I qualified in Medicine from Newcastle University in 1991, obtained my MRCP in adult medicine in Glasgow, subsequently worked in paediatrics in Stirling, and then undertook training in Clinical Genetics at Yorkhill Hospital (1996 - 1999). Inspired by Professor John Stephenson and Dr John Tolmie I became interested in neurogenetics and moved to Leeds where I undertook a PhD on the genetics of Aicardi-Goutières syndrome (AGS) with Dr Geoff Woods and Sir Alex Markham. Between 2001 and 2006 I was a full-time NHS consultant in the Yorkshire Regional Genetics Service, at which point I took up a post as Senior Lecturer in the Leeds Institute of Molecular Medicine working closely with Professor David Bonthron. In 2008 I became a Professor in Genetic Medicine at the University of Manchester.
My work has two main themes:
1. Type I interferonopathies - most particularly AGS. My work on AGS has proven to be of considerable scientific interest, and has led to the study of Mendelian forms of systemic lupus erythematosus (SLE).
2. Paediatric neurogenetics. Taking intracranial calcification as a diagnostic starting point has allowed for the delineation of a number of other clinical entities, demonstrating this same radiological sign, the genetic basis of which are currently under investigation.
Dr Gillian Rice - Senior Postdoc employed by the University of Manchester
Dr Paul Kasher - Postdoc funded through the European Research Council
Dr Emma Jenkinson - Postdoc funded through the Great Ormond Street Children's Charity
Aicardi-Goutières syndrome (AGS) is a genetically-determined brain disease closely mimicing the sequelae of congenital infection. AGS and congenital viral infection are both associated with an increased production of interferon alpha (IFN-a). Furthermore, a disturbance of IFN-a homeostasis is considered central to the pathogenesis of the autoimmune disorder systemic lupus erythematosus (SLE). In keeping with this, some children with AGS develop an early-onset form of SLE.
In 2006 we reported that recessive mutations in any of the genes encoding the 3´- 5´ exonuclease TREX1 (AGS1) or the three non-allelic components of the RNASEH2 endonuclease complex (AGS2, 3 and 4) result in AGS. We further showed, in 2007, that heterozygous TREX1 mutations cause both a dominant form of AGS and a cutaneous subtype of SLE, called familial chilblain lupus. In 2009 we described the AGS5 gene SAMHD1 as a regulator of the innate immune response, in 2012 we showed that mutations in the RNA editing enzyme ADAR1 can also result in the AGS phenotype, and in 2014 we reported mutations in IFIH1 / MDA5 to cause a spectrum of 'type I interferonopathy' phenotypes, includng AGS.
The proteins TREX1, the RNASEH2 complex, SAMHD1, ADAR1 and IFIH1 are all involved in nucleic acid metabolism / sensing. Based on our results, and data from other laboratories, we hypothesise that the AGS-associated proteins are involved in removing / sensing endogenous nucleic acid species, and that a disturbance of this system results in triggering of an innate immune response that is more normally induced by viral nucleic acid. This understanding defines a novel cell-intrinsic mechanism for the initiation of autoimmunity by interferon-stimulatory nucleic acid, and offers an elegant mechanistic explanation for the phenotypic overlap of AGS with congenital infection and SLE.
Our ongoing work aims to define the pathway from gene mutation through to stimulation of the immune system. Considering the natural history of AGS, ‘windows of opportunity’ for the treatment of this devastating disease exist and it is realistic to expect that advances in our understanding of the mechanisms underlying the phenotype will lead to earlier diagnosis, and provide molecular targets for the development of therapeutic interventions.
The above studies prompted us to consider the identification and analysis of single-gene disorders predisposing to the development of SLE as a tractable approach to understanding the pathogenesis of lupus; such ‘experiments of nature’ representing the equivalent of genetically engineered animal models of disease – in the human context. As proof of principle then, in 2011, we identified the causative gene for the immuno-osseus dysplasia spondyloenchondrodysplasia, in which affected individuals are at very high risk of multiple autoimmune phenotypes including lupus, and demonstrate a so-called type I interferon signature.
The work described above has led to the suggestion that a group of diseases exist where enhanced type I interferon signalling is directly relevant to pathology. This latter point is important, since it suggests that therapy to reduce type I interferon activity / signallng might be of therapeutic benefit. This is an active area of research in my lab, involving screening for type I interferonopathies using an 'interferon signature' test, and investigating treatments including JAK inhibitors.
Finally, using intracranial calcification (ICC) as a clinical starting point, in collaboration with John Livingston (paediatric neurologist, Leeds), we have developed expertise in the recognition of disorders associated with this clinical sign. Successes deriving from this approach iniclude the identifcation of mutations in OCLN, CTC1, POT1 and SNORD118 as causative of distinct ICC phenotypes.