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MAP2K1
mitogen-activated protein kinase kinase 1
The MAP2K1 gene encodes the MEK1 protein, a key component of the RAS/MAPK signalling pathway, essential for cellular growth, division, and differentiation. MAP2K1 provides instructions for producing the MEK1 protein kinase, which is integral to cellular communication.
MAP2K1 is located on the long (q) arm of chromosome 15, at band 15q22.31. Arm ratio per GRCh38 - banding schematic.
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Overview
The MAP2K1 gene, also known as mitogen-activated protein kinase kinase 1, provides the blueprint for the MEK1 protein. This protein is a crucial part of the RAS/MAPK signalling pathway, which acts as a cellular communication system. This pathway transmits signals from the cell's exterior to its nucleus, influencing diverse cellular activities.
Dysregulation in the MAP2K1 gene and its encoded protein can have significant implications for health, as it is involved in fundamental processes leading to conditions affecting multiple body systems.
What the gene does
The MAP2K1 gene gives rise to the MEK1 protein, a specific type of enzyme known as a protein kinase. This MEK1 protein is a central element within the RAS/MAPK signalling pathway, facilitating the transmission of signals from the outer cell environment to the cell's nucleus. This intricate signalling cascade is responsible for governing several fundamental cellular processes.
These processes include the regulation of cell growth and division (proliferation), the specialisation of cells for particular functions (differentiation), and the coordinated movement of cells (migration). The MEK1 protein kinase is considered essential for normal development both before and after birth, maintaining cellular homeostasis and proper tissue formation.
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Chromosome location
The MAP2K1 gene is situated on chromosome 15, specifically at position 15q22.31. This genomic address pinpoints its location within the long arm (q arm) of chromosome 15, within region 22, band 31. This precise chromosomal localisation helps in understanding its genetic context and how it might be inherited or interact with other genes.
Protein structure
The MEK1 protein, encoded by the MAP2K1 gene, consists of 393 amino acids. Its structure includes a Disordered region spanning amino acids 1 to 27, which typically lacks a fixed three-dimensional structure and can be involved in molecular interactions. A prominent Protein kinase domain is located between amino acids 68 and 361, which is responsible for the protein's enzymatic activity in phosphorylating other proteins. Additionally, a RAF1-binding region is found between amino acids 270 and 307, indicating an important interaction site for the RAF1 protein in the signalling pathway.
Key variants
Variants within the MAP2K1 gene can impact the function of the MEK1 protein, potentially disrupting the critical RAS/MAPK signalling pathway. These genetic changes can range from small alterations in DNA sequence to larger structural rearrangements. The specific effect of a variant depends on its nature and location within the gene, determining how significantly the protein's activity is altered. Both germline variants (inherited) and somatic variants (acquired during life) have been associated with various health conditions.
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.124C>T | p.Leu42Phe | Pathogenic | ★★★☆ | RASopathy |
c.199G>A | p.Asp67Asn | Pathogenic | ★★★☆ | Cardio-facio-cutaneous syndrome |
c.275T>G | p.Leu92Arg | Pathogenic | ★★★☆ | RASopathy |
c.364A>G | p.Asn122Asp | Pathogenic | ★★★☆ | RASopathy |
c.370C>T | p.Pro124Ser | Pathogenic | ★★★☆ | RASopathy |
c.389A>G | p.Tyr130Cys | Pathogenic | ★★★☆ | Cardio-facio-cutaneous syndrome |
c.608A>G | p.Glu203Gly | Pathogenic | ★★★☆ | RASopathy |
c.171G>C | p.Lys57Asn | Pathogenic | ★★☆☆ | MAP2K1-related disorder |
c.173_187del | p.Gln58_Glu62del | Pathogenic/Likely pathogenic | ★★☆☆ | Vascular malformation |
c.306_311del | p.Ile103_Lys104del | Pathogenic/Likely pathogenic | ★★☆☆ | Vascular malformation |
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
Variants in the MAP2K1 gene are associated with several inherited conditions, primarily due to their role in the RAS/MAPK signalling pathway. These conditions include Cardiofaciocutaneous syndrome, which affects the heart, facial features, skin, and hair, often resulting from germline variants. Melorheostosis, a rare disorder characterised by abnormal bone growth, is typically linked to somatic MAP2K1 variants. Additionally, MAP2K1 variants have been identified in individuals with Noonan syndrome with multiple lentigines, a condition affecting multiple body systems including heart and skin pigmentation.
