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NBN
nibrin
The NBN gene provides instructions for producing nibrin, a protein crucial for DNA repair and maintaining genomic stability, which are vital functions for preventing various conditions including cancer. The NBN gene is essential for proper cellular function, particularly in the repair of damaged DNA.
NBN is located on the long (q) arm of chromosome 8, at band 8q21.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The NBN gene gives instructions for making the nibrin protein, a critical element in the cell's DNA repair systems. This protein is fundamental for preserving the genome's integrity by fixing double-strand breaks in DNA, which can arise from environmental factors or during normal cellular processes. Impaired nibrin function can result in accumulated genetic damage, contributing to conditions like Nijmegen breakage syndrome and an increased likelihood of certain cancers.
Nibrin's involvement in these essential pathways highlights its role as a tumour suppressor, ensuring stable cell division and preventing the growth of damaged cells.
What the gene does
Nibrin, the protein encoded by the NBN gene, is central to the cellular response to DNA damage, particularly double-strand breaks. It forms a complex with MRE11A and RAD50 proteins, known as the MRN complex. This complex serves as an initial detector of DNA damage and is vital for starting repair pathways. Nibrin assists in transporting the MRE11A and RAD50 proteins into the cell's nucleus, guiding them to where DNA repair is needed. Its regulatory action on the MRN complex is essential for recognising DNA damage and coordinating subsequent repair processes. Furthermore, the MRN complex interacts with the ATM protein, a significant signalling molecule in the DNA damage response, integrating nibrin into a broader network of cellular protection. By facilitating DNA repair and controlling cell division, nibrin helps prevent the accumulation of mutations that could lead to cancer.
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Chromosome location
The NBN gene is located on chromosome 8, specifically at band 8q21.3. This particular region of the chromosome contains the genetic instructions for producing the nibrin protein. Its precise chromosomal position is important for understanding potential genomic alterations or mutations that might impact the gene's function.
Protein structure
The nibrin protein consists of 754 amino acids and features several distinct functional domains and regions. These include an FHA domain from amino acids 24-83 and two BRCT domains (BRCT 1 from amino acids 105-181 and BRCT 2 from amino acids 224-315). Such domains are typically involved in protein-protein interactions and responses to DNA damage. Regions facilitating interaction with SP100 (amino acids 111-328) and with MTOR, MAPKAP1, and RICTOR (amino acids 221-402) further illustrate its role in complex cellular pathways. The protein also contains several disordered regions (amino acids 326-346, 396-415, and 430-478), a nuclear localisation signal (amino acids 461-467), and an FxF/Y motif (amino acids 740-749).
Key variants
Variants in the NBN gene can alter the structure and function of the nibrin protein, potentially impairing its critical role in DNA repair. These genetic changes can range from small alterations, such as single nucleotide changes, to larger deletions or insertions within the gene. Depending on their nature and location, NBN variants may lead to a reduced amount of functional protein or a completely non-functional protein, impacting the cell's ability to respond to DNA damage effectively.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1222A>T | p.Lys408Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Aplastic anemia |
c.1518del | p.Gln506fs | Pathogenic/Likely pathogenic | ★★☆☆ | Aplastic anemia |
c.1528G>T | p.Glu510Ter | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.2097dup | p.Pro700fs | Pathogenic | ★★☆☆ | Microcephaly, normal intelligence and immunodeficiency |
c.2152G>T | p.Glu718Ter | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.247dup | p.Met83fs | Pathogenic/Likely pathogenic | ★★☆☆ | Microcephaly, normal intelligence and immunodeficiency |
c.274A>T | p.Lys92Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Microcephaly, normal intelligence and immunodeficiency |
c.48_49del | p.Tyr16_Arg17delinsTer | Pathogenic/Likely pathogenic | ★★☆☆ | Microcephaly, normal intelligence and immunodeficiency |
c.742dup | p.Glu248fs | Pathogenic/Likely pathogenic | ★★☆☆ | Aplastic anemia |
c.794dup | p.Pro266fs | Pathogenic/Likely pathogenic | ★★☆☆ | NBN-related disorder |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the NBN gene are primarily associated with Nijmegen breakage syndrome, a rare genetic disorder characterised by growth delays, immune deficiency leading to recurrent infections, and a significantly increased risk of developing cancer. Additionally, inherited variants in NBN have been linked to an elevated predisposition to certain cancers, including breast, ovarian, and prostate cancer, and other unspecified cancers, particularly in some Eastern European populations.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic NBN variants typically follow ad/ar inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
The NBN gene is included on several NHS England Genomic Medicine Service approved panels. These include panels for Childhood solid tumours, Childhood solid tumours cancer susceptibility, COVID-19 research, Cytopenias and congenital anaemias, DDG2P, Familial rhabdomyosarcoma, Foetal anomalies (R21), Haematological malignancies cancer susceptibility, Haematological malignancies for rare disease, IUGR and IGF abnormalities, Monogenic short stature (R453), Nijmegen breakage syndrome (R259.2), Primary immunodeficiency or monogenic inflammatory bowel disease (R15), Sarcoma of possible germline origin (R457), and Severe microcephaly (R88).
