title: KIF1A missense mutations in SPG30, an autosomal recessive spastic paraplegia: distinct phenotypes according to the nature of the mutations.
abstract: The hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative diseases characterised by progressive spasticity in the lower limbs. The nosology of autosomal recessive forms is complex as most mapped loci have been identified in only one or a few families and account for only a small percentage of patients. We used next-generation sequencing focused on the SPG30 chromosomal region on chromosome 2q37.3 in two patients from the original linked family. In addition, wide genome scan and candidate gene analysis were performed in a second family of Palestinian origin. We identified a single homozygous mutation, p.R350G, that was found to cosegregate with the disease in the SPG30 kindred and was absent in 970 control chromosomes while affecting a strongly conserved amino acid at the end of the motor domain of KIF1A. Homozygosity and linkage mapping followed by mutation screening of KIF1A allowed us to identify a second mutation, p.A255V, in the second family. Comparison of the clinical features with the nature of the mutations of all reported KIF1A families, including those reported recently with hereditary sensory and autonomic neuropathy, suggests phenotype-genotype correlations that may help to understand the mechanisms involved in motor neuron degeneration. We have shown that mutations in the KIF1A gene are responsible for SPG30 in two autosomal recessive HSP families. In published families, the nature of the KIF1A mutations seems to be of good predictor of the underlying phenotype and vice versa.
authors.affiliation: INSERM, U975, Paris, France.
authors.forename: Stephan
authors.initials: S
authors.lastname: Klebe
authors.forename: Alexander
authors.initials: A
authors.lastname: Lossos
authors.forename: Hamid
authors.initials: H
authors.lastname: Azzedine
authors.forename: Emeline
authors.initials: E
authors.lastname: Mundwiller
authors.forename: Ruth
authors.initials: R
authors.lastname: Sheffer
authors.forename: Marion
authors.initials: M
authors.lastname: Gaussen
authors.forename: Cecilia
authors.initials: C
authors.lastname: Marelli
authors.forename: Magdalena
authors.initials: M
authors.lastname: Nawara
authors.forename: Wassila
authors.initials: W
authors.lastname: Carpentier
authors.forename: Vincent
authors.initials: V
authors.lastname: Meyer
authors.forename: Agnès
authors.initials: A
authors.lastname: Rastetter
authors.forename: Elodie
authors.initials: E
authors.lastname: Martin
authors.forename: Delphine
authors.initials: D
authors.lastname: Bouteiller
authors.forename: Laurent
authors.initials: L
authors.lastname: Orlando
authors.forename: Gabor
authors.initials: G
authors.lastname: Gyapay
authors.forename: Khalid H
authors.initials: KH
authors.lastname: El-Hachimi
authors.forename: Batel
authors.initials: B
authors.lastname: Zimmerman
authors.forename: Moriya
authors.initials: M
authors.lastname: Gamliel
authors.forename: Adel
authors.initials: A
authors.lastname: Misk
authors.forename: Israela
authors.initials: I
authors.lastname: Lerer
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.forename: Alexandra
authors.initials: A
authors.lastname: Durr
authors.forename: Giovanni
authors.initials: G
authors.lastname: Stevanin
mesh_terms: D002874:Chromosome Mapping; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D005190:Family; D005808:Genes, Recessive; D018740:Genetic Heterogeneity; D006720:Homozygote; D006801:Humans; D016547:Kinesins / Q000235:genetics*; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics* / Q000378:metabolism
chemical_list: C094065:KIF1A protein, human; D016547:Kinesins