title: Sphingosine 1-phosphate lyase deficiency causes Charcot-Marie-Tooth neuropathy.
abstract: OBJECTIVE
  To identify the unknown genetic cause in a nuclear family with an axonal form of peripheral neuropathy and atypical disease course.
  
  
  METHODS
  Detailed neurologic, electrophysiologic, and neuropathologic examinations of the patients were performed. Whole exome sequencing of both affected individuals was done. The effect of the identified sequence variations was investigated at cDNA and protein level in patient-derived lymphoblasts. The plasma sphingoid base profile was analyzed. Functional consequences of neuron-specific downregulation of the gene were studied in Drosophila.
  
  
  RESULTS
  Both patients present an atypical form of axonal peripheral neuropathy, characterized by acute or subacute onset and episodes of recurrent mononeuropathy. We identified compound heterozygous mutations cosegregating with disease and absent in controls in the SGPL1 gene, encoding sphingosine 1-phosphate lyase (SPL). The p.Ser361* mutation triggers nonsense-mediated mRNA decay. The missense p.Ile184Thr mutation causes partial protein degradation. The plasma levels of sphingosine 1-phosphate and sphingosine/sphinganine ratio were increased in the patients. Neuron-specific downregulation of the Drosophila orthologue impaired the morphology of the neuromuscular junction and caused progressive degeneration of the chemosensory neurons innervating the wing margin bristles.
  
  
  CONCLUSIONS
  We suggest SPL deficiency as a cause of a distinct form of Charcot-Marie-Tooth disease in humans, thus extending the currently recognized clinical and genetic spectrum of inherited peripheral neuropathies. Our data emphasize the importance of sphingolipid metabolism for neuronal function.
authors.affiliation: From the Molecular Neurogenomics Group (D.A., B.E., A.E.-C., K.P., T.O., E.D.V., A.J.), VIB Department of Molecular Genetics (B.A.), University of Antwerp, Belgium; Clinic for Neurology and Psychiatry for Children and Youth (J.N.G), Belgrade, Serbia; Faculty of Medicine (V.M.R.), Clinic for Neurology and Psychiatry for Children and Youth, University of Belgrade, Serbia; Departments of Chemical Physiology and Cell and Molecular Biology (D.B., X.-L.Y.), The Scripps Research Institute, La Jolla, CA; and Institute of Clinical Chemistry (R.S., T.H.), University Hospital Zurich, University of Zurich, Switzerland.
authors.forename: Derek
authors.initials: D
authors.lastname: Atkinson
authors.affiliation: From the Molecular Neurogenomics Group (D.A., B.E., A.E.-C., K.P., T.O., E.D.V., A.J.), VIB Department of Molecular Genetics (B.A.), University of Antwerp, Belgium; Clinic for Neurology and Psychiatry for Children and Youth (J.N.G), Belgrade, Serbia; Faculty of Medicine (V.M.R.), Clinic for Neurology and Psychiatry for Children and Youth, University of Belgrade, Serbia; Departments of Chemical Physiology and Cell and Molecular Biology (D.B., X.-L.Y.), The Scripps Research Institute, La Jolla, CA; and Institute of Clinical Chemistry (R.S., T.H.), University Hospital Zurich, University of Zurich, Switzerland.
authors.forename: Jelena
authors.initials: J
authors.lastname: Nikodinovic Glumac
authors.affiliation: From the Molecular Neurogenomics Group (D.A., B.E., A.E.-C., K.P., T.O., E.D.V., A.J.), VIB Department of Molecular Genetics (B.A.), University of Antwerp, Belgium; Clinic for Neurology and Psychiatry for Children and Youth (J.N.G), Belgrade, Serbia; Faculty of Medicine (V.M.R.), Clinic for Neurology and Psychiatry for Children and Youth, University of Belgrade, Serbia; Departments of Chemical Physiology and Cell and Molecular Biology (D.B., X.-L.Y.), The Scripps Research Institute, La Jolla, CA; and Institute of Clinical Chemistry (R.S., T.H.), University Hospital Zurich, University of Zurich, Switzerland.
authors.forename: Bob
authors.initials: B
authors.lastname: Asselbergh
authors.affiliation: From the Molecular Neurogenomics Group (D.A., B.E., A.E.-C., K.P., T.O., E.D.V., A.J.), VIB Department of Molecular Genetics (B.A.), University of Antwerp, Belgium; Clinic for Neurology and Psychiatry for Children and Youth (J.N.G), Belgrade, Serbia; Faculty of Medicine (V.M.R.), Clinic for Neurology and Psychiatry for Children and Youth, University of Belgrade, Serbia; Departments of Chemical Physiology and Cell and Molecular Biology (D.B., X.-L.Y.), The Scripps Research Institute, La Jolla, CA; and Institute of Clinical Chemistry (R.S., T.H.), University Hospital Zurich, University of Zurich, Switzerland.
