| First Author | Adlkofer K | Year | 1997 |
| Journal | J Neurosci Res | Volume | 49 |
| Issue | 6 | Pages | 671-80 |
| PubMed ID | 9335255 | Mgi Jnum | J:43246 |
| Mgi Id | MGI:1097426 | Doi | 10.1002/(SICI)1097-4547(19970915)49:6<671::AID-JNR2>3.0.CO;2-4 |
| Citation | Adlkofer K, et al. (1997) Analysis of compound heterozygous mice reveals that the Trembler mutation can behave as a gain-of-function allele. J Neurosci Res 49(6):671-80 |
| abstractText | 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. |
