title: Mutations in the motor and stalk domains of KIF5A in spastic paraplegia type 10 and in axonal Charcot-Marie-Tooth type 2.
abstract: Spastic paraplegia type 10 (SPG10) is an autosomal dominant form of hereditary spastic paraplegia (HSP) due to mutations in KIF5A, a gene encoding the neuronal kinesin heavy chain implicated in anterograde axonal transport. KIF5A mutations were found in both pure and complicated forms of the disease; a single KIF5A mutation was also detected in a CMT2 patient belonging to an SPG10 mutant family. To confirm the involvement of the KIF5A gene in both CMT2 and SPG10 phenotypes and to define the frequency of KIF5A mutations in an Italian HSP patient population, we performed a genetic screening of this gene in a series of 139 HSP and 36 CMT2 affected subjects. We identified five missense changes, four in five HSP patients and one in a CMT2 subject. All mutations, including the one segregating in the CMT2 patient, are localized in the kinesin motor domain except for one, falling within the stalk domain and predicted to generate protein structure destabilization. The results obtained indicate a KIF5A mutation frequency of 8.8% in the Italian HSP population and identify a region of the kinesin protein, the stalk domain, as a novel target for mutation. In addition, the mutation found in the CMT2 patient strengthens the hypothesis that CMT2 and SPG10 are the extreme phenotypes resulting from mutations in the same gene.
authors.affiliation: Laboratory of Molecular Biology, E. Medea Scientific Institute, Bosisio Parini, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Crimella
authors.forename: C
authors.initials: C
authors.lastname: Baschirotto
authors.forename: A
authors.initials: A
authors.lastname: Arnoldi
authors.forename: A
authors.initials: A
authors.lastname: Tonelli
authors.forename: E
authors.initials: E
authors.lastname: Tenderini
authors.forename: G
authors.initials: G
authors.lastname: Airoldi
authors.forename: A
authors.initials: A
authors.lastname: Martinuzzi
authors.forename: A
authors.initials: A
authors.lastname: Trabacca
authors.forename: L
authors.initials: L
authors.lastname: Losito
authors.forename: M
authors.initials: M
authors.lastname: Scarlato
authors.forename: S
authors.initials: S
authors.lastname: Benedetti
authors.forename: E
authors.initials: E
authors.lastname: Scarpini
authors.forename: G
authors.initials: G
authors.lastname: Spinicci
authors.forename: N
authors.initials: N
authors.lastname: Bresolin
authors.forename: M T
authors.initials: MT
authors.lastname: Bassi
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D002648:Child; D005091:Exons; D006801:Humans; D016547:Kinesins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D054730:Protein Interaction Domains and Motifs / Q000235:genetics*; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics*; D055815:Young Adult
chemical_list: C500506:KIF5A protein, human; D016547:Kinesins