The Ataxia-Telangiectasia Mutated (ATM) gene provides instructions for creating a protein that acts as a sensor and coordinator for the cell’s most important process: DNA repair. Located on chromosome 11, this gene plays a significant role in maintaining the stability of the entire genome. When this gene contains a mutation, the cell’s ability to fix damaged DNA becomes compromised, which can lead to a range of serious health consequences. The severity of the resulting disorder depends on whether an individual inherits one or two copies of the non-functional gene.
The Core Function of the ATM Gene in DNA Integrity
The protein produced by the ATM gene is a large enzyme known as a serine/threonine protein kinase. This protein is a central component of the cell’s response system to severe DNA damage, specifically double-strand breaks (DSBs). DSBs are particularly dangerous because they involve breaking both strands of the DNA helix. In an undamaged cell, the ATM protein exists in an inactive form.
Upon detecting a double-strand break, the ATM protein rapidly becomes activated through autophosphorylation. Once active, it dissociates and is recruited to the site of the damage, where it acts as a master regulator of the DNA damage response. The activated ATM then phosphorylates a wide range of downstream proteins, launching a cascade of cellular defenses.
These defenses include initiating repair machinery, such as homologous recombination (HR) and nonhomologous end joining (NHEJ), to fix the broken strands. ATM also enforces cell-cycle checkpoints by phosphorylating key proteins like p53 and Chk2. This action temporarily halts the cell’s progression through division, ensuring that the damaged DNA is not replicated before it can be accurately repaired. When the ATM gene is defective, this coordinated response fails, leading to genomic instability and a heightened risk of malignant transformation.
Ataxia-Telangiectasia: The Severe Result of Two Mutations
Ataxia-Telangiectasia (A-T) is a rare, severe, multi-system disorder that results when an individual inherits two non-functional copies of the ATM gene. Since the body’s ability to repair double-strand breaks is almost entirely lost, A-T is characterized by progressive neurological deterioration, immune system dysfunction, and a high susceptibility to cancer. The condition is typically diagnosed in early childhood, often shortly after a child begins to walk, with the onset of progressive cerebellar ataxia.
Ataxia is the hallmark symptom, causing an unsteady gait, balance problems, and difficulty with fine motor tasks like writing. This progressive degeneration is due to the premature death of cells in the cerebellum, the area of the brain responsible for coordinating movement. As the disease advances, patients often develop slurred speech and oculomotor apraxia (difficulty coordinating eye movements).
Another distinguishing feature is the appearance of telangiectasias, which are small, dilated blood vessels visible on the eyes and skin. Defective ATM function also severely compromises the immune system, leading to recurrent, severe infections and a significantly increased risk for developing lymphoreticular cancers, such as lymphoma and leukemia. Individuals with the disorder are extremely sensitive to ionizing radiation, a factor that must be carefully considered in their medical care.
Implications of Being a Single-Copy Carrier
In contrast to A-T, an individual who inherits only one mutated copy of the ATM gene and one healthy copy is considered a carrier. These heterozygous individuals do not develop the full A-T syndrome because the single working copy is generally sufficient to prevent the severe neurological and immune symptoms. However, the partial loss of ATM function compromises DNA repair efficiency, leading to a moderate lifetime risk for several types of cancer.
The most well-studied risk for ATM carriers is female breast cancer, with studies suggesting a lifetime risk that is two to four times higher than the general population, often estimated to be around 25%. This increased risk is partly due to the fact that ATM-associated tumors are frequently estrogen receptor-positive. The risk for cancer can also vary depending on the specific location of the mutation in the gene.
Beyond breast cancer, single-copy ATM mutations are also linked to an elevated risk for pancreatic, prostate, and gastric cancers. Studies suggest a moderate increase in the risk for prostate cancer, with some evidence indicating these cancers may be more aggressive. This elevation in risk across multiple cancer types highlights the ATM protein’s broader role as a tumor suppressor and underscores the importance of personalized cancer surveillance strategies for carriers.
Inheritance Patterns and Genetic Screening
The inheritance of ATM mutations follows two distinct patterns. Ataxia-Telangiectasia is an autosomal recessive disorder, meaning a child must inherit a non-working copy of the gene from both parents to develop the condition. If both parents are single-copy carriers, their child has a 25% chance of inheriting two mutated copies and developing A-T.
The increased cancer risk associated with single-copy carrier status follows an autosomal dominant pattern of inheritance. A carrier has a 50% chance of passing their single mutated copy to any child, who would then also be a single-copy carrier with an elevated cancer risk. The population frequency of ATM carriers is estimated to be high, with roughly one in 100 people carrying a pathogenic variant.
Genetic testing for ATM mutations is an important diagnostic and screening tool. It is used to confirm an A-T diagnosis in symptomatic children and is increasingly included in multi-gene panel testing for individuals with a personal or strong family history of certain cancers, particularly breast, ovarian, and pancreatic cancer. Identifying carrier status allows for proactive risk management, such as earlier and more intensive cancer surveillance protocols.