Marked phenotypic variation in a family with a new myelin protein zero mutation

Myelin protein zero (MPZ) is a member of the immunoglobulin gene superfamily, which has a role in myelin compaction. MPZ gene mutations cause mostly demyelinating neuropathies of the Charcot-Marie-Tooth 1B type (CMT1B), but axonal CMT have been described as well. There is a broad spectrum of phenotypic manifestation of neuropathies caused by MPZ mutations. Some mutations of MPZ cause severe early-onset neuropathies such as Dejerine-Sottas disease, while others cause the classical CMT phenotype with normal early milestones but development of disability during the first two decades of life. We describe a family in which five members of three consecutive generations had a heterozygous mutation in nucleotide position 143 with a T-C transition in exon 2 of the MPZ gene. The resulting substitution of Leu48 with proline has not been previously described. The age of onset of symptoms varied from 8 months to 41 years. The marked variation of the age of disease onset and clinical phenotype in this one family, related to the same MPZ mutation, suggests that in addition to the type and intragenic location of the mutation, other putative modifying gene(s) are regulating MPZ gene expression, mRNA stability and posttranslational protein modification and may have an important effect on the ultimate clinical phenotype.