Myelin-associated glycoprotein gene mutation causes Pelizaeus-Merzbacher disease-like disorder

Alexander Lossos, Nimrod Elazar, Israela Lerer, Ora Schueler-Furman, Yakov Fellig, Benjamin Glick, Bat El Zimmerman, Haim Azulay, Shlomo Dotan, Sharon Goldberg, John M. Gomori, Penina Ponger, J. P. Newman, Hodaifah Marreed, Andreas J. Steck, Nicole Schaeren-Wiemers, Nofar Mor, Michal Harel, Tamar Geiger, Yael Eshed-EisenbachVardiella Meiner*, Elior Peles

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

47 Scopus citations


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.

Original languageAmerican English
Pages (from-to)2521-2536
Number of pages16
Issue number9
StatePublished - 1 Sep 2015

Bibliographical note

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© 2015 The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email:


  • MAG
  • Pelizaeus-Merzbacher-like disease
  • hereditary spastic paraplegia


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