MYELIN PROTEIN ZERO (MPZ) GENE-MUTATIONS IN NONDUPLICATION TYPE-1 CHARCOT-MARIE-TOOTH DISEASE

The myelin protein zero gene (MPZ) maps to chromosome 1q22-q23 and enc odes the most abundant peripheral nerve myelin protein. The P-0 protei n functions as a homophilic adhesion molecule in myelin compaction. Mu tations in the MPZ gene are associated with the demyelinating peripher al neuropathies Charcot-Marie-Tooth disease type 1B (CMT1B), and the m ore severe Dejerine-Sottas syndrome (DSS). We have surveyed a cohort o f 70 unrelated patients with demyelinating polyneuropathy for addition al mutations in the MPZ gene. The 1.5-Mb DNA duplication on chromosome 17p11.2-p12 associated with CMT type 1A (CMT1A) was not present. By D NA heteroduplex analysis, four base mismatches were detected in three exons of MPZ. Nucleotide sequence analysis identified a de novo mutati on in MPZ exon 3 that predicts an Ile(135)Thr substitution in a family with clinically severe early-onset CMT1, and an exon 3 mutation encod ing a Gly(137)Ser substitution was identified in a second CMT1 family. Each predicted amino acid substitution resides in the extracellular d omain of the P-0 protein. Heteroduplex analysis did not detect either base change in 104 unrelated controls, indicating that these substitut ions are disease associated mutations rather than common polymorphisms . In addition, two polymorphic mutations were identified in MPZ exon 5 and exon 6, which do not alter the codons for Gly(200) and Ser(228), respectively. These observations provide further confirmation of the r ole of MPZ in CMT1B and suggest that MPZ coding region mutations may a ccount for a limited percentage of disease causing mutations in nondup lication CMT1 patients. (C) 1996 Wiley Liss, Inc.