DNA is organized into segments known as genes. These genes serve as blueprints for creating proteins. The FXN gene is one such blueprint, and its proper function is directly linked to the maintenance of cellular energy and overall health. When this gene malfunctions, the resulting protein deficiency disrupts core metabolic processes. This article will examine the normal function of the FXN gene and its protein product, and explore the biological consequences that occur when its instructions are compromised.
The Genetics of FXN
The FXN gene is located on the long arm of human chromosome 9, providing the genetic instructions for synthesizing a protein known as frataxin. This gene is expressed across all tissues of the body, but its protein product is found in the highest concentrations within cells that have particularly high energy demands. These high-demand tissues include the heart, skeletal muscles, the spinal cord, and the pancreas. Frataxin is initially synthesized in the cell’s cytoplasm before being transported into the mitochondria. The gene’s structure includes a non-coding segment called an intron, and within the first intron is a specific sequence of guanine-adenine-adenine (GAA) trinucleotide repeats.
The number of GAA repeats in a healthy FXN gene ranges from fewer than 12 up to about 33 repeats. This sequence serves as a stable part of the gene’s structure and does not impede the process of creating the frataxin protein. The primary function of the gene is to ensure a continuous and adequate supply of frataxin to support the metabolic needs of the body’s most active cells.
Normal Frataxin Function
Once inside the mitochondria, the frataxin protein becomes a central player in the cell’s energy production system. Its primary role involves the regulation and management of iron within this organelle, an element necessary for respiration. Frataxin acts as an activator and modulator in the process of assembling iron-sulfur clusters (ISCs).
ISCs are modular cofactors composed of iron and sulfur atoms that are incorporated into many proteins. The presence of ISCs is necessary for the function of numerous mitochondrial enzymes, including those that make up the electron transport chain, which is the final stage of energy (ATP) synthesis. Frataxin facilitates this assembly process by interacting with a core protein complex that includes a scaffold protein and a cysteine desulfurase.
The protein complex uses iron and sulfur from the amino acid cysteine to construct the ISCs, and frataxin’s presence accelerates this chemical reaction. By helping to manage the available iron and transfer sulfur, frataxin ensures that the ISCs are formed efficiently and delivered to various respiratory chain complexes. This regulation prevents free iron from accumulating in the mitochondria, where it can become chemically reactive and cause damage.
The proper assembly of ISCs allows the cell to perform cellular respiration, a process that continuously generates the necessary energy to sustain life. Frataxin is instrumental in maintaining this balance of iron and energy metabolism. Without sufficient frataxin activity, the mitochondrial machinery, which is responsible for about 90% of the cell’s energy, begins to fail.
The Impact of FXN Mutations
A pathogenic change to the FXN gene involves an expansion of the GAA trinucleotide repeat sequence located in the first intron. In individuals with this mutation, the number of GAA repeats increases, often reaching hundreds or even over a thousand copies. This abnormal expansion does not change the coding sequence of the protein, but severely disrupts the gene’s ability to be transcribed into messenger RNA (mRNA).
The repeat expansion causes a type of genetic interference known as transcriptional silencing, which is driven by epigenetic changes. Repressive chromatin structures spread from the expanded repeat region, blocking the cellular machinery from accessing and reading the gene’s instructions. This epigenetic silencing leads to a severe reduction in the amount of FXN mRNA being produced.
Because less mRNA is created, the amount of frataxin protein synthesized is lowered, often to a fraction of normal levels. This deficiency compromises the mitochondrial iron regulation system. Unmanaged iron begins to build up within the mitochondria because the assembly of ISCs is impaired, leading to a toxic accumulation of the mineral. The combination of iron toxicity and the failure of ISC-containing enzymes causes the production of reactive oxygen species (ROS), or free radicals, to increase. This oxidative stress damages cellular components, further disrupting mitochondrial function and ultimately leading to the death of the cell.
Resulting Effects on the Body
The cellular damage caused by frataxin deficiency is most pronounced in tissues with the highest energy requirements, leading to specific, progressive physical manifestations. The nervous system is heavily affected, particularly the large sensory neurons of the dorsal root ganglia, which carry information about body position and movement back to the brain. Degeneration of these neurons and the nerve tracts in the spinal cord results in progressive ataxia. Ataxia is characterized by a loss of coordination and balance, making walking unsteady and difficult, and it is often accompanied by dysarthria, or difficulty with clear speech. This neurological damage also leads to the loss of deep tendon reflexes, particularly in the lower limbs.
The cardiac system is also susceptible to frataxin deficiency, as the heart muscle requires constant, high energy. The lack of functional frataxin contributes to hypertrophic cardiomyopathy, where the walls of the heart muscle thicken and enlarge. This thickening impairs the heart’s ability to pump blood effectively and can lead to complications such as arrhythmias and heart failure.
Beyond the nervous system and heart, the endocrine system is impacted, increasing the risk for developing diabetes mellitus in affected individuals. The cells of the pancreas that produce insulin are energy-intensive, and their function is compromised by the mitochondrial failure caused by frataxin deficiency. The combined effects of neurological dysfunction, heart disease, and metabolic issues create a severe, multi-systemic disorder.