Analysis of compound heterozygous mice reveals that the Trembler mutation can behave as a gain-of-function allele
✍ Scribed by Katrin Adlkofer; Roland Naef; Ueli Suter
- Book ID
- 102653427
- Publisher
- John Wiley and Sons
- Year
- 1997
- Tongue
- English
- Weight
- 643 KB
- Volume
- 49
- Category
- Article
- ISSN
- 0360-4012
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✦ Synopsis
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.