title: P(0) glycoprotein overexpression causes congenital hypomyelination of peripheral nerves.
abstract: We show that normal peripheral nerve myelination depends on strict dosage of the most abundantly expressed myelin gene, myelin protein zero (Mpz). Transgenic mice containing extra copies of Mpz manifested a dose-dependent, dysmyelinating neuropathy, ranging from transient perinatal hypomyelination to arrested myelination and impaired sorting of axons by Schwann cells. Myelination was restored by breeding the transgene into the Mpz-null background, demonstrating that dysmyelination does not result from a structural alteration or Schwann cell-extrinsic effect of the transgenic P(0) glycoprotein. Mpz mRNA overexpression ranged from 30-700%, whereas an increased level of P(0) protein was detected only in nerves of low copy-number animals. Breeding experiments placed the threshold for dysmyelination between 30 and 80% Mpz overexpression. These data reveal new points in nerve development at which Schwann cells are susceptible to increased gene dosage, and suggest a novel basis for hereditary neuropathy.
authors.affiliation: Department of Neurology and Department of Biological and Technological Research (DIBIT), San Raffaele Scientific Institute, 20132 Milano, Italy. l.wrabetz@hsr.it
authors.forename: L
authors.initials: L
authors.lastname: Wrabetz
authors.forename: M L
authors.initials: ML
authors.lastname: Feltri
authors.forename: A
authors.initials: A
authors.lastname: Quattrini
authors.forename: D
authors.initials: D
authors.lastname: Imperiale
authors.forename: S
authors.initials: S
authors.lastname: Previtali
authors.forename: M
authors.initials: M
authors.lastname: D'Antonio
authors.forename: R
authors.initials: R
authors.lastname: Martini
authors.forename: X
authors.initials: X
authors.lastname: Yin
authors.forename: B D
authors.initials: BD
authors.lastname: Trapp
authors.forename: L
authors.initials: L
authors.lastname: Zhou
authors.forename: S Y
authors.initials: SY
authors.lastname: Chiu
authors.forename: A
authors.initials: A
authors.lastname: Messing
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003711:Demyelinating Diseases / Q000151:congenital* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018628:Gene Dosage; D005786:Gene Expression Regulation; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D004676:Myelin Basic Protein / Q000096:biosynthesis / Q000235:genetics; D018993:Myelin P0 Protein / Q000096:biosynthesis* / Q000235:genetics*; D009185:Myelin Proteins / Q000096:biosynthesis / Q000235:genetics; D009928:Organ Specificity; D010523:Peripheral Nervous System Diseases / Q000151:congenital* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012583:Schwann Cells / Q000378:metabolism / Q000648:ultrastructure; D012584:Sciatic Nerve / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D004676:Myelin Basic Protein; D018993:Myelin P0 Protein; D009185:Myelin Proteins; C489545:Pmp22 protein, mouse; D020033:Protein Isoforms; D012333:RNA, Messenger