To characterize the molecular function of spastin, we used the yeast two-hybrid approach to identify new interacting partners of spastin. Here, we report ZFYVE27, a novel member of the FYVE-finger family of proteins, as a specific spastin-binding protein, and we validate the interaction by both in vivo coimmunoprecipitation and colocalization experiments in mammalian cells. More importantly, we report a German family with AD-HSP in which ZFYVE27 (SPG33) is mutated; furthermore, we demonstrate that the mutated ZFYVE27 protein shows an aberrant intracellular pattern in its tubular structure and that its interaction with spastin is severely affected. We postulate that this specific mutation in ZFYVE27 affects neuronal intracellular trafficking in the corticospinal tract, which is consistent with the pathology of HSP.
authors.affiliation: Institute of Human Genetics, University of Goettingen, Heinrich-Dueker Weg 12, D-37073, Goettingen, Germany. amannan@gwdg.de
authors.forename: Ashraf U
authors.initials: AU
authors.lastname: Mannan
authors.forename: Philip
authors.initials: P
authors.lastname: Krawen
authors.forename: Simone M
authors.initials: SM
authors.lastname: Sauter
authors.forename: Johann
authors.initials: J
authors.lastname: Boehm
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Chronowska
authors.forename: Walter
authors.initials: W
authors.lastname: Paulus
authors.forename: Juergen
authors.initials: J
authors.lastname: Neesen
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Engel
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism*; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D041681:NIH 3T3 Cells; D009474:Neurons / Q000378:metabolism; D010375:Pedigree; D011485:Protein Binding / Q000235:genetics; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics* / Q000378:metabolism; D000074181:Spastin; D033921:Vesicular Transport Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D033921:Vesicular Transport Proteins; C513390:ZFYVE27 protein, human; D000251:Adenosine Triphosphatases; D000074181:Spastin; C400283:SPAST protein, human