Charcot-Marie-Tooth neuropathy type 1B is associated with mutations of the myelin P0 gene.

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.

De novo mutation of the myelin P0 gene in Dejerine-Sottas disease (hereditary motor and sensory neuropathy type III).

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.

Localization of PMP-22 gene (candidate gene for the Charcot-Marie-Tooth disease 1A) to band 17p11.2 by direct R-banding fluorescence in situ hybridization.

We mapped PMP-22 gene, candidate gene for the Charcot-Marie-Tooth disease (CMT) 1A, by direct R-banding fluorescence in situ hybridization. The signals of PMP-22 probe were localized to chromosome band 17p11.2. The present result was within the map position of the CMT 1A gene by genetic linkage analysis, and strongly indicated that PMP-22 gene is a candidate gene for the CMT 1A.

Structure and localization of the gene encoding human peripheral myelin protein 2 (PMP2).

Peripheral myelin protein 2 (PMP2) is a small, basic, and cytoplasmic lipid binding protein of peripheral myelin. In this paper, we describe the cloning, characterization, and chromosomal mapping of the human PMP2 gene. The gene is about 8 kb long and consists of four exons. All exon-intron junction sequences conform to the GT/AG rule. The 5'-flanking region of the gene has a TA-rich element (TATA-like box) and a single defined transcription initiation site detected by the primer extension method. The gene for human PMP2 was assigned to chromosome 8q21.3-q22.1 by spot hybridization of flow-sorted human chromosomes and fluorescence in situ hybridization.

Isolation and sequence determination of cDNA encoding PMP-22 (PAS-II/SR13/Gas-3) of human peripheral myelin.

A full length cDNA of PMP-22 (PAS-II/SR13/Gas-3) of peripheral myelin has been isolated from a cDNA library of human fetus spinal cord. The clone is 1823 base pairs (bp) in length and contains a 480 bp open reading frame encoding a polypeptide of 160 residues. The deduced amino acid sequence is highly homologous to PMP-22 from bovine (PAS-II), rat (SR13) and mouse (Gas-3).

Structure and chromosomal localization of the gene encoding the human myelin protein zero (MPZ).

We describe the cloning, characterization, and chromosomal mapping of the human myelin protein zero (MPZ) gene. The gene is about 7 kb long and consists of six exons corresponding to the functional domains. All exon-intron junction sequences conform to the GT/AG rule. The 5'-flanking region of the gene has a TA-rich element (TATA-like box), two CAAT boxes, and a single defined transcription initiation site detected by the primer extension method. The gene for human MPZ was assigned to chromosome 1q22-q23 by spot blot hybridization of flow-sorted human chromosomes and fluorescence in situ hybridization. The localization of the MPZ gene coincides with the locus for Charcot-Marie-Tooth disease type 1B, determined by linkage analysis.

Elevated expression of messenger RNA for peripheral myelin protein 22 in biopsied peripheral nerves of patients with Charcot-Marie-Tooth disease type 1A.

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.

New mutation of the myelin P0 gene in a pedigree of Charcot-Marie-Tooth neuropathy 1.

P0, the major structural protein of peripheral myelin, is a homophilic adhesion molecule with a single immunoglobulin (Ig) domain, which contains a single N-linked glycosylation site and two cysteines. We have previously reported four different mutations of the myelin P0 gene in four families of Charcot-Marie-Tooth neuropathy type 1 (CMT1). In this study we found a new mutation of the myelin P0 gene in a small family of CMT1. The affected persons had an A - to - G substitution of nucleotide 245 of the myelin P0 gene in one allele, leading to a cysteine substitution for tyrosine82 in the extracellular Ig-domain. An additional cysteine in the extracellular domain may form a disulfide bond and cause an inappropriate change in the tertiary structure of the functional Ig-domain of P0.