CMT 1B and MPZ mutations - Wayne State research

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From Brain. 2004 Jan 7

Phenotypic clustering in MPZ mutations.

Shy ME, Jani A, Krajewski K, Grandis M, RA, Li J, Shy RR, Balsamo

J, Lilien J, Garbern JY, Kamholz J.

Department of Neurology, Detroit, Michigan, USA; Center for Molecular

Medicine and Genetics, Wayne State University School of Medicine,

Detroit, Michigan, USA.

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.