title: Nerve conduction velocity is regulated by the inositol polyphosphate-4-phosphatase II gene.
abstract: Impairment of nerve conduction is common in neurodegenerative and neuroinflammatory diseases such as multiple sclerosis (MS), and measurement of evoked potentials (visual, motor, or sensory) has been widely used for diagnosis and recently also as a prognostic marker for MS. We used a classical genetic approach to identify novel genes controlling nerve conduction. First, we used quantitative trait mapping in F2 progeny of B10/SJL mice to identify EAE31, a locus controlling latency of motor evoked potentials (MEPs) and clinical onset of experimental autoimmune encephalomyelitis. Then, by combining congenic mapping, in silico haplotype analyses, and comparative genomics we identified inositol polyphosphate-4-phosphatase, type II (Inpp4b) as the quantitative trait gene for EAE31. Sequence variants of Inpp4b (C/A, exon 13; A/C, exon 14) were identified as differing among multiple mouse strains and correlated with individual cortical MEP latency differences. To evaluate the functional relevance of the amino acid exchanges at positions S474R and H548P, we generated transgenic mice carrying the longer-latency allele (Inpp4b(474R/548P)) in the C57BL/6J background. Inpp4b(474R/548P) mice exhibited significantly longer cortical MEP latencies (4.5 ± 0.22 ms versus 3.7 ± 0.13 ms; P = 1.04 × 10(-9)), indicating that INPP4B regulates nerve conduction velocity. An association of an INPP4B polymorphism (rs13102150) with MS was observed in German and Spanish MS cohorts (3676 controls and 911 cases) (P = 8.8 × 10(-3)).
authors.affiliation: Department of Dermatology, Venereology and Allergology, University of Lübeck, Lübeck, Germany. Electronic address: susanne.lemcke@uksh.de.
authors.forename: Susanne
authors.initials: S
authors.lastname: Lemcke
authors.affiliation: Department of Dermatology, Venereology and Allergology, University of Lübeck, Lübeck, Germany; Neurodegeneration Research Lab, Department of Neurology, University of Magdeburg, Magdeburg, Germany.
authors.forename: Susen
authors.initials: S
authors.lastname: Müller
authors.affiliation: Department of Dermatology, Venereology and Allergology, University of Lübeck, Lübeck, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Möller
authors.affiliation: Institute of Medical Biometry and Statistics, University of Lübeck, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.
authors.forename: Arne
authors.initials: A
authors.lastname: Schillert
authors.affiliation: Institute of Medical Biometry and Statistics, University of Lübeck, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Ziegler
authors.affiliation: Department of Neurology, University Hospital, Technical University of Munich, Munich, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Cepok-Kauffeld
authors.affiliation: Department of Neurology-Neuroimmunology, Multiple Sclerosis Center of Catalonia, University Hospital Vall d'Hebron, Barcelona, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Comabella
authors.affiliation: Department of Neurology-Neuroimmunology, Multiple Sclerosis Center of Catalonia, University Hospital Vall d'Hebron, Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Montalban
authors.affiliation: Institute of Laboratory Animal Science, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rülicke
authors.affiliation: Medical Inflammation Research Division, Karolinska Institute, Stockholm, Sweden.
authors.forename: Kutty Selva
authors.initials: KS
authors.lastname: Nandakumar
authors.affiliation: Department of Neurology, University Hospital, Technical University of Munich, Munich, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Hemmer
authors.affiliation: Medical Inflammation Research Division, Karolinska Institute, Stockholm, Sweden.
authors.forename: Rikard
authors.initials: R
authors.lastname: Holmdahl
authors.affiliation: Neurodegeneration Research Lab, Department of Neurology, University of Magdeburg, Magdeburg, Germany; German Center for Neurodegenerative Diseases Magdeburg, Magdeburg, Germany; Department of Behavioral Neurology, Leibniz Institute for Neurobiology, Magdeburg, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Pahnke
authors.affiliation: Department of Dermatology, Venereology and Allergology, University of Lübeck, Lübeck, Germany.
authors.forename: Saleh M
authors.initials: SM
authors.lastname: Ibrahim
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental; D019054:Evoked Potentials, Motor / Q000235:genetics*; D005838:Genotype; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000235:genetics*; D009431:Neural Conduction / Q000235:genetics*; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D040641:Quantitative Trait Loci; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D010744:Phosphoric Monoester Hydrolases; C053153:phosphatidylinositol-3,4-bisphosphate 4-phosphatase