The role of the transcription factor Nuclear Factor I/X (NFIX) in the pathogenesis of Marshall-Smith Syndrome (MSS)

Marshall-Smith Syndrome (MSS) is a congenital disorder affecting skeletal and neural development due to mutations in the nuclear factor I/X (NFIX) gene (Malan, et al. 2010). These mutations are significantly clustered in exons 6 to 10 of the NFIX gene and introduce frame shifts and splice site variants which result in the production of aberrant transcripts that escape the nonsense mediated decay mechanism, leading to the production of dysfunctional mutant NFIX proteins (Malan, et al. 2010). NFIX is a transcription factor that regulates gene expression in many tissues (including lung, kidney, liver, blood, heart, skeleton and nervous system). It binds as homo- or hetero- dimers to the promoter regions of viral and cellular genes where it can act as either a suppressor or activator of gene transcription. Homozygous NFIX deficient mouse models with targeted mutations in exon 2 have variable phenotypes, which do not reflect either the type of mutations or some of the severe phenotypes observed in MSS patients (Campbell, et al. 2008; Driller, et al. 2007).



Our aim is to generate in vitro assays (Gorvin, et al., 2014; Kooblall, et al., 2015; Newey, et al. 2013) and in vivo mouse models (Lines, et al. 2016) expressing mutant NFIX that more closely resembles the mutations and phenotypes observed in MSS patients. These models will then be used to study the role of NFIX in the pathogenesis of MSS and to identify potential treatments for MSS. Our group is currently generating several mouse models of MSS using the CRISPR-Cas gene editing system. The objective of this DPhil project is therefore to investigate the effects of MSS-associated NFIX mutations on NFIX activity in vitro as well as characterise the phenotypes of our established MSS mouse models in order to gain greater insight into the role of MSS-associated NFIX mutations in bone development and identify compounds that can modulate NFIX activity in vitro and in vivo. Specifically, the student will; 1) elucidate the mechanisms of action of MSS-associated NFIX mutations in bone development; 2) identify pathways that are differentially altered by the MSS-associated NFIX mutations as these may represent potential targets for drugs; 3) establish high throughput screening of compounds with the aim of identifying compounds that could modulate NFIX activity; and 4) assess the efficacy of potential compounds at modulating NFIX activity in vitro and in vivo.