authors.forename: Biljana
authors.initials: B
authors.lastname: Ermanoska
authors.affiliation: From the Molecular Neurogenomics Group (D.A., B.E., A.E.-C., K.P., T.O., E.D.V., A.J.), VIB Department of Molecular Genetics (B.A.), University of Antwerp, Belgium; Clinic for Neurology and Psychiatry for Children and Youth (J.N.G), Belgrade, Serbia; Faculty of Medicine (V.M.R.), Clinic for Neurology and Psychiatry for Children and Youth, University of Belgrade, Serbia; Departments of Chemical Physiology and Cell and Molecular Biology (D.B., X.-L.Y.), The Scripps Research Institute, La Jolla, CA; and Institute of Clinical Chemistry (R.S., T.H.), University Hospital Zurich, University of Zurich, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Blocquel
authors.affiliation: From the Molecular Neurogenomics Group (D.A., B.E., A.E.-C., K.P., T.O., E.D.V., A.J.), VIB Department of Molecular Genetics (B.A.), University of Antwerp, Belgium; Clinic for Neurology and Psychiatry for Children and Youth (J.N.G), Belgrade, Serbia; Faculty of Medicine (V.M.R.), Clinic for Neurology and Psychiatry for Children and Youth, University of Belgrade, Serbia; Departments of Chemical Physiology and Cell and Molecular Biology (D.B., X.-L.Y.), The Scripps Research Institute, La Jolla, CA; and Institute of Clinical Chemistry (R.S., T.H.), University Hospital Zurich, University of Zurich, Switzerland.
authors.forename: Regula
authors.initials: R
authors.lastname: Steiner
authors.affiliation: From the Molecular Neurogenomics Group (D.A., B.E., A.E.-C., K.P., T.O., E.D.V., A.J.), VIB Department of Molecular Genetics (B.A.), University of Antwerp, Belgium; Clinic for Neurology and Psychiatry for Children and Youth (J.N.G), Belgrade, Serbia; Faculty of Medicine (V.M.R.), Clinic for Neurology and Psychiatry for Children and Youth, University of Belgrade, Serbia; Departments of Chemical Physiology and Cell and Molecular Biology (D.B., X.-L.Y.), The Scripps Research Institute, La Jolla, CA; and Institute of Clinical Chemistry (R.S., T.H.), University Hospital Zurich, University of Zurich, Switzerland.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Estrada-Cuzcano
authors.affiliation: From the Molecular Neurogenomics Group (D.A., B.E., A.E.-C., K.P., T.O., E.D.V., A.J.), VIB Department of Molecular Genetics (B.A.), University of Antwerp, Belgium; Clinic for Neurology and Psychiatry for Children and Youth (J.N.G), Belgrade, Serbia; Faculty of Medicine (V.M.R.), Clinic for Neurology and Psychiatry for Children and Youth, University of Belgrade, Serbia; Departments of Chemical Physiology and Cell and Molecular Biology (D.B., X.-L.Y.), The Scripps Research Institute, La Jolla, CA; and Institute of Clinical Chemistry (R.S., T.H.), University Hospital Zurich, University of Zurich, Switzerland.
authors.forename: Kristien
authors.initials: K
authors.lastname: Peeters
authors.affiliation: From the Molecular Neurogenomics Group (D.A., B.E., A.E.-C., K.P., T.O., E.D.V., A.J.), VIB Department of Molecular Genetics (B.A.), University of Antwerp, Belgium; Clinic for Neurology and Psychiatry for Children and Youth (J.N.G), Belgrade, Serbia; Faculty of Medicine (V.M.R.), Clinic for Neurology and Psychiatry for Children and Youth, University of Belgrade, Serbia; Departments of Chemical Physiology and Cell and Molecular Biology (D.B., X.-L.Y.), The Scripps Research Institute, La Jolla, CA; and Institute of Clinical Chemistry (R.S., T.H.), University Hospital Zurich, University of Zurich, Switzerland.
