Our group uses molecular genetic and cell biology techniques to understand inherited neurological diseases with a view to improving the clinical management patients and their families.
Our principal interest is human mitochondrial disease. Mitochondrial disorders are amongst the most common genetic diseases, affecting ~1 in 5000. Patients characteristically present with a diverse range of phenotypes, often involving the central and peripheral nervous system, the eye, auditory system and muscle, the heart and endocrine organs. Central to our understanding of the pathogenesis is the mechanism underpinning the clinical variability. This is a major focus of research in our group, especially the ocular phenotype.
Mitochondria contain their own DNA (mtDNA) which codes for 13 essential proteins that form part of the final common pathway for cellular metabolism. MtDNA is maternally inherited and each human cell contains thousands of copies. Patients with pathogenic mutations of mtDNA often harbour a mixture of mutated and wildtype genomes (heteroplasmy). The clinical phenotype is related to the proportion of mutated mtDNA inherited from the mother, and this can vary markedly, both between siblings and also within the same individual.
We are currently studying the process of mtDNA segregation in somatic cells and during embryogenesis. This will help us understand the mechanism of transmission of mtDNA, and ultimately define recurrence risks which can be used to counsel families in the neurogenetic clinic. Mitochondria do not exist in isolation, and it is becoming clear that nuclear genes modulate the clinical phenotype in a number of ostensibly monogenic mtDNA diseases. We are currently mapping nuclear loci that interact with pathogenic mtDNA mutations, and defining the genetic basis and clinical phenotype of a novel nuclearmitochondrial diseases.
There is increasing evidence that mitochondria are involved in the pathogenesis of a number of complex traits, including ischaemic stroke and late onset neurodegenerative diseases such as Parkinson’s disease, and even the ageing process itself. We have been studying the evolution of mtDNA at the population level and in disease cohorts with a view to identifying the key genetic variants that influence the aetiology of these disorders.
Recently, our research has evolved a major translational focus. We are working with industrial partners to develop new treatments for mitochondrial disease. We have recently begun clinical trials in Newcastle using two agents which show great promise.