title: Motor protein mutations cause a new form of hereditary spastic paraplegia.
abstract: OBJECTIVE
  To identify a novel disease gene in 2 families with autosomal recessive hereditary spastic paraplegia (HSP).
  
  
  METHODS
  We used whole-exome sequencing to identify the underlying genetic disease cause in 2 families with apparently autosomal recessive spastic paraplegia. Endogenous expression as well as subcellular localization of wild-type and mutant protein were studied to support the pathogenicity of the identified mutations.
  
  
  RESULTS
  In 2 families, we identified compound heterozygous or homozygous mutations in the kinesin gene KIF1C to cause hereditary spastic paraplegia type 58 (SPG58). SPG58 can be complicated by cervical dystonia and cerebellar ataxia. The same mutations in a heterozygous state result in a mild or subclinical phenotype. KIF1C mutations in SPG58 affect the domains involved in adenosine triphosphate hydrolysis and microtubule binding, key functions for this microtubule-based motor protein.
  
  
  CONCLUSIONS
  KIF1C is the third kinesin gene involved in the pathogenesis of HSPs and is characterized by a mild dominant and a more severe recessive disease phenotype. The identification of KIF1C as an HSP disease gene further supports the key role of intracellular trafficking processes in the pathogenesis of hereditary axonopathies.
authors.affiliation: From the Hertie-Institute for Clinical Brain Research (A.C.O., J.R., L.S., R.S.), Department of Neurodegenerative Diseases, University of Tübingen, Germany; Bogazici University (E.B., B.O.), Department of Molecular Biology and Genetics, Istanbul; Tepecik Research and Training Hospital (L.O., Y.Z.), Clinics of Neurology, Izmir, Turkey; Diagnostic and Interventional Neuroradiology (T.L., B.B.), Department of Radiology, University Hospital Tübingen; German Research Center for Neurodegenerative Diseases (DZNE) (J.R., R.S., L.S.), Tübingen, Germany; Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics (A.P.R., M.A.G., S.Z., R.S.), University of Miami Miller School of Medicine, FL; Department of Neurology (D.T.), University of Duisburg-Essen; and Department of Physics E22 (Biophysics) (G.W.), Technical University Munich, Garching, Germany.
authors.forename: Andrés
authors.initials: A
authors.lastname: Caballero Oteyza
authors.affiliation: From the Hertie-Institute for Clinical Brain Research (A.C.O., J.R., L.S., R.S.), Department of Neurodegenerative Diseases, University of Tübingen, Germany; Bogazici University (E.B., B.O.), Department of Molecular Biology and Genetics, Istanbul; Tepecik Research and Training Hospital (L.O., Y.Z.), Clinics of Neurology, Izmir, Turkey; Diagnostic and Interventional Neuroradiology (T.L., B.B.), Department of Radiology, University Hospital Tübingen; German Research Center for Neurodegenerative Diseases (DZNE) (J.R., R.S., L.S.), Tübingen, Germany; Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics (A.P.R., M.A.G., S.Z., R.S.), University of Miami Miller School of Medicine, FL; Department of Neurology (D.T.), University of Duisburg-Essen; and Department of Physics E22 (Biophysics) (G.W.), Technical University Munich, Garching, Germany.
authors.forename: Esra
authors.initials: E
authors.lastname: Battaloğlu
authors.affiliation: From the Hertie-Institute for Clinical Brain Research (A.C.O., J.R., L.S., R.S.), Department of Neurodegenerative Diseases, University of Tübingen, Germany; Bogazici University (E.B., B.O.), Department of Molecular Biology and Genetics, Istanbul; Tepecik Research and Training Hospital (L.O., Y.Z.), Clinics of Neurology, Izmir, Turkey; Diagnostic and Interventional Neuroradiology (T.L., B.B.), Department of Radiology, University Hospital Tübingen; German Research Center for Neurodegenerative Diseases (DZNE) (J.R., R.S., L.S.), Tübingen, Germany; Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics (A.P.R., M.A.G., S.Z., R.S.), University of Miami Miller School of Medicine, FL; Department of Neurology (D.T.), University of Duisburg-Essen; and Department of Physics E22 (Biophysics) (G.W.), Technical University Munich, Garching, Germany.
