The NBN gene, also known as the Nijmegen breakage syndrome 1 or $NBS1$ gene, produces a protein called Nibrin. This protein plays an important part in maintaining the stability of the human genome. When the $NBN$ gene carries a mutation, the resulting faulty Nibrin protein cannot perform its duties correctly, leading to a breakdown in the cell’s ability to protect and repair its DNA. This failure in DNA maintenance can result in serious health consequences, ranging from a severe congenital disorder to an elevated, lifelong risk of developing certain cancers. The severity of the outcome depends largely on whether an individual inherits one or two copies of the mutated gene.
The Role of the NBN Gene in DNA Repair
The Nibrin protein functions primarily as a component of the MRN complex, which is composed of three proteins: MRE11, RAD50, and Nibrin ($NBN$). The MRN complex serves as the cell’s initial detection system for a specific and highly damaging type of DNA damage called a double-strand break (DSB). These breaks, where both strands of the DNA helix are severed, occur constantly due to normal cellular processes and environmental factors. The MRN complex must rapidly identify these breaks to prevent genomic chaos.
Acting as a central hub, the MRN complex senses the DSB and then recruits and activates other repair proteins, particularly the ATM kinase. Nibrin acts as an adapter, connecting the MRE11 and RAD50 proteins to other signaling and repair pathways. This activation of ATM kinase coordinates the repair process and can also trigger a temporary stop in the cell cycle. This pause allows the cell time to fix the damage before attempting to divide, which is important for tumor suppression and maintaining genome integrity.
Primary Condition: Nijmegen Breakage Syndrome
The most serious consequence of $NBN$ gene mutation is Nijmegen Breakage Syndrome (NBS), a rare, inherited disorder that occurs when an individual inherits two faulty copies of the gene, one from each parent. Because the body cannot produce functional Nibrin, the MRN complex is severely impaired, leading to a high degree of chromosomal instability. This profound defect in DNA repair underlies the syndrome’s characteristic clinical features, which affect multiple body systems.
One of the earliest signs of NBS is progressive microcephaly, where the head circumference is unusually small and falls behind growth standards. Affected children also experience early growth deficiency, resulting in short stature, along with characteristic craniofacial features such as a sloping forehead, a prominent nose, and retrognathia (a small lower jaw). A severe combined immunodeficiency is another defining feature, caused by low levels of immune proteins (IgG and IgA) and a shortage of T-cells.
The immunodeficiency makes individuals highly susceptible to recurrent respiratory infections, such as pneumonia and bronchitis, which can be life-threatening. While intellectual development may be normal initially, many individuals experience a decline in cognitive abilities, leading to mild to moderate intellectual disability as they age. Females with the syndrome commonly experience premature ovarian failure, resulting in infertility.
Cancer Risk Associated with NBN Mutations
Individuals who inherit only one mutated $NBN$ copy, known as heterozygous carriers, face health risks, most notably a predisposition to cancer. The $NBN$ gene is classified as a moderate-penetrance cancer susceptibility gene; the risk is elevated but generally lower than that associated with high-penetrance genes like $BRCA1$ or $BRCA2$. This increased risk stems from a partial deficiency in Nibrin protein, which impairs DNA surveillance and repair, making the cell less effective at preventing tumor formation.
Studies show that carriers of the common $NBN$ founder mutation, 657del5, particularly prevalent in Slavic populations, have a significantly increased risk of developing various malignancies. For women, the risk of breast cancer is notably higher, with lifetime estimates reaching up to 30%, compared to the general population risk of about 12%. The mutation is also associated with an increased occurrence of other solid tumors, including prostate and colorectal cancers.
Furthermore, heterozygous carriers show a heightened susceptibility to hematologic malignancies, such as non-Hodgkin’s lymphoma and lymphoblastic leukemia. This partial defect highlights the delicate balance required for effective DNA repair and tumor suppression.
Identifying and Managing NBN Gene Mutations
Identifying an $NBN$ gene mutation involves molecular genetic testing, typically through sequencing panels that analyze the DNA for pathogenic variants. For a diagnosis of Nijmegen Breakage Syndrome, testing confirms the presence of biallelic pathogenic variants in the $NBN$ gene, sometimes supported by an immunoblotting assay to check for Nibrin absence. For asymptomatic individuals concerned about family history, genetic counseling and testing can determine their carrier status for a single mutation.
Management for patients with the full syndrome (NBS) requires a multidisciplinary approach focused on addressing immune and cancer risks. This includes standard antimicrobial therapies for infections and often immunoglobulin replacement therapy to compensate for the immune system deficiency. NBS patients are extremely sensitive to ionizing radiation, so diagnostic imaging should prioritize non-ionizing methods like ultrasound and magnetic resonance imaging (MRI) over traditional X-rays or CT scans.
For asymptomatic carriers with a single $NBN$ mutation, management centers on rigorous cancer surveillance tailored to their elevated lifetime risks. Female carriers are recommended to begin heightened breast cancer screening, often including an annual mammogram and breast MRI, beginning around age 40. Since specific guidelines for other cancer types are still emerging, all carriers should consult with a genetics expert to create a personalized screening schedule based on their specific mutation and family cancer history.