MT-TL1

The MT-TL1 gene provides instructions for making a molecule that is a chemical cousin of DNA. This molecule, called a transfer RNA (tRNA), helps assemble protein building blocks known as amino acids into functioning proteins. The MT-TL1 gene provides instructions for making a specific form of tRNA that is designated as tRNA^Leu(UUR). During protein assembly, this molecule attaches to the amino acid leucine (Leu) and inserts it into the appropriate locations in the protein.

The tRNA^Leu(UUR) molecule is present only in cellular structures called mitochondria. These structures convert energy from food into a form that cells can use. Within mitochondria, tRNA^Leu(UUR) is involved in the assembly of proteins that carry out a series of chemical steps called oxidative phosphorylation. This process uses oxygen, simple sugars, and fatty acids to create adenosine triphosphate (ATP), the cell's main energy source.

mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes - caused by mutations in the MT-TL1 gene

Several mutations in the MT-TL1 gene have been identified in people with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). Most of these mutations change single DNA building blocks (nucleotides) in the gene. The most common mutation, A3243G, is responsible for about 80 percent of all MELAS cases. This genetic change replaces the nucleotide adenine with the nucleotide guanine at position 3243 in the MT-TL1 gene. The A3243G mutation impairs the ability of mitochondria to make proteins, use oxygen, and produce energy. Researchers have not determined how changes in mtDNA lead to the specific signs and symptoms of MELAS. They continue to investigate the effects of mitochondrial gene mutations in different tissues, particularly in the brain.

myoclonic epilepsy with ragged-red fibers - caused by mutations in the MT-TL1 gene

Mutations in the MT-TL1 gene have been found in a few people with the characteristics of myoclonic epilepsy and ragged red fibers (MERRF). These individuals also have some features of MELAS. This combination of signs and symptoms is called MERRF/MELAS overlap syndrome. The features of this syndrome include muscle twitches (myoclonus), muscle weakness (myopathy), difficulty coordinating movement (ataxia), hearing loss, seizures, and diabetes.

Mutations that cause MERRF/MELAS overlap syndrome each change a single nucleotide in the MT-TL1 gene. Researchers have not determined how these genetic changes cause the signs and symptoms of MERRF/MELAS overlap syndrome.

progressive external ophthalmoplegia - caused by mutations in the MT-TL1 gene

Mutations in the MT-TL1 gene are responsible for some cases of an eye condition called progressive external ophthalmoplegia. This disorder weakens the muscles that control eye movement and causes the eyelids to droop (ptosis).

Some cases of progressive external ophthalmoplegia result from the A3243G mutation (described above), which is the same genetic change that typically causes MELAS. It is unclear how the same MT-TL1 gene mutation can result in different signs and symptoms. Researchers have not determined how changes in mtDNA lead to the specific signs and symptoms of progressive external ophthalmoplegia, although the features of the condition may be related to impaired oxidative phosphorylation. It has been suggested that eye muscles are commonly affected by mitochondrial defects because they are especially dependent on oxidative phosphorylation for energy.

other disorders - associated with the MT-TL1 gene

About 20 mutations in the MT-TL1 gene have been reported, most of which change single nucleotides in the gene. These mutations are associated with a variety of signs and symptoms chiefly affecting the muscles and nervous system. People with MT-TL1 mutations often have muscle weakness, pain, and extreme fatigue, particularly during exercise (exercise intolerance). In some cases, the heart muscle is also weakened, preventing the heart from pumping as it should.

A few children with changes in the MT-TL1 gene have experienced delayed development, psychiatric problems, or developmental disorders that affect communication and social interaction (autistic spectrum disorders). MT-TL1 mutations also have been identified in a small number of cases of sudden infant death syndrome (SIDS), which is a major cause of death in children younger than 1 year.

The A3243G mutation, which typically causes MELAS, is also associated with a condition called maternally inherited diabetes and deafness (MIDD). Most people with this MT-TL1 mutation develop diabetes in adulthood, usually in their mid-thirties. Many also experience hearing loss, particularly at high tones. Less commonly, heart problems and kidney failure are associated with this condition. Researchers believe that the A3243G mutation impairs the function of certain cells in the pancreas. These cells, known as beta cells, normally produce a hormone called insulin that helps control blood sugar levels. Diabetes results when the beta cells do not produce enough insulin to regulate blood sugar effectively. Researchers have not determined how the A3243G mutation leads to hearing loss or the other medical problems associated with maternally inherited diabetes and deafness.