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Myelin protein zero (MPZ) gene mutations in nonduplication type 1 Charcot-Marie-Tooth disease
B B Roa1, L E Warner, C A Garcia
1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Abstract:
The myelin protein zero gene (MPZ) maps to chromosome 1q22-q23 and encodes the most abundant peripheral nerve myelin protein. The Po protein functions as a homophilic adhesion molecule in myelin compaction. Mutations in the MPZ gene are associated with the demyelinating peripheral neuropathies Charcot-Marie-Tooth disease type 1B (CMT1B), and the more severe Dejerine-Sottas syndrome (DSS). We have surveyed a cohort of 70 unrelated patients with demyelinating polyneuropathy for additional 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 DNA heteroduplex analysis, four base mismatches were detected in three exons of MPZ. Nucleotide sequence analysis identified a de novo mutation 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 encoding a Gly(137)Ser substitution was identified in a second CMT1 family. Each predicted amino acid substitution resides in the extracellular domain of the Po protein. Heteroduplex analysis did not detect either base change in 104 unrelated controls, indicating that these substitutions 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 role of MPZ in CMT1B and suggest that MPZ coding region mutations may account for a limited percentage of disease-causing mutations in nonduplication CMT1 patients.
Insights
Mutations in the myelin protein zero (MPZ) gene are linked to Charcot-Marie-Tooth disease type 1B (CMT1B). Researchers identified two new MPZ mutations in patients with severe demyelinating polyneuropathy, confirming MPZ
Area of Science:
- Genetics
- Neuroscience
- Molecular Biology
Background:
- The myelin protein zero (MPZ) gene encodes the primary protein in peripheral nerve myelin.
- MPZ's Po protein is crucial for myelin compaction, acting as a homophilic adhesion molecule.
- Mutations in MPZ are known causes of demyelinating peripheral neuropathies like Charcot-Marie-Tooth disease type 1B (CMT1B) and Dejerine-Sottas syndrome (DSS).
Purpose of the Study:
- To identify additional mutations in the MPZ gene within a cohort of 70 unrelated patients diagnosed with demyelinating polyneuropathy.
- To investigate the role of MPZ coding region mutations in patients with Charcot-Marie-Tooth disease type 1A (CMT1A)-like phenotypes but lacking the characteristic 17p11.2-p12 duplication.
Main Methods:
- DNA heteroduplex analysis was employed to screen for base mismatches in the MPZ gene across 70 patients.
- Positive heteroduplex findings prompted nucleotide sequence analysis to confirm and characterize mutations.
- Analysis included screening 104 unrelated controls to differentiate disease-causing mutations from common polymorphisms.
Main Results:
- Two novel mutations in MPZ exon 3 were identified: one predicting an Ile(135)Thr substitution and another a Gly(137)Ser substitution.
- These substitutions occurred in families with severe, early-onset CMT1 and are located in the Po protein's extracellular domain.
- Two common polymorphisms were found in MPZ exons 5 and 6, which do not affect amino acid residues Gly(200) and Ser(228).
Conclusions:
- The identified MPZ mutations are disease-associated and not common polymorphisms, further implicating MPZ in the pathogenesis of CMT1B.
- These findings confirm the role of MPZ in demyelinating neuropathies and suggest its coding region mutations contribute to a subset of non-duplication CMT1 cases.