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CDKN1B
cyclin dependent kinase inhibitor 1B
The CDKN1B gene provides instructions for producing the p27 protein, a crucial regulator of cell growth and division, functioning as a tumour suppressor. CDKN1B encodes the p27 protein, which is vital for preventing uncontrolled cell proliferation by inhibiting cell cycle progression.
CDKN1B is located on the short (p) arm of chromosome 12, at band 12p13.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The CDKN1B gene, also known as cyclin dependent kinase inhibitor 1B, is a fundamental component in controlling cell growth and division within the human body. It produces a protein called p27, which acts as a tumour suppressor. This protein is found in various cells and tissues, primarily within the cell's nucleus, where it performs its regulatory functions.
The p27 protein is essential for maintaining the ordered process of the cell cycle, ensuring that cells replicate themselves in a controlled manner. Its main role involves blocking cells from advancing into the DNA replication phase of the cell cycle, thereby preventing excessive or untimely cell division. Disruptions in the normal function of CDKN1B can therefore lead to conditions characterised by uncontrolled cell growth.
What the gene does
The CDKN1B gene directs the synthesis of the p27 protein, a key regulator of cellular processes, particularly cell proliferation. Within cells, p27 is predominantly located in the nucleus, where it exerts its control over the cell cycle. The cell cycle is the intricate series of events by which a cell duplicates its DNA and divides into two daughter cells. P27 functions by inhibiting the progression of the cell cycle, specifically preventing cells from entering the phase where DNA is copied in preparation for division [PMID:24177579].
By blocking cell cycle progression, p27 acts as a tumour suppressor, preventing cells from multiplying too quickly or at inappropriate times. This regulatory action is tightly controlled through mechanisms such as protein modification, interactions with other proteins, or its subcellular localisation. For instance, if p27 is retained in the cytoplasm rather than being transported into the nucleus, it cannot effectively halt cell cycle progression [PMID:24177579]. Beyond its established role in cell division, p27 is also thought to influence cell differentiation, the process where cells mature to fulfil specialised roles. Further research is ongoing to fully characterise any additional functions of p27 within the cytoplasm.
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Chromosome location
The CDKN1B gene is situated on the short arm of chromosome 12, specifically at position 12p13.1. This genomic location describes the gene's precise address within the human genome. The full-length protein produced from this gene consists of 198 amino acids.
Protein structure
The p27 protein, encoded by the CDKN1B gene, is composed of 198 amino acids and features several distinct functional regions. The N-terminal portion, from amino acids 1-34, is characterised as a Disordered region. A key functional area is located between amino acids 51-91, which forms the Interaction with CDK2 region, facilitating its ability to inhibit cyclin-dependent kinases. A significant portion of the protein, spanning amino acids 85-198, is also defined as a Disordered region. Additionally, a Nuclear localisation signal motif is found between amino acids 153-169, which is crucial for directing the p27 protein to the cell nucleus, where it performs its primary functions.
Key variants
Variants within the CDKN1B gene can influence its function, potentially leading to alterations in cell cycle control. These genetic changes can range from small single nucleotide polymorphisms to larger deletions or insertions, and their impact depends on their location and nature. Some variants may reduce the efficiency of the p27 protein in inhibiting cell division, while others might affect its localisation within the cell, preventing it from reaching the nucleus where it is most active. Understanding these genetic variations is important for assessing their potential clinical significance.
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.13C>T | p.Arg5Ter | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.151_152del | p.Asp51fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.169C>T | p.Gln57Ter | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.174dup | p.Lys59fs | Pathogenic/Likely pathogenic | ★★☆☆ | Multiple endocrine neoplasia type 4 |
c.175A>T | p.Lys59Ter | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.179G>A | p.Trp60Ter | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.180G>A | p.Trp60Ter | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.215dup | p.Lys73fs | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.21dup | p.Asn8Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Multiple endocrine neoplasia type 4 |
c.229C>T | p.Gln77Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
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
Mutations in the CDKN1B gene have been identified as a cause of multiple endocrine neoplasia type 4 (MEN4), a relatively uncommon inherited condition. This syndrome typically involves the development of benign or cancerous tumours in two or more of the body's hormone-producing glands, known as endocrine glands. The specific endocrine glands affected can vary. At least eight different mutations in the CDKN1B gene have been linked to MEN4 [PMID:27083033]. Additionally, mutations in CDKN1B have been associated with developing single endocrine gland tumours, such as those in the pituitary or parathyroid glands. Some of these single-gland tumours have somatic mutations, meaning the genetic change is not inherited but arises within the tumour cells themselves.
