title: Variants in KIF1A gene in dominant and sporadic forms of hereditary spastic paraparesis.
abstract: KIF1A gene encodes the kinesin 1a protein, an axonal motor protein working in cargo transport along neurites. Variants in KIF1A were identified in different forms of neurodegenerative diseases with dominant and recessive inheritance. Homozygous recessive mutations were found in the hereditary sensory and autonomic neuropathy type 2, HSAN2 and in a recessive subtype of hereditary spastic paraparesis, SPG30. De novo heterozygous dominant variants were found both in a dominant form of SPG30 (AD-SPG30) with one single family reported and in patients with different forms of progressive neurodegenerative diseases. We report the results of a genetic screening of 192 HSP patients, with the identification of four heterozygous variants in KIF1A in four cases, two of whom with family history for the disease. Three of the four variants fall within the motor domain, a frequent target for variants related to the AD-SPG30 subtype. The fourth variant falls downstream the motor domain in a region lacking any functional domain. The KIF1A-related patients show clinical pictures overlapping the known AD-SPG30 phenotype including pure and complicated forms with few differences. Of note, one of the families, originating from the Sicily island, carries the same variant p.S69L detected in the first AD-SPG30 family of Finnish origin reported; differently from the first one, the latter family shows a wide intra-familial phenotype variability. Overall, these data reveal a very low frequency of the AD-SPG30 subtype while confirming the presence of amino acid residues in the motor domain representing preferential targets for mutations, thereby supporting their functional relevance in kinesin 1a activity.
authors.affiliation: Laboratory of Molecular Biology, Scientific Institute IRCCS E. Medea, Via D. L. Monza 20, 23842, Bosisio Parini, Lecco, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Citterio
authors.affiliation: Laboratory of Molecular Biology, Scientific Institute IRCCS E. Medea, Via D. L. Monza 20, 23842, Bosisio Parini, Lecco, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Arnoldi
authors.affiliation: Laboratory of Molecular Biology, Scientific Institute IRCCS E. Medea, Via D. L. Monza 20, 23842, Bosisio Parini, Lecco, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Panzeri
authors.affiliation: SC Laboratory of Musculoskeletal Cell Biology, Istituto Ortopedico Rizzoli, IRCCS, Bologna, Italy.
authors.forename: Luciano
authors.initials: L
authors.lastname: Merlini
authors.affiliation: Neuromuscular Disorders Unit, Scientific Institute IRCCS E. Medea, 23842, Bosisio Parini, Lecco, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: D'Angelo
authors.affiliation: Department of Neurosciences, University of Messina, Messina, Italy.
authors.forename: Olimpia
authors.initials: O
authors.lastname: Musumeci
authors.affiliation: Department of Neurosciences, University of Messina, Messina, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Toscano
authors.affiliation: Department of Rizzoli-Sicilia, Istituto Ortopedico Rizzoli, 90011, Palermo, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Bondi
authors.affiliation: Conegliano Research Center, Scientific Institute IRCCS E. Medea, Conegliano, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Martinuzzi
authors.affiliation: Laboratory of Molecular Biology, Scientific Institute IRCCS E. Medea, Via D. L. Monza 20, 23842, Bosisio Parini, Lecco, Italy.|Neurology Unit, IRCCS Ca' Granda, Ospedale Maggiore Policlinico Foundation, Dino Ferrari Centre, Department of Physiopathology and Transplantation, Universita' di Milano, Milan, Italy.
authors.forename: Nereo
authors.initials: N
authors.lastname: Bresolin
authors.affiliation: Laboratory of Molecular Biology, Scientific Institute IRCCS E. Medea, Via D. L. Monza 20, 23842, Bosisio Parini, Lecco, Italy. mariateresa.bassi@bp.lnf.it.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Bassi
mesh_terms: D000328:Adult; D000368:Aged; D002648:Child; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D016547:Kinesins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics* / Q000503:physiopathology*; D055815:Young Adult
chemical_list: C094065:KIF1A protein, human; D016547:Kinesins
keywords: Dominant inheritance; KIF1A; NGS-targeted resequencing; Spastic paraparesis