Mutations in a gene causing mixed neurological and muscular
disease in children have been found for the first time.
Researchers at 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 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 humans. 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 are 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.
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 said: "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."
The paper, Loss-of-function mutations in MICU1 cause a brain and muscle
disorder linked to primary alterations in mitochondrial calcium
signaling, is published in Nature
Genetics.