Charcot-Marie-Tooth type 1B neuropathy: a mutation at the single glycosylation site in the major peripheral myelin glycoprotein Po

Charcot-Marie-Tooth disease type 1 (CMT1) is the most common inherited demyelinating peripheral neuropathy in humans. Clinical manifestations are variable with an onset age in childhood or adolescence and include distal muscle weakness and atrophy, hollow feet, mild sensory loss, lowered nerve conduction velocities below 38 m/s, and evidence on nerve biopsy of segmental demyelination and remyelination with typical onionbulb formation. Two autosomal dominant forms have been characterized. In CMT1A, a major locus has been mapped to chromosome 17p11.2. The majority of patients present with a duplication of a region containing the gene coding for the peripheral myelin protein 22 (PMP-22); point mutations in PMP-22 gene also have been identified recently in some CMT1A patients. CMT1B, a minor locus mapped to chromosome 1q21.3-q23, results from a mutation in the gene encoding PO, the major peripheral myelin glycoprotein. Here, we report a French family where the propositus, a 53-year-old woman, appears to be the only affected individual in a three-generation pedigree. The propositus did not present with any symptom until the age of 44 years, at which time areflexia, severe scoliosis, onion-bulbs at nerve biopsy, and median nerve conduction velocity of 32 m/s were observed. Screening of the patient's genomic DNA with probes specific for the duplication of the PMP-22 gene region of chromosome 17p11.2 was negative. We subsequently tested each of the six exons of the PO gene for the presence of mutations, by single strand conformational polymorphism (SSCP) analysis, Only the amplified exon 3 showed an aberrant profile of migration. Direct sequencing of this exon was performed with intron-specific PO primers. The mutation, an A-to-G-transition found at nucleotide 409, would lead to a serine substitution for asparagine at position 122, the single N-linked glycosylation site of PO. The patient was heterozygous for the mutant and normal alleles. None of her three children appeared to be affected clinically. The possibility that they carry the mutation but have not as yet developed any symptoms was investigated by direct sequencing of exon 3 amplified from their genomic DNA. The sequence was normal for the three children, and their normal median nerve conduction velocities corroborated these results. This is the first report of a mutation affecting the single glycosylation site in PO.