authors.forename: Levent
authors.initials: L
authors.lastname: Ocek
authors.affiliation: From the Hertie-Institute for Clinical Brain Research (A.C.O., J.R., L.S., R.S.), Department of Neurodegenerative Diseases, University of Tübingen, Germany; Bogazici University (E.B., B.O.), Department of Molecular Biology and Genetics, Istanbul; Tepecik Research and Training Hospital (L.O., Y.Z.), Clinics of Neurology, Izmir, Turkey; Diagnostic and Interventional Neuroradiology (T.L., B.B.), Department of Radiology, University Hospital Tübingen; German Research Center for Neurodegenerative Diseases (DZNE) (J.R., R.S., L.S.), Tübingen, Germany; Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics (A.P.R., M.A.G., S.Z., R.S.), University of Miami Miller School of Medicine, FL; Department of Neurology (D.T.), University of Duisburg-Essen; and Department of Physics E22 (Biophysics) (G.W.), Technical University Munich, Garching, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Lindig
authors.affiliation: From the Hertie-Institute for Clinical Brain Research (A.C.O., J.R., L.S., R.S.), Department of Neurodegenerative Diseases, University of Tübingen, Germany; Bogazici University (E.B., B.O.), Department of Molecular Biology and Genetics, Istanbul; Tepecik Research and Training Hospital (L.O., Y.Z.), Clinics of Neurology, Izmir, Turkey; Diagnostic and Interventional Neuroradiology (T.L., B.B.), Department of Radiology, University Hospital Tübingen; German Research Center for Neurodegenerative Diseases (DZNE) (J.R., R.S., L.S.), Tübingen, Germany; Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics (A.P.R., M.A.G., S.Z., R.S.), University of Miami Miller School of Medicine, FL; Department of Neurology (D.T.), University of Duisburg-Essen; and Department of Physics E22 (Biophysics) (G.W.), Technical University Munich, Garching, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Reichbauer
authors.affiliation: From the Hertie-Institute for Clinical Brain Research (A.C.O., J.R., L.S., R.S.), Department of Neurodegenerative Diseases, University of Tübingen, Germany; Bogazici University (E.B., B.O.), Department of Molecular Biology and Genetics, Istanbul; Tepecik Research and Training Hospital (L.O., Y.Z.), Clinics of Neurology, Izmir, Turkey; Diagnostic and Interventional Neuroradiology (T.L., B.B.), Department of Radiology, University Hospital Tübingen; German Research Center for Neurodegenerative Diseases (DZNE) (J.R., R.S., L.S.), Tübingen, Germany; Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics (A.P.R., M.A.G., S.Z., R.S.), University of Miami Miller School of Medicine, FL; Department of Neurology (D.T.), University of Duisburg-Essen; and Department of Physics E22 (Biophysics) (G.W.), Technical University Munich, Garching, Germany.
authors.forename: Adriana P
authors.initials: AP
authors.lastname: Rebelo
authors.affiliation: From the Hertie-Institute for Clinical Brain Research (A.C.O., J.R., L.S., R.S.), Department of Neurodegenerative Diseases, University of Tübingen, Germany; Bogazici University (E.B., B.O.), Department of Molecular Biology and Genetics, Istanbul; Tepecik Research and Training Hospital (L.O., Y.Z.), Clinics of Neurology, Izmir, Turkey; Diagnostic and Interventional Neuroradiology (T.L., B.B.), Department of Radiology, University Hospital Tübingen; German Research Center for Neurodegenerative Diseases (DZNE) (J.R., R.S., L.S.), Tübingen, Germany; Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics (A.P.R., M.A.G., S.Z., R.S.), University of Miami Miller School of Medicine, FL; Department of Neurology (D.T.), University of Duisburg-Essen; and Department of Physics E22 (Biophysics) (G.W.), Technical University Munich, Garching, Germany.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Gonzalez
authors.affiliation: From the Hertie-Institute for Clinical Brain Research (A.C.O., J.R., L.S., R.S.), Department of Neurodegenerative Diseases, University of Tübingen, Germany; Bogazici University (E.B., B.O.), Department of Molecular Biology and Genetics, Istanbul; Tepecik Research and Training Hospital (L.O., Y.Z.), Clinics of Neurology, Izmir, Turkey; Diagnostic and Interventional Neuroradiology (T.L., B.B.), Department of Radiology, University Hospital Tübingen; German Research Center for Neurodegenerative Diseases (DZNE) (J.R., R.S., L.S.), Tübingen, Germany; Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics (A.P.R., M.A.G., S.Z., R.S.), University of Miami Miller School of Medicine, FL; Department of Neurology (D.T.), University of Duisburg-Essen; and Department of Physics E22 (Biophysics) (G.W.), Technical University Munich, Garching, Germany.
