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

Brain. 2015 Sep;138(Pt 9):2521-36. doi: 10.1093/brain/awv204.

Alexander Lossos ¹, Nimrod Elazar ², Israela Lerer ³, Ora Schueler-Furman ⁴, Yakov Fellig ⁵, Benjamin Glick ⁶, Bat-El Zimmerman ³, Haim Azulay ⁵, Shlomo Dotan ⁷, Sharon Goldberg ⁷, John M Gomori ⁸, Penina Ponger ⁹, J P Newman ⁹, Hodaifah Marreed ³, Andreas J Steck ¹⁰, Nicole Schaeren-Wiemers ¹⁰, Nofar Mor ², Michal Harel ¹¹, Tamar Geiger ¹¹, Yael Eshed-Eisenbach ², Vardiella Meiner ¹², Elior Peles ²

Affiliations

1 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.
2 2 Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
3 3 Department of Genetics and Metabolic Diseases, Hebrew University-Hadassah Medical Centre, Jerusalem, Israel.
4 4 Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, Faculty of Medicine, Hebrew University, Jerusalem, Israel.
5 5 Department of Pathology, Hebrew University-Hadassah Medical Centre, Jerusalem, Israel.
6 6 Paediatric Neuromuscular Service, Alyn Paediatric Rehabilitation Centre, Jerusalem, Israel.
7 7 Department of Ophthalmology, Hebrew University-Hadassah Medical Centre, Jerusalem, Israel.
8 8 Department of Radiology, Hebrew University-Hadassah Medical Centre, Jerusalem, Israel.
9 1 Department of Neurology and Agnes Ginges Centre for Human Neurogenetics, Hebrew University-Hadassah Medical Centre, Jerusalem, Israel.
10 9 Department of Biomedicine, University Hospital Basel, University of Basel, Switzerland.
11 10 Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
12 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.

PMID: 26179919 DOI: 10.1093/brain/awv204

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.

Keywords

MAG; Pelizaeus-Merzbacher-like disease; hereditary spastic paraplegia.

Name
Email *

	Sorry, but the email address you supplied was invalid.