Novel genetic mutations that cause neuro-muscular disease in children discovered

Mutations in a gene causing mixed neurological and muscular disease in children have been found for the first time.

Researchers at University College London (UCL) and the University of Leeds have identified an entirely novel mechanism responsible for a childhood onset neuromuscular diseases with associated brain involvement.

The research, published in Nature Genetics, identified mutations of the gene MICU1 in a group of children affected by this previously undescribed condition, and provides the first evidence that a defective MICU1 gene can cause disease 'in man'. The researchers used a technique called exome sequencing to analyse the genes of 15 children with similar clinical features and found two different mutations in the MICU1 gene.

The protein product of the MICU1 gene is found in mitochondria - the ''batteries'' of the cell, which are essential in generating energy for cells and found in large numbers in nerve and muscle cells, which have high energy demands. The MICU1 gene contains the genetic blueprint for a protein that helps regulate mitochondrial calcium balance.

To function properly, mitochondria need a certain amount of calcium. If calcium levels are either too high or too low, they stop providing cells with energy, leading to cellular dysfunction and cell death.

"This research provides useful information about how muscle functions and will lead to more patients receiving accurate diagnosis in the future," says professor Francesco Mutoni, UCL Institute of Child Health

The MICU1 gene was discovered only very recently and was shown to carry genes important for mitochondrial calcium signalling. However, the functional importance of the gene is only now revealed by the discovery that MICU1 mutations lead to impaired mitochondrial function sufficiently severe to cause profound defects in the nervous system and muscle of children who are unfortunate enough to carry these mutations.

The work was carried out by an international team of researchers that included Professor Michael Duchen and Dr Gyorgy Szabadkai (UCL Cell and Developmental Biology) and Professor Francesco Muntoni (UCL Institute for Child Health), including a major contribution from Jenny Sharpe, a PhD student working with Professor Duchen. The UCL group are members of the UCL-MRC Centre for Neuromuscular Diseases.

Professor Michael Duchen, who was a major contributor to the work, says, ''Mitochondrial calcium signalling has long been thought to be important in regulating cellular energy supply, and defects in these pathways have been thought to be important in many conditions. However, this is the first time that a human condition has been directly linked to a gene defect in this pathway, so this is very exciting for us.''

Professor Francesco Muntoni who identified and characterised some of the original families said: ''It is not understood precisely how these changes lead to myopathy, but this research provides useful information about how muscle functions and suggests possible targets for developing therapeutic interventions. The research will lead to more patients receiving accurate diagnosis in the future.