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Analysis of compound heterozygous mice reveals that the Trembler mutation can behave as a gain‐of‐function allele
Author(s) -
Adlkofer Katrin,
Naef Roland,
Suter Ueli
Publication year - 1997
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/(sici)1097-4547(19970915)49:6<671::aid-jnr2>3.0.co;2-4
Subject(s) - null allele , peripheral myelin protein 22 , allele , biology , genetics , gene duplication , point mutation , mutation , compound heterozygosity , myelin , gene , heterozygote advantage , microbiology and biotechnology , endocrinology , central nervous system
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. J. Neurosci. Res. 49:671–680, 1997. © 1997 Wiley‐Liss, Inc.