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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.
Human Mutation
|January 1, 1996
Summary
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.