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the NBN gene?
The NBN gene provides instructions for the nibrin protein, which is crucial for repairing damaged DNA and maintaining the stability of the cell's genetic material. It is a key component of the MRN complex, which detects and responds to DNA double-strand breaks.
What health conditions are associated with NBN gene variants?
Variants in the NBN gene are primarily associated with Nijmegen breakage syndrome, a condition characterised by slow growth, recurrent infections, and increased cancer risk. Additionally, NBN variants have been linked to an elevated risk for certain cancers, including breast, ovarian, and prostate cancer.
How does NBN contribute to cancer prevention?
NBN acts as a tumour suppressor gene by ensuring accurate DNA repair. By fixing DNA damage, the nibrin protein prevents mutations from accumulating, which could otherwise lead to uncontrolled cell growth and the development of cancer. Its role in maintaining genomic integrity is vital.
References
- Lins S, Kim R, Krüger L. Clinical variability and expression of the NBN c.657del5 allele in Nijmegen Breakage Syndrome. Gene. 2009. PMID: 19635536
- Pluth JM, Yamazaki V, Cooper BA. DNA double-strand break and chromosomal rejoining defects with misrejoining in Nijmegen breakage syndrome cells. DNA repair. 2008. PMID: 17919995
- Bogdanova N, Feshchenko S, Schürmann P. Nijmegen Breakage Syndrome mutations and risk of breast cancer. International journal of cancer. 2008. PMID: 17957789
- Krüger L, Demuth I, Neitzel H. Cancer incidence in Nijmegen breakage syndrome is modulated by the amount of a variant NBS protein. Carcinogenesis. 2007. PMID: 16840438
- Zhang Y, Zhou J, Lim CU. The role of NBS1 in DNA double strand break repair, telomere stability, and cell cycle checkpoint control. Cell research. 2006. PMID: 16467875
- Heikkinen K, Rapakko K, Karppinen SM. RAD50 and NBS1 are breast cancer susceptibility genes associated with genomic instability. Carcinogenesis. 2006. PMID: 16474176
- Steffen J, Nowakowska D, Niwińska A. Germline mutations 657del5 of the NBS1 gene contribute significantly to the incidence of breast cancer in Central Poland. International journal of cancer. 2006. PMID: 16770759
- Cheung VG, Ewens WJ. Heterozygous carriers of Nijmegen Breakage Syndrome have a distinct gene expression phenotype. Genome research. 2006. PMID: 16809669
- Cybulski C, Górski B, Debniak T. NBS1 is a prostate cancer susceptibility gene. Cancer research. 2004. PMID: 14973119
- Kobayashi J, Antoccia A, Tauchi H. NBS1 and its functional role in the DNA damage response. DNA repair. 2004. PMID: 15279770
- Adam MP, Bick S, Mirzaa GM. Nijmegen Breakage Syndrome. 1993. PMID: 20301355