This Italian study of the KIF5A gene strengthens the case that SPG10 HSP and Charcot-Marie-Tooth type 2 are two possible outcomes of mutations in this gene.
The prevalence of the SPG10 form of HSP was found to be around 9% in the Italian HSP population.
Mutations in the motor and stalk domains of KIF5A in spastic paraplegia type 10 and in axonal Charcot-Marie-Tooth type 2. 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.
SOURCE: Clin Genet. 2012 Aug;82(2):157-164. doi: 10.1111/j.1399-0004.2011.01717.x. Epub 2011 Jun 21. © 2011 John Wiley & Sons A/S. PMID: 21623771 [PubMed – as supplied by publisher]
Mutations in the motor and stalk domains of KIF5A in spastic paraplegia type 10 and in axonal Charcot-Marie-Tooth type 2.
Laboratory of Molecular Biology, E. Medea Scientific Institute, Bosisio Parini, Italy Conegliano Research Center, E Medea Scientific Institute, Conegliano, Italy Unit of Neurorehabilitation I, Developmental Neurology and Functional Rehabilitation, E. Medea Scientific Institute, Ostuni, Italy Department of Neurology and Institute of Experimental Neurology (INSpe), San Raffaele Scientific Institute, Milan, Italy Laboratory of Clinical Molecular Biology, Diagnostica e Ricerca San Raffaele, DIBIT 2 Milan, Italy Department of Neurological Sciences, Dino Ferrari Centre, IRCCS Ca’ Granda, Ospedale Maggiore Policlinico Foundation, University of Milan, Italy Center for Multiple Sclerosis, Binaghi Hospital, ASL8 Cagliari, Italy.