Inheritance pattern
Conditions caused by pathogenic MAP2K1 variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
In the UK, the MAP2K1 gene is recognised on several NHS Genomic Medicine Service national test panels through PanelApp. It is classified as 'green' for conditions such as Childhood solid tumours cancer susceptibility, DDG2P, Foetal anomalies, Foetal hydrops, Intellectual disability, and RASopathies, indicating strong evidence for its gene-disease association in these contexts. MAP2K1 is also listed for Early onset or syndromic epilepsy, Monogenic short stature, Mosaic skin disorders - deep sequencing, Paediatric or syndromic cardiomyopathy, Pigmentary skin disorders, and Primary lymphoedema.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
General population research indicates that maintaining a balanced lifestyle can contribute to overall health. For individuals with conditions related to MAP2K1 variants, healthcare providers typically offer specific recommendations tailored to their diagnosis. While a healthy diet, regular physical activity, and avoiding smoking are generally beneficial for well-being, there is no conclusive evidence that specific lifestyle interventions can prevent or directly treat MAP2K1-related genetic conditions.
Supplement considerations
There is currently no conclusive scientific evidence to support the use of specific dietary supplements to prevent, treat, or manage conditions directly associated with MAP2K1 gene variants. Any decision to take supplements should be carefully considered and discussed with a healthcare professional to ensure safety and appropriateness, particularly given the potential for interactions with medications or existing health conditions.
Frequently asked questions
What is the primary function of the MAP2K1 gene?
The MAP2K1 gene provides instructions for making the MEK1 protein, a key component of the RAS/MAPK signalling pathway. This pathway is crucial for controlling fundamental cellular processes like growth, division, and differentiation.
What health conditions are associated with MAP2K1 gene variants?
Variants in the MAP2K1 gene are linked to several conditions, including Cardiofaciocutaneous syndrome and Melorheostosis. It also plays a role in Noonan syndrome with multiple lentigines, Langerhans cell histiocytosis, and some forms of lung cancer.
Is MAP2K1 involved in cancer?
Yes, MAP2K1 is recognised for its involvement in cancer susceptibility and is listed on the NHS Genomic Medicine Service panel for Childhood solid tumours cancer susceptibility. It is also implicated in some cases of lung cancer.
What is the RAS/MAPK pathway?
The RAS/MAPK pathway is a vital cellular communication system that transmits signals from outside the cell to its nucleus. It orchestrates cellular activities such as proliferation, differentiation, and migration, with the MEK1 protein (from MAP2K1) being a critical intermediary.
Are MAP2K1 variants always inherited?
Variants in MAP2K1 can be either germline (inherited from a parent and present in all cells) or somatic (acquired during a person's lifetime and present only in certain cells). The type of variant often influences the specific condition presented.
References
- Kang H, Jha S, Deng Z. Somatic activating mutations in MAP2K1 cause melorheostosis. Nature communications. 2018. PMID: 29643386
- Nishi E, Mizuno S, Nanjo Y. A novel heterozygous MAP2K1 mutation in a patient with Noonan syndrome with multiple lentigines. American journal of medical genetics. Part A. 2015. PMID: 25423878
- Nelson DS, van Halteren A, Quispel WT. MAP2K1 and MAP3K1 mutations in Langerhans cell histiocytosis. Genes, chromosomes & cancer. 2015. PMID: 25899310
- Brown NA, Furtado LV, Betz BL. High prevalence of somatic MAP2K1 mutations in BRAF V600E-negative Langerhans cell histiocytosis. Blood. 2014. PMID: 24982505
- Chakraborty R, Hampton OA, Shen X. Mutually exclusive recurrent somatic mutations in MAP2K1 and BRAF support a central role for ERK activation in LCH pathogenesis. Blood. 2014. PMID: 25202140
- Nava C, Hanna N, Michot C. Cardio-facio-cutaneous and Noonan syndromes due to mutations in the RAS/MAPK signalling pathway: genotype-phenotype relationships and overlap with Costello syndrome. Journal of medical genetics. 2007. PMID: 17704260
- Rodriguez-Viciana P, Tetsu O, Tidyman WE. Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome. Science (New York, N.Y.). 2006. PMID: 16439621