authors.forename: Tinne
authors.initials: T
authors.lastname: Ooms
authors.affiliation: From the Molecular Neurogenomics Group (D.A., B.E., A.E.-C., K.P., T.O., E.D.V., A.J.), VIB Department of Molecular Genetics (B.A.), University of Antwerp, Belgium; Clinic for Neurology and Psychiatry for Children and Youth (J.N.G), Belgrade, Serbia; Faculty of Medicine (V.M.R.), Clinic for Neurology and Psychiatry for Children and Youth, University of Belgrade, Serbia; Departments of Chemical Physiology and Cell and Molecular Biology (D.B., X.-L.Y.), The Scripps Research Institute, La Jolla, CA; and Institute of Clinical Chemistry (R.S., T.H.), University Hospital Zurich, University of Zurich, Switzerland.
authors.forename: Els
authors.initials: E
authors.lastname: De Vriendt
authors.affiliation: From the Molecular Neurogenomics Group (D.A., B.E., A.E.-C., K.P., T.O., E.D.V., A.J.), VIB Department of Molecular Genetics (B.A.), University of Antwerp, Belgium; Clinic for Neurology and Psychiatry for Children and Youth (J.N.G), Belgrade, Serbia; Faculty of Medicine (V.M.R.), Clinic for Neurology and Psychiatry for Children and Youth, University of Belgrade, Serbia; Departments of Chemical Physiology and Cell and Molecular Biology (D.B., X.-L.Y.), The Scripps Research Institute, La Jolla, CA; and Institute of Clinical Chemistry (R.S., T.H.), University Hospital Zurich, University of Zurich, Switzerland.
authors.forename: Xiang-Lei
authors.initials: XL
authors.lastname: Yang
authors.affiliation: From the Molecular Neurogenomics Group (D.A., B.E., A.E.-C., K.P., T.O., E.D.V., A.J.), VIB Department of Molecular Genetics (B.A.), University of Antwerp, Belgium; Clinic for Neurology and Psychiatry for Children and Youth (J.N.G), Belgrade, Serbia; Faculty of Medicine (V.M.R.), Clinic for Neurology and Psychiatry for Children and Youth, University of Belgrade, Serbia; Departments of Chemical Physiology and Cell and Molecular Biology (D.B., X.-L.Y.), The Scripps Research Institute, La Jolla, CA; and Institute of Clinical Chemistry (R.S., T.H.), University Hospital Zurich, University of Zurich, Switzerland.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Hornemann
authors.affiliation: From the Molecular Neurogenomics Group (D.A., B.E., A.E.-C., K.P., T.O., E.D.V., A.J.), VIB Department of Molecular Genetics (B.A.), University of Antwerp, Belgium; Clinic for Neurology and Psychiatry for Children and Youth (J.N.G), Belgrade, Serbia; Faculty of Medicine (V.M.R.), Clinic for Neurology and Psychiatry for Children and Youth, University of Belgrade, Serbia; Departments of Chemical Physiology and Cell and Molecular Biology (D.B., X.-L.Y.), The Scripps Research Institute, La Jolla, CA; and Institute of Clinical Chemistry (R.S., T.H.), University Hospital Zurich, University of Zurich, Switzerland. albena.jordanova@molgen.vib-ua.be vedrana.milic.npk@gmail.com.
authors.forename: Vedrana
authors.initials: V
authors.lastname: Milic Rasic
authors.affiliation: From the Molecular Neurogenomics Group (D.A., B.E., A.E.-C., K.P., T.O., E.D.V., A.J.), VIB Department of Molecular Genetics (B.A.), University of Antwerp, Belgium; Clinic for Neurology and Psychiatry for Children and Youth (J.N.G), Belgrade, Serbia; Faculty of Medicine (V.M.R.), Clinic for Neurology and Psychiatry for Children and Youth, University of Belgrade, Serbia; Departments of Chemical Physiology and Cell and Molecular Biology (D.B., X.-L.Y.), The Scripps Research Institute, La Jolla, CA; and Institute of Clinical Chemistry (R.S., T.H.), University Hospital Zurich, University of Zurich, Switzerland. albena.jordanova@molgen.vib-ua.be vedrana.milic.npk@gmail.com.
authors.forename: Albena
authors.initials: A
authors.lastname: Jordanova
mesh_terms: D000328:Adult; D000446:Aldehyde-Lyases / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D002478:Cells, Cultured; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000503:physiopathology; D018389:Codon, Nonsense; D015331:Cohort Studies; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D005260:Female; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology; D008246:Lysophospholipids / Q000097:blood; D008297:Male; D020125:Mutation, Missense; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D035781:Siblings; D013110:Sphingosine / Q000031:analogs & derivatives / Q000097:blood
chemical_list: D018389:Codon, Nonsense; D029721:Drosophila Proteins; D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; D000446:Aldehyde-Lyases; C000619494:Sply protein, Drosophila; C022649:sphingosine 1-phosphate lyase (aldolase); D013110:Sphingosine