title: Myelin-associated glycoprotein gene mutation causes Pelizaeus-Merzbacher disease-like disorder.
abstract: Pelizaeus-Merzbacher disease is an X-linked hypomyelinating leukodystrophy caused by mutations or rearrangements in PLP1. It presents in infancy with nystagmus, jerky head movements, hypotonia and developmental delay evolving into spastic tetraplegia with optic atrophy and variable movement disorders. A clinically similar phenotype caused by recessive mutations in GJC2 is known as Pelizaeus-Merzbacher-like disease. Both genes encode proteins associated with myelin. We describe three siblings of a consanguineous family manifesting the typical infantile-onset Pelizaeus-Merzbacher disease-like phenotype slowly evolving into a form of complicated hereditary spastic paraplegia with mental retardation, dysarthria, optic atrophy and peripheral neuropathy in adulthood. Magnetic resonance imaging and spectroscopy were consistent with a demyelinating leukodystrophy. Using genetic linkage and exome sequencing, we identified a homozygous missense c.399C>G; p.S133R mutation in MAG. This gene, previously associated with hereditary spastic paraplegia, encodes myelin-associated glycoprotein, which is involved in myelin maintenance and glia-axon interaction. This mutation is predicted to destabilize the protein and affect its tertiary structure. Examination of the sural nerve biopsy sample obtained in childhood in the oldest sibling revealed complete absence of myelin-associated glycoprotein accompanied by ill-formed onion-bulb structures and a relatively thin myelin sheath of the affected axons. Immunofluorescence, cell surface labelling, biochemical analysis and mass spectrometry-based proteomics studies in a variety of cell types demonstrated a devastating effect of the mutation on post-translational processing, steady state expression and subcellular localization of myelin-associated glycoprotein. In contrast to the wild-type protein, the p.S133R mutant was retained in the endoplasmic reticulum and was subjected to endoplasmic reticulum-associated protein degradation by the proteasome. Our findings identify involvement of myelin-associated glycoprotein in this family with a disorder affecting the central and peripheral nervous system, and suggest that loss of the protein function is responsible for the unique clinical phenotype.
authors.affiliation: 1 Department of Neurology and Agnes Ginges Centre for Human Neurogenetics, Hebrew University-Hadassah Medical Centre, Jerusalem, Israel vmeiner@hadassah.org.il also@hadassah.org.il peles@weizmann.ac.il.
authors.forename: Alexander
authors.initials: A
authors.lastname: Lossos
authors.affiliation: 2 Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Nimrod
authors.initials: N
authors.lastname: Elazar
authors.affiliation: 3 Department of Genetics and Metabolic Diseases, Hebrew University-Hadassah Medical Centre, Jerusalem, Israel.
authors.forename: Israela
authors.initials: I
authors.lastname: Lerer
authors.affiliation: 4 Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, Faculty of Medicine, Hebrew University, Jerusalem, Israel.
authors.forename: Ora
authors.initials: O
authors.lastname: Schueler-Furman
authors.affiliation: 5 Department of Pathology, Hebrew University-Hadassah Medical Centre, Jerusalem, Israel.
authors.forename: Yakov
authors.initials: Y
authors.lastname: Fellig
authors.affiliation: 6 Paediatric Neuromuscular Service, Alyn Paediatric Rehabilitation Centre, Jerusalem, Israel.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Glick
authors.affiliation: 3 Department of Genetics and Metabolic Diseases, Hebrew University-Hadassah Medical Centre, Jerusalem, Israel.
authors.forename: Bat-El
authors.initials: BE
authors.lastname: Zimmerman
authors.affiliation: 5 Department of Pathology, Hebrew University-Hadassah Medical Centre, Jerusalem, Israel.
authors.forename: Haim
authors.initials: H
authors.lastname: Azulay
authors.affiliation: 7 Department of Ophthalmology, Hebrew University-Hadassah Medical Centre, Jerusalem, Israel.
authors.forename: Shlomo
authors.initials: S
authors.lastname: Dotan
authors.affiliation: 7 Department of Ophthalmology, Hebrew University-Hadassah Medical Centre, Jerusalem, Israel.
authors.forename: Sharon
authors.initials: S
authors.lastname: Goldberg
authors.affiliation: 8 Department of Radiology, Hebrew University-Hadassah Medical Centre, Jerusalem, Israel.
authors.forename: John M
authors.initials: JM
authors.lastname: Gomori
authors.affiliation: 1 Department of Neurology and Agnes Ginges Centre for Human Neurogenetics, Hebrew University-Hadassah Medical Centre, Jerusalem, Israel.
authors.forename: Penina
authors.initials: P
authors.lastname: Ponger
authors.affiliation: 1 Department of Neurology and Agnes Ginges Centre for Human Neurogenetics, Hebrew University-Hadassah Medical Centre, Jerusalem, Israel.
authors.forename: J P
authors.initials: JP
authors.lastname: Newman
authors.affiliation: 3 Department of Genetics and Metabolic Diseases, Hebrew University-Hadassah Medical Centre, Jerusalem, Israel.
authors.forename: Hodaifah
authors.initials: H
authors.lastname: Marreed
authors.affiliation: 9 Department of Biomedicine, University Hospital Basel, University of Basel, Switzerland.
authors.forename: Andreas J
authors.initials: AJ
authors.lastname: Steck
authors.affiliation: 9 Department of Biomedicine, University Hospital Basel, University of Basel, Switzerland.
authors.forename: Nicole
authors.initials: N
authors.lastname: Schaeren-Wiemers
authors.affiliation: 2 Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Nofar
authors.initials: N
authors.lastname: Mor
authors.affiliation: 10 Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Harel
authors.affiliation: 10 Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Tamar
authors.initials: T
authors.lastname: Geiger
authors.affiliation: 2 Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Eshed-Eisenbach
authors.affiliation: 3 Department of Genetics and Metabolic Diseases, Hebrew University-Hadassah Medical Centre, Jerusalem, Israel vmeiner@hadassah.org.il also@hadassah.org.il peles@weizmann.ac.il.
authors.forename: Vardiella
authors.initials: V
authors.lastname: Meiner
authors.affiliation: 2 Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Elior
authors.initials: E
authors.lastname: Peles
mesh_terms: D000328:Adult; D017630:Connexins / Q000235:genetics; D004252:DNA Mutational Analysis; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005192:Family Health; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics*; D018991:Myelin Proteolipid Protein / Q000235:genetics; D018992:Myelin-Associated Glycoprotein / Q000235:genetics* / Q000378:metabolism; D020371:Pelizaeus-Merzbacher Disease / Q000235:genetics*; D021381:Protein Transport / Q000235:genetics; D040901:Proteomics; D009418:S100 Proteins / Q000378:metabolism; D013497:Sural Nerve / Q000473:pathology; D055815:Young Adult
chemical_list: D017630:Connexins; D018991:Myelin Proteolipid Protein; D018992:Myelin-Associated Glycoprotein; C472930:PLP1 protein, human; D009418:S100 Proteins; C427305:connexin 47; D049452:Green Fluorescent Proteins
keywords: MAG; Pelizaeus-Merzbacher-like disease; hereditary spastic paraplegia