Journal article
Phenotypic clustering in MPZ mutations
Brain (London, England : 1878), Vol.127(2), pp.371-384
2004
DOI: 10.1093/brain/awh048
PMID: 14711881
Abstract
Myelin protein zero (MPZ) is a member of the immunoglobulin gene superfamily with single extracellular, transmembrane and cytoplasmic domains. Homotypic interactions between extracellular domains of MPZ adhere adjacent myelin wraps to each other. MPZ is also necessary for myelin compaction since mice which lack MPZ develop severe dysmyelinating neuropathies in which compaction is dramatically disrupted. MPZ mutations in humans cause the inherited demyelinating neuropathy CMT1B. Some mutations cause the severe neuropathies of infancy designated as Dejerine-Sottas disease, while others cause a 'classical' Charcot-Marie-Tooth (CMT) disease Type 1B (CMT1B) phenotype with normal early milestones but development of disability during the first two decades of life. Still other mutations cause a neuropathy that presents in adults, with normal nerve conduction velocities, designated as a 'CMT2' form of CMT1B. To correlate the phenotype of patients with MPZ mutations with their genotype, we identified and evaluated 13 patients from 12 different families with eight different MPZ mutations. In addition, we re-analysed the clinical data from 64 cases of CMT1B from the literature. Contrary to our expectations, we found that most patients presented with either an early onset neuropathy with signs and symptoms prior to the onset of walking or a late onset neuropathy with signs and symptoms at around age 40 years. Only occasional patients presented with a 'classical' CMT phenotype. Correlation of specific MPZ mutations with their phenotypes demonstrated that addition of either a charged amino acid or altering a cysteine residue in the extracellular domain caused a severe early onset neuropathy. Severe neuropathy was also caused by truncation of the cytoplasmic domain or alteration of an evolutionarily conserved amino acid. Taken together, these data suggest that early onset neuropathy is caused by MPZ mutations that significantly disrupt the tertiary structure of MPZ and thus interfere with MPZ-mediated adhesion and myelin compaction. In contrast, late onset neuropathy is caused by mutations that more subtly alter myelin structure and which probably disrupt Schwann cell-axonal interactions.
Details
- Title: Subtitle
- Phenotypic clustering in MPZ mutations
- Creators
- Michael E SHY - Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan, United StatesAgnes JANI - Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan, United StatesJohn KANIHOLZ - Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan, United StatesKaren KRAJEWSKI - Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan, United StatesMarina GRANDIS - Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan, United StatesRichard A LEWIS - Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan, United StatesJun Li - Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan, United StatesRosemary R SHY - Department of Pediatrics, Childrens Hospital of Michigan, Detroit, Michigan, United StatesJanne BALSAMO - Department of Biological Sciences, University of Iowa, Iowa City, Iowa, United StatesJack LILIEN - Department of Biological Sciences, University of Iowa, Iowa City, Iowa, United StatesJames Y GARBERN - Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan, United States
- Resource Type
- Journal article
- Publication Details
- Brain (London, England : 1878), Vol.127(2), pp.371-384
- Publisher
- Oxford University Press; Oxford
- DOI
- 10.1093/brain/awh048
- PMID
- 14711881
- ISSN
- 0006-8950
- eISSN
- 1460-2156
- Language
- English
- Date published
- 2004
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Biology
- Record Identifier
- 9984013919702771
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