In last week’s WCMR Science Seminar, we heard two fantastic talks from Lucie Taylor and Dr Tiago Gomes who shared updates on their research projects. Read on to find out more:
My research concentrates on disease caused by the pathogenic mitochondrial variant m.3243A>G. This mutation is one of the most common pathogenic variants in the mitochondrial genome and therefore is the most common cause of mitochondrial disease in adults. It is associated with a wide range of clinical phenotypes, including seizures, diabetes, deafness, and cerebellar ataxia, as well as MELAS (Mitochondrial myopathy, encephalopathy, lactis acidosis and stroke-like episodes), a genetic condition which affects many of the body’s symptoms.
This highly variable clinical spectrum suggests an unidentified influence outside of mitochondrial DNA involvement. Some of the changes may be explained by heteroplasmy, i.e. the ratio of ‘normal vs abnormal’ mitochondrial DNA within a cell, but not all. I am attempting to understand what else could be affecting the m.3243A>G variant.
Family studies suggest that nuclear DNA variation also influences clinical outcome. Therefore in order to confirm this, whole genome sequencing of a large m.3243A>G clinical cohort, and further genetic analyses have been utilised to identify and assess these potential nuclear modifiers. I focus on the nuclear DNA sequencing data from both single individuals and members of families, alongside information from other genetic analyses to try and pinpoint an area of interest within the genome. All the data is combined in an attempt to determine a variant which could be exacerbating three of the most severe conditions associated with m. 3243A>G: encephalopathy, stroke-like episodes and seizures.
Dr Tiago Gomes
My project focuses on a complex and diverse group of inherited conditions called mitochondrial diseases, which affect 12.5 per 100,000 adults in the UK.
Inside our cells, mitochondria are crucial to produce energy and when they malfunction, the most energy demanding organs are affected as part of mitochondrial diseases. They contain mitochondrial DNA (mtDNA) with the blueprints for crucial mitochondrial proteins involved in energy production. If the mtDNA has errors, called mutations, these proteins may be lost, and the cells become energy deficient.
The muscle is very frequently involved causing what clinicians call ‘mitochondrial myopathy’, which causes muscle weakness, pain and fatigue. However, muscle function goes way beyond the ability to mobilise or use arms and hands for tasks. Eye movement, speech and facial expression, breathing, chewing and swallowing can also be severely affected by mitochondrial myopathy. These symptoms are often absent at birth but develop later in life and often worsen with increasing disability overtime.
There are different types of mtDNA errors, but mitochondrial myopathies are most commonly caused by the loss of long stretches of the mtDNA molecule, called deletions. Despite understanding their genetic origin, little is known about how these conditions progress, or worsen, with age. Progression of symptoms can also vary significantly even amongst patients with the same mutation and most of the molecular mechanisms that contribute to this variability remain unknown. Our ability to predict disease progression and prognosis is currently very limited because it is not known how the disease progresses and how could it be prevented, delayed, stopped or even reverted.
However, we know that ageing causes accumulation of mitochondrial dysfunction in the muscle of individuals without mitochondrial diseases and as part of an age-related decreased in muscle bulk and function called sarcopenia. For this reason, I became interested in investigating how ageing affects the mitochondria that are already malfunctioning due to a hereditary mitochondrial disease. My project aims to learn how mitochondrial disease and normal ageing interact to create disease progression. This knowledge will help future studies to develop treatments directed against these progression mechanisms to prevent or delay mitochondrial disease in patients.
In this type of research, we require muscle tissue samples from patients, and it would not be possible without the generosity of our patients. I would like to thank all our patients whose contribution will be essential for our ability to continue to carry out research to help people with mitochondrial diseases.