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ROSE, Anna M
Post PhD: MBBS Year 6 - Preparation for Practice
Transcriptional regulation of PRPF31: the role of variable gene expression in determining phenotype in retinitis pigmentosa
Professor Shomi Bhattacharya - Institute of Ophthalmology
Jointly funded by The Astor Foundation and the Rosetrees Charitable Trust
Description of Project:
Retinitis Pigmentosa (RP) is an inherited, degenerative eye disease, that is both clinically and genetically heterogeneous. The disease is a major cause of blindness worldwide, especially in younger patients. Autosomal dominant RP (adRP) can be caused by mutations in many genes, including PRPF31, which codes for the ubiquitously expressed splicing factor hPRP31. PRPF31-associated adRP is notable for two reasons – firstly, although a ubiquitous splicing factor, disease only affects the retina and secondly, families show a unique pattern of inheritance known as non-penetrance. These two phenomena are as yet unexplained.
Classically, a disease is said to be autosomal dominant when there is clear family history of disease, with an affected parent passing the disease to children. Non-penetrance is a variant on autosomal dominant inheritance, whereby the disease appears to skip generations. This means there are obligate carriers of the disease mutation who
do not show symptoms of disease. In the case of PRPF31-associated adRP, it is known that this is due to the existence of two wild-type (normal) alleles of the gene – a high expressivity allele and a low expressivity allele (McGee et al., 1997; Vithana et al., 2001). It is hypothesised that when a patient has a mutant allele and a high expressivity wild type allele, they do not show the disease symptoms. However, if the wildtype allele is a low expressivity allele, the level of hPRP31 falls below the threshold required for normal retinal function, and the disease manifests. Although a variable wild type expression level has been demonstrated in the population (unpublished data), the underlying molecular mechanisms that control PRPF31 expression are not understood. The aim of this research project is to begin to understand the basis of these mechanisms. In the first six months, work has focussed on three main areas: identification of a new family, promoter characterization and preliminary design of a next-generation sequencing study.
Rose AM, Webster AR, Mukhopadhyay R, Bhattacharya SS, Waseem NH. Identification of Large Deletions in PRPF31 in Autosomal Dominant Retinitis Pigmentosa. IOVS 2010; 51:ARVO E-Abstract 5093
Rose AM, Gradin DS, Mundia D. Bilateral lens subluxation in a patient with suspected Loeys-Dietz syndrome. Afr J Paediatr Surg 2011; 8:119-20.
Rose AM, Kabiru J, Rose GE. Alveolar soft-part sarcoma of the orbit. Afr J Paediatr Surg 2011; 8:82-4.
Rose AM, Mukhopadhyay R, Webster AR, Bhattacharya SS, Waseem NH. A 112kb deletion in chromosome 19q13.42 leads to retinitis pigmentosa. IOVS 2011; 52:6597-6603
Mitchison NA, Rose AM. Epistasis: The key to understanding immunological disease? Eur J Immunol 2011; 41:2152–2154
Rose AM, Bell LC. Epistasis and immunity: the role of genetic interactions in
autoimmune diseases. Immunology. 2012 Oct;137(2):131-8. doi:
10.1111/j.1365-2567.2012.03623.x. Review. PubMed PMID: 22804709;
Venturini G, Rose AM, Shah AZ, Bhattacharya SS, Rivolta C. CNOT3 is a modifier
of PRPF31 mutations in retinitis pigmentosa with incomplete penetrance. PLoS
Genet. 2012;8(11):e1003040. doi: 10.1371/journal.pgen.1003040. Epub 2012 Nov 8.
Rose AM, Shah AZ, Waseem NH, Chakarova CF, Alfano G, Coussa RG, Ajlan R,
Koenekoop RK, Bhattacharya SS. Expression of PRPF31 and TFPT: regulation in
health and retinal disease. Hum Mol Genet. 2012 Sep 15;21(18):4126-37. doi:
10.1093/hmg/dds242. Epub 2012 Jun 20.
Prizes and Awards
- Tony Jackson Memorial Prize for 2011 for her work with HIV positive children in Zambia. More...
- Royal Society of Medicine (Ophthalmology Section and Student Members Group) UCO 2009 Best Case Presentation – April 2009
- Royal Society of Medicine Student Research Prize (First Place) – November 2009 (news link http://www.ucl.ac.uk/news/news-articles/0911/09111001)
- Royal Society of Medicine Brigadier Haywood prize (shortlisted) – February 2010
- Royal College of Paediatrics and Child Health Tony Jackson Memorial Prize – January 2012
- Cordwainer's Prize for Best MBPhD Thesis 2012
Page last modified on 09 oct 13 14:03 by Susan Beesley