authors.forename: Yasar
authors.initials: Y
authors.lastname: Zorlu
authors.affiliation: From the Hertie-Institute for Clinical Brain Research (A.C.O., J.R., L.S., R.S.), Department of Neurodegenerative Diseases, University of Tübingen, Germany; Bogazici University (E.B., B.O.), Department of Molecular Biology and Genetics, Istanbul; Tepecik Research and Training Hospital (L.O., Y.Z.), Clinics of Neurology, Izmir, Turkey; Diagnostic and Interventional Neuroradiology (T.L., B.B.), Department of Radiology, University Hospital Tübingen; German Research Center for Neurodegenerative Diseases (DZNE) (J.R., R.S., L.S.), Tübingen, Germany; Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics (A.P.R., M.A.G., S.Z., R.S.), University of Miami Miller School of Medicine, FL; Department of Neurology (D.T.), University of Duisburg-Essen; and Department of Physics E22 (Biophysics) (G.W.), Technical University Munich, Garching, Germany.
authors.forename: Burcak
authors.initials: B
authors.lastname: Ozes
authors.affiliation: From the Hertie-Institute for Clinical Brain Research (A.C.O., J.R., L.S., R.S.), Department of Neurodegenerative Diseases, University of Tübingen, Germany; Bogazici University (E.B., B.O.), Department of Molecular Biology and Genetics, Istanbul; Tepecik Research and Training Hospital (L.O., Y.Z.), Clinics of Neurology, Izmir, Turkey; Diagnostic and Interventional Neuroradiology (T.L., B.B.), Department of Radiology, University Hospital Tübingen; German Research Center for Neurodegenerative Diseases (DZNE) (J.R., R.S., L.S.), Tübingen, Germany; Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics (A.P.R., M.A.G., S.Z., R.S.), University of Miami Miller School of Medicine, FL; Department of Neurology (D.T.), University of Duisburg-Essen; and Department of Physics E22 (Biophysics) (G.W.), Technical University Munich, Garching, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Timmann
authors.affiliation: From the Hertie-Institute for Clinical Brain Research (A.C.O., J.R., L.S., R.S.), Department of Neurodegenerative Diseases, University of Tübingen, Germany; Bogazici University (E.B., B.O.), Department of Molecular Biology and Genetics, Istanbul; Tepecik Research and Training Hospital (L.O., Y.Z.), Clinics of Neurology, Izmir, Turkey; Diagnostic and Interventional Neuroradiology (T.L., B.B.), Department of Radiology, University Hospital Tübingen; German Research Center for Neurodegenerative Diseases (DZNE) (J.R., R.S., L.S.), Tübingen, Germany; Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics (A.P.R., M.A.G., S.Z., R.S.), University of Miami Miller School of Medicine, FL; Department of Neurology (D.T.), University of Duisburg-Essen; and Department of Physics E22 (Biophysics) (G.W.), Technical University Munich, Garching, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Bender
authors.affiliation: From the Hertie-Institute for Clinical Brain Research (A.C.O., J.R., L.S., R.S.), Department of Neurodegenerative Diseases, University of Tübingen, Germany; Bogazici University (E.B., B.O.), Department of Molecular Biology and Genetics, Istanbul; Tepecik Research and Training Hospital (L.O., Y.Z.), Clinics of Neurology, Izmir, Turkey; Diagnostic and Interventional Neuroradiology (T.L., B.B.), Department of Radiology, University Hospital Tübingen; German Research Center for Neurodegenerative Diseases (DZNE) (J.R., R.S., L.S.), Tübingen, Germany; Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics (A.P.R., M.A.G., S.Z., R.S.), University of Miami Miller School of Medicine, FL; Department of Neurology (D.T.), University of Duisburg-Essen; and Department of Physics E22 (Biophysics) (G.W.), Technical University Munich, Garching, Germany.
