P0, a major structural protein of peripheral myelin, is a homophilic adhesion molecule and maps to chromosome 1q22-q23, in the region of the locus for Charcot-Marie-Tooth neuropathy type 1B (CMT1B). We have investigated P0 as a candidate gene in two pedigrees with CMT1B and found point mutations which are completely linked with the disease (Z = 5.5, theta = 0). The mutations, glutamate substitution for lysine 96 or aspartate 90, are located in the extracellular domain, which plays a significant role in myelin membrane adhesion. Individuals with CMT1B are heterozygous for the normal allele and the mutant allele. Our results indicate that P0 is a gene responsible for CMT1B.

We have investigated the myelin P0 gene on chromosome 1 as a candidate gene in two sporadic cases with Dejerine-Sottas disease or hereditary motor and sensory neuropathy (HMSN) type III. We found different mutations, a cysteine substitution for serine 63 in the extracellular domain and an arginine substitution for glycine 167 in the transmembrane domain. The patients were genetically heterozygous for the normal allele and the mutant allele, which was absent in their parents and in one hundred unrelated, healthy controls. The results strongly suggest that a de novo dominant mutation of the P0 gene is responsible for at least some sporadic cases of Dejerine-Sottas disease.

The human peripheral myelin protein 22 (PMP-22) gene has been mapped to chromosome 17p11.2 in the duplicated region associated with Charcot-Marie-Tooth disease type 1A. Southern blot analysis using PMP-22 as a probe indicated that the PMP-22 gene was duplicated in 5 patients from unrelated Japanese families with Charcot-Marie-Tooth disease type 1. In order to investigate whether or not an extra copy of PMP-22 has an effect on its gene expression, we analyzed relative expression of messenger RNA for PMP-22 and protein 0 (P0) against beta-actin by Northern blotting in biopsied nerves of the patients with type 1A disease, and compared the results with those of patients having other demyelinating neuropathies and the autopsied nerves of patients without neuropathies. The relative expression of PMP-22 messenger RNA in 5 patients with Charcot-Marie-Tooth disease type 1A was significantly higher than that in 5 patients with other demyelinating neuropathies (p < 0.05). There was no statistically significant difference in P0 expression between them. This study provided direct evidence for elevated expression of PMP-22 in peripheral nerves of patients with Charcot-Marie-Tooth disease type 1A as the result of a gene dosage effect. However, the relation between elevated expression of PMP-22 and the mechanism causing demyelination remains undetermined.

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