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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Lee JR, Shin H, Ko J, Choi J, Lee H, Kim E (2003) Characterization of the movement of the kinesin motor KIF1A in living cultured neurons. J Biol Chem 278:2624–2629. doi:10.1074/jbc.M211152200
Okada Y, Yamazaki H, Sekine-Aizawa Y, Hirokawa N (1995) The neuron-specific kinesin superfamily protein KIF1A is a unique monomeric motor for anterograde axonal transport of synaptic vesicle precursors. Cell 81:769–780. doi:10.1016/0092-8674(95)90538-3
Rivière JB, Ramalingam S, Lavastre V, Shekarabi M, Holbert S, Lafontaine J, Srour M, Merner N, Rochefort D, Hince P, Gaudet R, Mes-Masson AM, Baets J, Houlden H, Brais B, Nicholson GA, Van Esch H, Nafissi S, De Jonghe P, Reilly MM, Timmerman V, Dion PA, Rouleau GA (2011) KIF1A, an axonal transporter of synaptic vesicles, is mutated in hereditary sensory and autonomic neuropathy type 2. Am J Hum Genet 89:219–230. doi:10.1016/j.ajhg.2011.06.013
Erlich Y, Edvardson S, Hodges E, Zenvirt S, Thekkat P, Shaag A, Dor T, Hannon GJ, Elpeleg O (2011) Exome sequencing and disease-network analysis of a single family implicate a mutation in KIF1A in hereditary spastic paraparesis. Genome Res 21:658–664. doi:10.1101/gr.117143.110
Klebe S, Lossos A, Azzedine H, Mundwiller E, Sheffer R, Gaussen M, Marelli C, Nawara M, Carpentier W, Meyer V, Rastetter A, Martin E, Bouteiller D, Orlando L, Gyapay G, El-Hachimi KH, Zimmerman B, Gamliel M, Misk A, Lerer I, Brice A, Durr A, Stevanin G (2012) KIF1A missense mutations in SPG30, an autosomal recessive spastic paraplegia: distinct phenotypes according to the nature of the mutations. Eur J Hum Genet 20:645–649. doi:10.1038/ejhg.2011.261
Hamdan FF, Gauthier J, Araki Y, Lin DT, Yoshizawa Y, Higashi K, Park AR, Spiegelman D, Dobrzeniecka S, Piton A, Tomitori H, Daoud H, Massicotte C, Henrion E, Diallo O, S2D Group, Shekarabi M, Marineau C, Shevell M, Maranda B, Mitchell G, Nadeau A, D’Anjou G, Vanasse M, Srour M, Lafrenière RG, Drapeau P, Lacaille JC, Kim E, Lee JR, Igarashi K, Huganir RL, Rouleau GA, Michaud JL (2011) Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability. Am J Hum Genet 88:306–316. doi:10.1016/j.ajhg.2011.02.001
Okamoto N, Miya F, Tsunoda T, Yanagihara K, Kato M, Saitoh S, Yamasaki M, Kanemura Y, Kosaki K (2014) KIF1A mutation in a patient with progressive neurodegeneration. J Hum Genet 59:639–641. doi:10.1038/jhg.2014.80
Esmaeeli Nieh S, Madou MR, Sirajuddin M, Fregeau B, McKnight D, Lexa K, Strober J, Spaeth C, Hallinan BE, Smaoui N, Pappas JG, Burrow TA, McDonald MT, Latibashvili M, Leshinsky-Silver E, Lev D, Blumkin L, Vale RD, Barkovich AJ, Sherr EH (2015) De novo mutations in KIF1A cause progressive encephalopathy and brain atrophy. Ann Clin Transl Neurol 2(6):623–635. doi:10.1002/acn3.198
Lee JR, Srour M, Kim D, Hamdan FF, Lim SH, Brunel-Guitton C, Décarie JC, Rossignol E, Mitchell GA, Schreiber A, Moran R, Van Haren K, Richardson R, Nicolai J, Oberndorff KM, Wagner JD, Boycott KM, Rahikkala E, Junna N, Tyynismaa H, Cuppen I, Verbeek NE, Stumpel CT, Willemsen MA, de Munnik SA, Rouleau GA, Kim E, Kamsteeg EJ, Kleefstra T, Michaud JL (2015) De novo mutations in the motor domain of KIF1A cause cognitive impairment, spastic paraparesis, axonal neuropathy, and cerebellar atrophy. Hum Mutat 36:69–78. doi:10.1002/humu.22709
Ylikallio E, Kim D, Isohanni P, Auranen M, Kim E, Lönnqvist T, Tyynismaa H (2015) Dominant transmission of de novo KIF1A motor domain variant underlying pure spastic paraplegia. Eur J Hum Genet. doi:10.1038/ejhg.2014.297
Shin H, Wyszynski M, Huh KH, Valtschanoff JG, Lee JR, Ko J, Streuli M, Weinberg RJ, Sheng M, Kim E (2003) Association of the kinesin motor KIF1A with the multimodular protein liprin-alpha. J Biol Chem 278:11393–11401. doi:10.1074/jbc.M211874200
Harding AE (1983) Classification of the hereditary ataxias and paraplegias. Lancet 1(8334):1151–1155. doi:10.1016/S0140-6736(83)92879-9
Citterio A, Arnoldi A, Panzeri E, D’Angelo MG, Filosto M, Dilena R, Arrigoni F, Castelli M, Maghini C, Germiniasi C, Menni F, Martinuzzi A, Bresolin N, Bassi MT (2014) Mutations in CYP2U1, DDHD2 and GBA2 genes are rare causes of complicated forms of hereditary spastic paraparesis. J Neurol 267:373–381. doi:10.1007/s00415-013-7206-6
Goizet C, Boukhris A, Mundwiller E, Tallaksen C, Forlani S, Toutain A, Carriere N, Paquis V, Depienne C, Durr A, Stevanin G, Brice A (2009) Complicated forms of autosomal dominant hereditary spastic paraplegia are frequent in SPG10. Hum Mutat 30:E376–E385. doi:10.1002/humu.20920
Web Resources
Genome database: http://browser.1000genomes.org/index.html
NCBI dbSNP: http://www.ncbi.nlm.nih.gov/SNP/
SIFT and Provean: http://sift.jcvi.org/
MutPred: http://mutpred.mutdb.org/
Acknowledgments
The authors wish to thanks the patients and their families for participation to this work and all referring clinicians for collaboration. This work was supported by the Italian Ministry of health under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases” Grant NEUROLIPID and Grant No. 2015 and 5xMille.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflicts of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
Ethical standards
All human studies have been approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in 1964 Declaration of Helsinki and its later amendments. All persons gave their informed consent prior to their inclusion in the study. We have not included any details that might disclose the identity of the subjects in the study.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Citterio, A., Arnoldi, A., Panzeri, E. et al. Variants in KIF1A gene in dominant and sporadic forms of hereditary spastic paraparesis. J Neurol 262, 2684–2690 (2015). https://doi.org/10.1007/s00415-015-7899-9
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00415-015-7899-9