title: Analysis of compound heterozygous mice reveals that the Trembler mutation can behave as a gain-of-function allele.
abstract: The most common form of Charcot-Marie-Tooth disease, CMT1A, is correlated with a 1.5 megabase duplication on chromosome 17p.11.2 containing the peripheral myelin protein 22 (PMP22) gene. Deletion of the same region is associated with a second inherited neural disorder, the hereditary neuropathy with liability to pressure palsies (HNPP). Moreover, several distinct point mutations within the PMP22 coding region are associated with CMT1A and Dejerine-Sottas Syndrome in humans and the Trembler (Tr) and Trembler-J phenotypes in mice. Heterozygous Tr mutants (Tr/+) display severe hypomyelination of peripheral nerve fibers while heterozygous pmp22 knockout mice (pmp22+/0) are characterized by focal hypermyelination. These findings suggest that the Tr mutation does not generate a pmp22 null allele but rather produces its deleterious effects by either a dominant-negative or gain-of-function mechanism. To address this question in detail, we have compared various combinations of pmp22 alleles including Tr/+, Tr/Tr, Tr/0, pmp22+/0, and pmp22(0/0) mice with respect to the resulting myelin abnormalities. The combined analysis of these mutants demonstrates that the Tr allele can act as a true gain-of-function mutation in both, the heterozygous state on a null background (Tr/0) as well as in homozygous Tr animals (Tr/Tr). Furthermore, increasing the relative Tr gene dosage correlates with more pronounced myelin deficiencies and decreased levels of MBP and P0 in 18-day-old mice.
authors.affiliation: Institute of Cell Biology, Department of Biology, Swiss Federal Institute of Technology, Zurich.
authors.forename: K
authors.initials: K
authors.lastname: Adlkofer
authors.forename: R
authors.initials: R
authors.lastname: Naef
authors.forename: U
authors.initials: U
authors.lastname: Suter
mesh_terms: D000483:Alleles; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D015153:Blotting, Western; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D005838:Genotype; D015417:Hereditary Sensory and Motor Neuropathy / Q000235:genetics; D006579:Heterozygote; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants / Q000502:physiology*; D008854:Microscopy, Electron; D016296:Mutagenesis / Q000502:physiology; D009185:Myelin Proteins / Q000032:analysis / Q000235:genetics*; D009186:Myelin Sheath / Q000737:chemistry / Q000648:ultrastructure; D010641:Phenotype; D017354:Point Mutation / Q000502:physiology*
chemical_list: D009185:Myelin Proteins; C489545:Pmp22 protein, mouse