1. A Mouse Model with a Frameshift Mutation in the Nuclear Factor I/X (NFIX) Gene Has Phenotypic Features of Marshall-Smith Syndrome.
- Author
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Kooblall, Kreepa, Stevenson, Mark, Stewart, Michelle, Harris, Lachlan, Zalucki, Oressia, Dewhurst, Hannah, Butterfield, Natalie, Leng, Houfu, Hough, Tertius, Ma, Da, Siow, Bernard, Potter, Paul, Cox, Roger, Brown, Stephen, Horwood, Nicole, Wright, Benjamin, Lockstone, Helen, Buck, David, Vincent, Tonia, Hannan, Fadil, Bassett, J, Williams, Graham, Lines, Kate, Piper, Michael, Wells, Sara, Teboul, Lydia, Hennekam, Raoul, and Thakker, Rajesh
- Subjects
NFIX ,brain abnormalities ,frameshift mutation ,kyphosis ,osteopenia - Abstract
The nuclear factor I/X (NFIX) gene encodes a ubiquitously expressed transcription factor whose mutations lead to two allelic disorders characterized by developmental, skeletal, and neural abnormalities, namely, Malan syndrome (MAL) and Marshall-Smith syndrome (MSS). NFIX mutations associated with MAL mainly cluster in exon 2 and are cleared by nonsense-mediated decay (NMD) leading to NFIX haploinsufficiency, whereas NFIX mutations associated with MSS are clustered in exons 6-10 and escape NMD and result in the production of dominant-negative mutant NFIX proteins. Thus, different NFIX mutations have distinct consequences on NFIX expression. To elucidate the in vivo effects of MSS-associated NFIX exon 7 mutations, we used CRISPR-Cas9 to generate mouse models with exon 7 deletions that comprised: a frameshift deletion of two nucleotides (Nfix Del2); in-frame deletion of 24 nucleotides (Nfix Del24); and deletion of 140 nucleotides (Nfix Del140). Nfix +/Del2, Nfix +/Del24, Nfix +/Del140, Nfix Del24/Del24, and Nfix Del140/Del140 mice were viable, normal, and fertile, with no skeletal abnormalities, but Nfix Del2/Del2 mice had significantly reduced viability (p
- Published
- 2023