authors.forename: Günther
authors.initials: G
authors.lastname: Woehlke
authors.affiliation: From the Hertie-Institute for Clinical Brain Research (A.C.O., J.R., L.S., R.S.), Department of Neurodegenerative Diseases, University of Tübingen, Germany; Bogazici University (E.B., B.O.), Department of Molecular Biology and Genetics, Istanbul; Tepecik Research and Training Hospital (L.O., Y.Z.), Clinics of Neurology, Izmir, Turkey; Diagnostic and Interventional Neuroradiology (T.L., B.B.), Department of Radiology, University Hospital Tübingen; German Research Center for Neurodegenerative Diseases (DZNE) (J.R., R.S., L.S.), Tübingen, Germany; Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics (A.P.R., M.A.G., S.Z., R.S.), University of Miami Miller School of Medicine, FL; Department of Neurology (D.T.), University of Duisburg-Essen; and Department of Physics E22 (Biophysics) (G.W.), Technical University Munich, Garching, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Züchner
authors.affiliation: From the Hertie-Institute for Clinical Brain Research (A.C.O., J.R., L.S., R.S.), Department of Neurodegenerative Diseases, University of Tübingen, Germany; Bogazici University (E.B., B.O.), Department of Molecular Biology and Genetics, Istanbul; Tepecik Research and Training Hospital (L.O., Y.Z.), Clinics of Neurology, Izmir, Turkey; Diagnostic and Interventional Neuroradiology (T.L., B.B.), Department of Radiology, University Hospital Tübingen; German Research Center for Neurodegenerative Diseases (DZNE) (J.R., R.S., L.S.), Tübingen, Germany; Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics (A.P.R., M.A.G., S.Z., R.S.), University of Miami Miller School of Medicine, FL; Department of Neurology (D.T.), University of Duisburg-Essen; and Department of Physics E22 (Biophysics) (G.W.), Technical University Munich, Garching, Germany.
authors.forename: Ludger
authors.initials: L
authors.lastname: Schöls
authors.affiliation: From the Hertie-Institute for Clinical Brain Research (A.C.O., J.R., L.S., R.S.), Department of Neurodegenerative Diseases, University of Tübingen, Germany; Bogazici University (E.B., B.O.), Department of Molecular Biology and Genetics, Istanbul; Tepecik Research and Training Hospital (L.O., Y.Z.), Clinics of Neurology, Izmir, Turkey; Diagnostic and Interventional Neuroradiology (T.L., B.B.), Department of Radiology, University Hospital Tübingen; German Research Center for Neurodegenerative Diseases (DZNE) (J.R., R.S., L.S.), Tübingen, Germany; Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics (A.P.R., M.A.G., S.Z., R.S.), University of Miami Miller School of Medicine, FL; Department of Neurology (D.T.), University of Duisburg-Essen; and Department of Physics E22 (Biophysics) (G.W.), Technical University Munich, Garching, Germany. r.schule@med.miami.edu.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Schüle
mesh_terms: D000328:Adult; D002465:Cell Movement / Q000235:genetics; D005260:Female; D005858:Germany; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D042541:Intracellular Space / Q000235:genetics; D016547:Kinesins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D012720:Severity of Illness Index; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics*
chemical_list: C114063:KIF1C protein, human; D016547:Kinesins