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KIF1C mutations in two families with hereditary spastic paraparesis and cerebellar dysfunction
  1. Talya Dor1,
  2. Yuval Cinnamon2,
  3. Laure Raymond3,4,
  4. Avraham Shaag2,
  5. Naima Bouslam3,5,
  6. Ahmed Bouhouche5,
  7. Marion Gaussen3,4,
  8. Vincent Meyer6,
  9. Alexandra Durr3,7,
  10. Alexis Brice3,7,
  11. Ali Benomar5,8,
  12. Giovanni Stevanin3,4,7,
  13. Markus Schuelke9,
  14. Simon Edvardson1
  1. 1Department of Pediatrics, Neuropediatric Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
  2. 2Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
  3. 3Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, UPMC Univ Paris VI UMR_S975; CNRS UMR 7225; INSERM U975, Hôpital de la Pitié-Salpêtrière, Paris, France
  4. 4Groupe de Neurogénétique, Ecole Pratique des Hautes Etudes, Institut du Cerveau et de la Moelle épinière, Paris, France
  5. 5Faculté de Médecine et de Pharmacie de Rabat, Université Mohammed V Souissi, Equipe de recherche des maladies neurodégéneratives (ERMN), Rabat, Morocco
  6. 6Genoscope, Evry, France
  7. 7APHP, Fédération de Génétique, Hôpital de la Pitié-Salpêtrière, Paris, France
  8. 8Faculté de Médecine et de Pharmacie de Rabat, Université Mohammed V Souissi, Centre de recherche en épidémiologie clinique et essai thérapeutique (CRECET), Rabat, Morocco
  9. 9Department of Neuropediatrics and NeuroCure Clinical Research Center, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, Berlin, Germany
  1. Correspondence to Professor Markus Schuelke, Department of Neuropediatrics, Charité Universitäts medizin Berlin, Augustenburger Platz 1, Berlin D-13353, Germany; markus.schuelke{at}charite.de Dr. Simon Edvardson, Department of Pediatrics, Neuropediatric unit, Hebrew University Medical Center, 91120 Jerusalem, Israel; simon{at}hadassah.org.il

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.

Methods and 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.

  • Movement Disorders (other than Parkinsons)
  • Neurology
  • Clinical Genetics
  • Genetics

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