Clinically distinct codon 69 mutations in major myelin protein zero in demyelinating neuropathies

Abstract

Mutations in the major peripheral myelin protein zero (PO) gene on chromosome Iq21-q23 have been found with the hereditary demyelinating polyneuropathy Char co t-Marie-Tooth type IB. Here, we describe 2 patients with distinct neurological characteristics, carrying differ ent substitutions at the saíne codon-Arg69His and Arg69Cys. The patients were heterozygous for the mutation3 which in both appeared to be de novo. Histological exam ination of sural nerve biopsy specimens revealed defective myelin as well as marked differences, confirming the im portance of PO in the compaction of myelin.

Peripheral neuropathies caused by mutations in the myelin protein zero

“…For example, a patient who died, who had an Arg69Cys mutation, developed weakness at 6 months of age and a head lag at 14 months, could not cough and cry without sound. She lost the ability to roll over, developed a flaccid quadriparesis and died at the age of 22 months [46,47]. More typical is the original MPZ family in which atrophy of legs and intrinsic hand muscles developed prior to adolescence in most patients.…”

“…Despite the severity of the neuropathy, life expectancy did not appear to be reduced in most patients with early onset disease. The two patients who died in childhood did so because of respiratory compromise [46,47]. The most likely outcome appeared to be a normal lifespan requiring significant assistance in ambulation.…”

Ultrastructural protein zero expression in Charcot-Marie-Tooth type 1B Disease

“…However, even with a detailed electron microscopic study, anomalies of the myelin compaction were not observed. Meijerink et al 22 propose a role for arginine 69 in the formation and compaction of myelin sheaths, as 2 of their patients with a point mutation (Arg 69 → His and Arg 69 → Cys) in exon 3 had uncompacted myelin, and arginine 69 is conserved in a large number of species. 12 By contrast, tomaculae were observed in significant numbers.…”

“…The two mutations are located in two different exons (exon 2 and exon 3), but which code for P0-ED, 19 which is believed to confer the adhesive function of the protein 34 by homophilic adhesion. Some mutations leading to a systematic substitution by a cysteine amino acid are marked by a more severe phenotype, 22 which could be due to a ''dominant negative effect.'' This negative effect could be explained by the formation of abnormal P0 complexes with disulfide-bridged aggregates in the extracellular domain of the protein.…”

Charcot-Marie-Tooth disease and related neuropathies: Molecular basis for distinction and diagnosis

“…22,107 Different amino acid substitutions at the same site have been associated with either a CMT1 phenotype or a lethal infantile neuropathy. 62 Missense mutations within the extracellular domain usually cause less severe neuropathy (CMT1B), whereas mutations affecting the transmembrane or the intracellular domains are more deleterious and are associated with DSD or even CH. Mutations involving the disulfide bond that stabilizes the immunoglobulin domain in the extracellular region also cause severe neuropathy.…”