0113 343 8443
Summary: Group Leader, Ciliopathy Research Group Principal Investigator, International Resource for Autozygosity Mapping
Location: 8.16, Wellcome Trust Brenner Building
Teaching Commitments: MBChB 1st year “Introduction to Medical Science” lectures and small group teaching on clinical and medical genetics MBChB 2nd year “Genetics in Medicine” module, lectures and small group teaching on clinical and medical genetics MSc. Mol. Med. lectures, small group teaching and practical classes on human molecular genetics
In recent years, an ever-increasing number of inherited diseases, of previously unknown aetiology, are caused by defects in primary cilia and basal bodies. The aim of my research is to gain novel insights into the molecular mechanisms of early embryogenesis and neurodevelopment, by elucidating the role of primary ciliary and basal body function with key pathways of development.
In May 2010 I received a promotional chair at the University of Leeds, with the title Professor of Medical and Molecular Genetics, following my appointment of Reader after a move from the University of Birmingham in November 2007. From May 2001, I took up the position of Lecturer in Human Molecular Genetics, and was based at the Section of Molecular and Medical Genetics, University of Birmingham, headed by Eamonn Maher. In 2005, I was promoted to Senior Lecturer in Human Molecular Genetics. I developed my interest in mechanisms of gene expression and genetics following my first degree (BA Hons. Biochemistry, University of Oxford, 1992), and pursued this interest in further post-graduate studies towards a PhD in Biochemistry (1996) with Roger Adams, University of Glasgow. Further training as post-doctoral research fellow was with Bryan Turner, University of Birmingham (1996-2001).
I joined the Section of Molecular and Medical Genetics, University of Birmingham, in 2001. Under the mentorship and generous support of Eamonn Maher, I started several projects to identify the disease genes for several recessive neurodevelopmental disorders. In 2005, with my student Ursie Smith, we finally identified the genetic cause of Meckel-Gruber syndrome. This was the long-sought first gene for this enigmatic neurodevelopmental condition (published in Nature Genetics, 2006). The gene, MKS3/TMEM67, encodes a novel protein that I called meckelin, which proved to be a unique transmembrane receptor. My subsequent research work has shown that Meckel-Gruber syndrome is the most severe condition in a suite of developmental conditions known as “ciliopathies”. Following my move to Leeds, my work on the MKS3/TMEM67 gene and the meckelin protein also enabled me to secure highly competitive grant awards from the Medical Research Council, the Newlife Foundation, and to contribute to an EU FP7 Collaborative Project/Large-scale Integrating Project (“SysCilia”) for systems biology approaches to dissect cilia function and its disruption in human genetic disease at the molecular level. This has led to a recent project to identify the long-sought MKS2/TMEM216 gene for Meckel-Gruber syndrome in a large, international team with long-term collaborators in the ciliopathy field (published in Nature Genetics, 2010). A major component of the “SysCilia” project has beena recently completed whole genome reverse genetics screen for genes that can contribute to ciliogenesis or cilia maintenance.
The most recent development in my research, has been the award in 2009 of the Sir Jules Thorn Charitable Trust annual Award for Biomedical Research. This is a prestigious award, given after competition between leading medical schools throughout the UK. The Award is given to support an original programme of applied medical research, with a clear strategy that leads to benefits for patients. With a strong team of colleagues at LIMM and Yorkshire Regional Genetics Service, I applied as the principal investigator to lead a programme of work to identify new recessive disease genes. This built on my track-record in mapping and finding such genes in Birmingham.
The level of funding from the Sir Jules Thorn Charitable Trust has allowed the establishment of a new research initiative at the national and international level. Further details on the work of the resource are described at our web-site http://autozygosity.org. The aims of this resource are to recruit consanguineous families with an autosomal recessive condition for research studies. This enables novel disease-causing genes to be identified by using autozygosity mapping. Once a gene has been identified then accurate molecular diagnostic tests can be developed and translated into NHS service provision. This has immediate patient benefit, for local families that were originally recruited for the research, and for other families with the same condition that are referred for diagnostic testing by clinicians throughout the UK and the world. As a research grouping, we have identified a remarkable 15 recessive disease genes in less than two years, with many scientific insights gained into the normal processes of tooth formation, embryogenesis and eye development. A very recent successful example is my group’s recent identification of mutations in MEGF10 as a cause of the early-onset myopathy EMARDD (published in Nature Genetics, 2011). EMARDD is just the last in a long list of recessive conditions caused by mutations in a novel gene that were identified in Leeds, but has the added interest of affecting muscle stem cells and delineating an entirely new Mendelian condition that was previously unknown. This has relied on access to next generation sequencing and collaboration with a unique grouping of researchers and clinicians. Whole exome sequencing now allows disease-causing mutations to be quickly identified in a disease gene even without any initial mapping work, and in the next stage of my research I plan to use this approach for those families that have not previously been suited for genetic mapping.