title: KIF1C mutations in two families with hereditary spastic paraparesis and cerebellar dysfunction.
abstract: BACKGROUND
  Hereditary spastic paraparesis (HSP) (syn. Hereditary spastic paraplegia, SPG) are a group of genetic disorders characterised by spasticity of the lower limbs due to pyramidal tract dysfunction. Nearly 60 disease loci have been identified, which include mutations in two genes (KIF5A and KIF1A) that encode motor proteins of the kinesin superfamily. Here we report a novel genetic defect in KIF1C of patients with spastic paraparesis and cerebellar dysfunction in two consanguineous families of Palestinian and Moroccan ancestry.
  
  
  RESULTS
  We performed autozygosity mapping in a Palestinian and classic linkage analysis in a Moroccan family and found a locus on chromosome 17 that had previously been associated with spastic ataxia type 2 (SPAX2, OMIM %611302). Whole-exome sequencing revealed two homozygous mutations in KIF1C that were absent among controls: a nonsense mutation (c.2191C>T, p.Arg731*) that segregated with the disease phenotype in the Palestinian kindred resulted in the entire absence of KIF1C protein from the patient's fibroblasts, and a missense variant (c.505C>T, p.Arg169Trp) affecting a conserved amino acid of the motor domain that was found in the Moroccan kindred.
  
  
  CONCLUSIONS
  Kinesin genes encode a family of cargo/motor proteins and are known to cause HSP if mutated. Here we identified nonsense and missense mutations in a further member of this protein family. The KIF1C mutation is associated with a HSP subtype (SPAX2/SAX2) that combines spastic paraplegia and weakness with cerebellar dysfunction.
authors: Department of Pediatrics, Neuropediatric Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors: Talya
authors: T
authors: Dor
authors: Yuval
authors: Y
authors: Cinnamon
authors: Laure
authors: L
authors: Raymond
authors: Avraham
authors: A
authors: Shaag
authors: Naima
authors: N
authors: Bouslam
authors: Ahmed
authors: A
authors: Bouhouche
authors: Marion
authors: M
authors: Gaussen
authors: Vincent
authors: V
authors: Meyer
authors: Alexandra
authors: A
authors: Durr
authors: Alexis
authors: A
authors: Brice
authors: Ali
authors: A
authors: Benomar
authors: Giovanni
authors: G
authors: Stevanin
authors: Markus
authors: M
authors: Schuelke
authors: Simon
authors: S
authors: Edvardson
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D001483:Base Sequence; D002526:Cerebellar Diseases / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D008040:Genetic Linkage; D057809:HEK293 Cells; D006801:Humans; D007223:Infant; D016547:Kinesins / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D020336:Paraparesis, Spastic / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: C114063:KIF1C protein, human; D016547:Kinesins
keywords: Clinical Genetics; Genetics; Movement Disorders (other than Parkinsons); Neurology