Brain Advance Access originally published online on January 7, 2004
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Brain, Vol. 127, No. 2, 371-384, 2004
© 2004 Guarantors of Brain
doi: 10.1093/brain/awh048
Phenotypic clustering in MPZ mutations
1 Department of Neurology and 2 Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, 3 Department of Pediatrics, Childrens Hospital of Michigan, Detroit, Michigan, and 4 Department of Biological Sciences, University of Iowa, Iowa City, Iowa, USA
Correspondence to: Michael Shy, MD, 421 Ea Canfield, Elliman Bldg 3206, Detroit MI 48201, USA E-mail: m.shy{at}wayne.edu
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.
Key Words: MPZ; CMT1B; phenotype; myelin; PNS
Abbreviations: CMAP= compound muscle action potential; CMT = Charcot-Marie-Tooth; CMTNS = CMT Neuropathy Score; MNCV = motor nerve conduction velocity; MPZ = myelin protein zero; NCV = nerve conduction velocity; PKC = protein kinase C; SNAP = sensory nerve action potential; PLP1 = proteolipid protein 1; TNS = total neuropathy score
Received April 22 2003. Second revision September 23, 2003. Accepted September 25, 2003. .
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