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[P165]: Generation of a mouse model for a peripheral neuropathy due to a missense mutation in the Krox20 gene
Author(s) -
Desmazieres A.,
Decker L.,
GilardiHebenstreit P.,
Charnay P.,
Vallat J.M.
Publication year - 2006
Publication title -
international journal of developmental neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.761
H-Index - 88
eISSN - 1873-474X
pISSN - 0736-5748
DOI - 10.1016/j.ijdevneu.2006.09.225
Subject(s) - missense mutation , citation , mutation , combinatorics , gene , genetics , biology , library science , computer science , mathematics
WS4 resulted in a degradation of mutation-bearing mRNA by activating nonsense mediated decay (NMD). Thus, WS4 phenotype is a consequence of haploinsufficiency. In contrast, mRNAs carrying PCWH-associated PTC mutations appeared to escape NMD, thereby stably translated into truncated mutant proteins. These truncated proteins showed lack of transcriptional activities, but revealed enhanced DNA binding affinity to complete wild type SOX10, thus function as dominant-negative alleles. Furthermore, PCWH-causing extension mutation that add an ∼80 amino acid tail onto the carboxyl terminus of wild type SOX10 revealed unique features. A short polypeptide within the tail was apparently responsible for functional toxicity. The extension also changed the level of post-translational regulation of SOX10 proteins. Thus, this type of mutation most likely acts as a gain-of-function allele. Together, different molecular mechanisms including haploinsufficiency, dominant-negative and gain-of-function, may underlie phenotypic variation resulting from SOX10 mutations in human.