Mitochondrial complex III deficiency (Mitochondrial complex III deficiency) - Genes MT-CYB and BCS1L.
Deficiency of mitochondrial complex III is a genetic disorder that can affect various parts of the body, including the brain, kidney, liver, heart and skeletal muscles. Usually the signs and symptoms of mitochondrial complex III deficiency begin in childhood, but may appear later. The severity of the disease varies widely among affected individuals. People who are mildly affected tend to have myopathy and fatigue, particularly during exercise. Affected individuals more severely struggle with multiple body systems, such as liver disease that can cause liver failure, tubulopathy and encephalopathy. Encephalopathy can lead psychomotor retardation, circulation problems, hypotonia and difficulty with communication. Other signs and symptoms of the disease may include cardiomyopathy, lactic acidosis, ketoacidosis and hyperglycemia. Abnormally high levels of these chemicals in the body can be life threatening. The mitochondrial complex III deficiency can be fatal in childhood, although individuals with signs and symptoms can survive mild adolescence or adulthood.
Deficiency of mitochondrial complex III can be due to mutations in one of several genes. The encoded proteins from these genes are a part, or help to constitute a group of proteins called complex III. The two most frequently mutated genes associated with mitochondrial complex III deficiency are MT-CYB located in mtDNA and BCS1L, located on the long arm of chromosome 2 (2q33). It is likely that other genes have not been identified are also involved in this alteration.
The MT-CYB, gene encodes a component of complex III called cytochrome b, while the BCS1L gene encodes a protein that is critical for the complex formation. In mitochondria, complex III carries out a step in the process of oxidative phosphorylation. During oxidative phosphorylation, protein complexes, including complex III, drive ATP production via electron transfer. Action as a byproduct of oxidative phosphorylation, complex III produces reactive oxygen species. Cytochrome b is involved in the transfer of these particles through complex III. MtDNA contains many genes essential for normal mitochondrial function. Cytochrome b is the only component of the complex III which is encoded from a gene located in the mtDNA.
Mutations in MT-CYB and BCS1L genes associated with mitochondrial complex III deficiency alter the formation of molecules of complex III. These changes negatively affect the formation of complex III, dramatically reducing activity and oxidative phosphorylation complex. It is likely that impaired oxidative phosphorylation can cause cell death by reducing the amount of energy available in the cell. It is thought that energy - intensive tissue such as muscle, brain, heart, liver and kidneys are the most affected by the reduction of oxidative phosphorylation. Damage to these tissues and organs leads to the various features of the mitochondrial complex III deficiency.
When the mitochondrial complex III deficiency is associated with mutations in the gene BCS1L, the disease most commonly characterized with liver disease, tubulopathy and encephalopathy. When the alteration is due to mutations in the MT-CYB gene it is generally characterized by myopathy and pain, especially during exercise. Affected individuals more intensely may have problems with other body systems, including the liver, kidneys, heart and brain. Unlike most genes, the location of the MT-CYB gene in mtDNA may help explain why some people have more intense than other features. Most body cells contain thousands of mitochondria, each with one or more copies of mtDNA. It is thought that the severity of the mitochondrial complex III deficiency due to mutations in the MT-CYB gene is associated with the percentage of mitochondria with mutated mtDNA. In most of those affected, the percentage of mutated mtDNA is higher in skeletal muscles, which explains myopathy in these individuals. It is unclear why the mutation is more common in muscle tissue.
This disease is inherited in an autosomal recessive pattern, which means that both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease. In some cases due to mutations in the MT-CYB gene, the disease is not inherited but is due to new mutations in the gene that occur in people with no history of disease in your family. Other cases due to mutations in the MT-CYB gene are inherited mitochondrial pattern, also known as maternal inheritance. This pattern of inheritance applies to genes in mitochondrial DNA. Since egg cells, but not sperm, contribute mitochondria to the developing embryo, only women transmit mitochondrial alterations to their children. Mitochondrial disorders can appear in each generation of a family and can affect both men and women, but parents do not pass mitochondrial traits to their children.
Tests in IVAMI: in IVAMI perform detection of mutations associated with mitochondrial complex III deficiency, by complete PCR amplification of the exons of the MT-CYB and BCS1L genes, respectively, and subsequent sequencing.
Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).