Gene Mutation Causes Devastating Mitochondrial Diseases

A novel disease gene has been identified in which mutations cause rare but devastating genetic diseases known as mitochondrial disorder.

Mitochondrial diseases are caused by mutations in either mitochondrial DNA or in genes in the nucleus that encode for proteins that function in the mitochondria.


Scientists at the Loyola University Stritch School of Medicine (Maywood, IL, USA) and their multi-institute collaborators performed a battery of genetic tests to identify a nuclear gene that encodes for a protein called F-Box and Leucine-Rich Repeat Protein 4 (FBXL4).

They found that mutations of this FBXL4 gene lead to either truncated or altered forms of the protein. This results in cells having less mitochondrial DNA, decreased mitochondrial membrane potential and a faulty process in cell metabolism called oxidative phosphorylation. The study also proved that the FBXL4 protein is located exclusively in mitochondria, which was previously unrecognized.

The team used high-performance computer cluster to analyze billions of DNA sequences to identify the gene mutation in a child and her parents. The scientists then reached out to other collaborators to see if any of their patients also had the FBXL4 mutation. Eight additional affected children in six unrelated families were found to also have disease-causing mutations in this gene.

Biochemical assays performed on clinical basis in muscle and/or fibroblasts obtained from several subjects confirmed the deleterious effect of FBXL4 mutations on mitochondrial bioenergetics. Muscle homogenates or isolated mitochondria from subjects with FBXL4 mutations showed variably decreased activity of mitochondrial respiratory chain complexes.

The authors concluded that they provided evidence that recessive FBXL4 mutations are responsible for severe, infantile-onset mitochondrial encephalomyopathy. A child can inherit a mitochondrial disease either from the mother alone or from both parents carrying mutations in the same nuclear gene. Mitochondrial diseases affect between 1 in 4,000 and 1 in 5,000 people. The study was published on August 29, 2013, in the American Journal of Human Genetics.

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Loyola University Stritch School of Medicine