No disease links recorded for this gene in our reference set.
UK clinical status
In the UK, the CDKN1B gene is included on several NHS Genomic Medicine Service clinical panels, indicating its recognised role in various inherited conditions. For cancer susceptibility, it is listed on panels for Adult solid tumours, Neuroendocrine cancer, and Thyroid cancer. It is also significant for endocrine-related conditions, featuring on panels for Endocrine neoplasia, Familial hyperparathyroidism or hypocalciuric hypercalcaemia, and Multiple endocrine tumours. The inclusion of CDKN1B on these panels highlights its clinical relevance within the NHS.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Research suggests that general healthy lifestyle choices can contribute to overall well-being, though there's no conclusive evidence that specific lifestyle changes can prevent conditions associated with CDKN1B variants. Balanced nutrition, regular physical activity, and maintaining a healthy weight are generally recommended for population health. Avoiding smoking and excessive alcohol consumption are also widely accepted as beneficial health practices.
Supplement considerations
There is currently no conclusive scientific evidence to suggest that specific supplements can prevent or treat conditions associated with CDKN1B variants. Individuals should always discuss any considerations about taking supplements with a healthcare provider and ensure they are part of a balanced diet, rather than relying on them for disease prevention or treatment.
Frequently asked questions
What is the primary function of the CDKN1B gene?
The CDKN1B gene provides instructions for making the p27 protein, which acts as a key regulator of cell growth and division by preventing cells from dividing too quickly or at inappropriate times.
What health conditions are associated with CDKN1B?
Mutations in the CDKN1B gene are associated with multiple endocrine neoplasia type 4 (MEN4), which involves tumours in endocrine glands, and can also be linked to sporadic tumours in single endocrine glands like the pituitary or parathyroid.
What is multiple endocrine neoplasia type 4 (MEN4)?
MEN4 is a relatively rare condition caused by CDKN1B mutations, characterised by the development of benign or cancerous tumours in two or more hormone-producing glands.
Where is the CDKN1B gene located in the human genome?
The CDKN1B gene is located on chromosome 12, specifically at position 12p13.1.
Is CDKN1B included in any NHS clinical panels?
Yes, CDKN1B is included in several NHS Genomic Medicine Service clinical panels, including those for Adult solid tumours, Neuroendocrine cancer, Thyroid cancer, Endocrine neoplasia, and Familial hyperparathyroidism or hypocalciuric hypercalcaemia.
References
- Lee M, Pellegata NS. Multiple endocrine neoplasia type 4. Frontiers of hormone research. 2013. PMID: 23652671
- Tichomirowa MA, Lee M, Barlier A. Cyclin-dependent kinase inhibitor 1B (CDKN1B) gene variants in AIP mutation-negative familial isolated pituitary adenoma kindreds. Endocrine-related cancer. 2012. PMID: 22291433
- Pellegata NS. MENX and MEN4. Clinics (Sao Paulo, Brazil). 2012. PMID: 22584700
- Marinoni I, Pellegata NS. p27kip1: a new multiple endocrine neoplasia gene? Neuroendocrinology. 2011. PMID: 20980721
- Costa-Guda J, Marinoni I, Molatore S. Somatic mutation and germline sequence abnormalities in CDKN1B, encoding p27Kip1, in sporadic parathyroid adenomas. The Journal of clinical endocrinology and metabolism. 2011. PMID: 21289244
- Molatore S, Pellegata NS. The MENX syndrome and p27: relationships with multiple endocrine neoplasia. Progress in brain research. 2010. PMID: 20541671
- Pellegata NS, Quintanilla-Martinez L, Siggelkow H. Germ-line mutations in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans. Proceedings of the National Academy of Sciences of the United States of America. 2006. PMID: 17030811