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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.

Training Opportunities

The project would be based at the Oxford Centre for Diabetes, Endocrinology and Metabolism. This DPhil would provide training in a wide range of basic molecular biology techniques including cloning techniques, PCR, RT-qPCR, RNA sequencing, Western Blot and immunohistochemistry; cellular biology techniques including cell culture, cell transfections, microscopy, in vitro expression assays and reporter assays; as well as the use of in vivo models. The successful applicant will be co-supervised by Dr Kreepa Kooblall, a postdoctoral research assistant within the group who is experienced in the above-mentioned techniques. 

As well as the specific training detailed above, students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford. Students are also able to attend the Methods and Techniques course run by the MRC Weatherall Institute of Molecular Medicine. This course runs through the year, ensuring that students have the opportunity to build a broad-based understanding of differing research techniques.

Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

The department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to support the careers of female students and staff.



Campbell CE, Piper M, Plachez C, Yeh Y-T, Baizer JS, Osinski JM, Litwack ED, Richards LJ & Gronostajski RM 2008 The transcription factor Nfix is essential for normal brain development. Bmc Developmental Biology 8.


Driller K, Pagenstecher A, Uhl M, Omran H, Berlis A, Gruender A & Sippel AE 2007 Nuclear factor I X deficiency causes brain malformation and severe skeletal defects. Molecular and Cellular Biology 27 3855-3867.


Gorvin CM, Newey PJ & Thakker RV 2014 Functional evaluation of rare genetic variants in the prolactin receptor. Endocrine reviews 35 OR35-31.


Kooblall K, Stevenson M, Piret S, Potter P, Cox R, Brown S, Hennekam, R, and Thakker, R (2015). Exploring the N-ethyl-N-nitrosourea (ENU) mutagenesis DNA archive for mutations in NFIX to derive mouse models for Marshall-Smith syndrome (MSS). Endocrine Abstracts, 34:P2.


Lines KE, Stevenson M & Thakker RV 2016 Animal models of pituitary neoplasia. Molecular and Cellular Endocrinology 421 68-81.


Malan V, Rajan D, Thomas S, Shaw AC, Picard HLD, Layet V, Till M, van Haeringen A, Mortier G, Nampoothiri S, et al. 2010 Distinct Effects of Allelic NFIX Mutations on Nonsense-Mediated mRNA Decay Engender Either a Sotos-like or a Marshall-Smith Syndrome. American Journal of Human Genetics 87 189-198.

Research Themes, Tools and Technologies


Key Dates for October 2018 Entry

We are no longer accepting applications for October 2018 entry.

Applications for October 2019 entry will open on Monday 3 September 2018. A revised list of projects will be available from mid-October 2018. We advise applicants to wait until the new list is published before making an application.

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How to apply

To apply for a place on the DPhil in Medical Sciences you will need to submit an application using the online application form.

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