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MESP2
mesoderm posterior bHLH transcription factor 2
The MESP2 gene provides instructions for a protein critical in the early embryonic development of the spine, specifically in the formation of vertebrae. The MESP2 gene is vital for producing a transcription factor involved in the precise segmentation of somites, which are precursors to the vertebral column.
MESP2 is located on the long (q) arm of chromosome 15, at band 15q26.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The MESP2 gene, also known as mesoderm posterior bHLH transcription factor 2, plays a fundamental role in human embryonic development. It is essential for the formation of the vertebral column, the bones that make up the spine. The protein encoded by MESP2 acts as a transcription factor, regulating the activity of other genes involved in this intricate process.
Proper functioning of the MESP2 gene is crucial for the normal segmentation of somites, which are transient blocks of mesoderm that give rise to various tissues, including the vertebrae. Abnormalities in MESP2 can lead to developmental disorders affecting spinal structure.
What the gene does
The MESP2 gene encodes a transcription factor that binds to specific DNA regions, thereby controlling the expression of target genes. This protein is a key regulator within the Notch signalling pathway, which is vital for embryonic development, particularly in the formation of spinal bones. MESP2's involvement in somite segmentation, the process where future vertebrae separate from each other, is critical.
During development, the MESP2 protein and other components of the Notch pathway oscillate in a specific pattern, which is necessary for correct segmentation. MESP2 activates certain genes within the Notch pathway, leading to the repression of NOTCH1 protein activity. Furthermore, the MESP2 protein appears to help define the boundaries between future vertebrae, although the precise mechanism for this function is not fully understood.
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Chromosome location
The MESP2 gene is located on chromosome 15 at band 15q26.1. This specific genomic address places MESP2 within a region of the human genome that is actively studied for its involvement in developmental processes and inherited conditions.
Protein structure
The MESP2 protein consists of 397 amino acids and features several distinct regions and domains crucial for its function. It contains two Disordered regions: one spanning amino acids 28-92 and another from amino acids 152-208. A key functional element is the bHLH (basic helix-loop-helix) domain, located between amino acids 81-135, which facilitates its role as a transcription factor. Additionally, the protein includes a series of 13 X 2 AA tandem repeats of G-Q (glycine-glutamine) from amino acids 179-204, with individual repeats numbered from 1 (amino acids 179-180) to 11 (amino acids 199-200).
Key variants
Variants within the MESP2 gene can alter the protein's structure or function, potentially disrupting its critical role in spinal development. These genetic changes can range from single nucleotide substitutions to larger deletions or insertions. The impact of a specific variant depends on its location and the nature of the change, influencing how the MESP2 protein regulates gene expression during embryonic development.
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.116C>A | p.Ser39Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Spondylocostal dysostosis 2, autosomal recessive |
c.11C>A | p.Ser4Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Inborn genetic diseases |
c.125C>A | p.Ser42Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Spondylocostal dysostosis 2, autosomal recessive |
c.229G>T | p.Gly77Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Spondylocostal dysostosis 2, autosomal recessive |
c.83G>A | p.Trp28Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Spondylocostal dysostosis 2, autosomal recessive |
g.(?_90319589)_(90321565_?)del | - | Pathogenic | ★☆☆☆ | not provided |
c.146_161dup | p.Gln55fs | Pathogenic | ★☆☆☆ | not provided |
c.413del | p.Val138fs | Pathogenic | ★☆☆☆ | Spondylocostal dysostosis 2, autosomal recessive |
c.427G>T | p.Glu143Ter | Pathogenic | ★☆☆☆ | not provided |
c.86dup | p.Asp29fs | Pathogenic | ★☆☆☆ | not provided |
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 MESP2 gene are associated with inherited conditions primarily affecting the development of the spine. These conditions include Spondylocostal dysostosis and Spondylothoracic dysostosis, both characterised by abnormal bone development in the spine and ribs. These disorders can lead to various skeletal abnormalities and may be identified during early development or at birth.
No disease links recorded for this gene in our reference set.
UK clinical status
The MESP2 gene is recognised in the UK National Health Service (NHS) Genomic Medicine Service. It is listed as 'green' on PanelApp for several panels, including DDG2P, Foetal anomalies (R21), and Skeletal dysplasia (R104), indicating strong evidence for its association with these conditions and its utility in diagnostic testing.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the MESP2 gene?
The MESP2 gene provides instructions for a transcription factor protein that is essential for the early embryonic development of the spine. It helps control the activity of genes involved in the precise segmentation of somites, which are precursors to the vertebrae.
What conditions are associated with MESP2 gene variants?
Variants in the MESP2 gene are associated with conditions such as Spondylocostal dysostosis and Spondylothoracic dysostosis. These are developmental disorders characterised by abnormalities in the bones of the spine and ribs.
How does MESP2 influence spinal development?
MESP2 regulates genes within the Notch signalling pathway, which is critical for forming vertebrae. It helps to define the boundaries between future vertebrae by activating certain genes and repressing the activity of the NOTCH1 protein, ensuring proper segmentation of the spine.
References
- Sasaki N, Kiso M, Kitagawa M. The repression of Notch signaling occurs via the destabilization of mastermind-like 1 by Mesp2 and is essential for somitogenesis. Development (Cambridge, England). 2011. PMID: 21098559
- Oginuma M, Takahashi Y, Kitajima S. The oscillation of Notch activation, but not its boundary, is required for somite border formation and rostral-caudal patterning within a somite. Development (Cambridge, England). 2010. PMID: 20335362
- Gibb S, Maroto M, Dale JK. The segmentation clock mechanism moves up a notch. Trends in cell biology. 2010. PMID: 20724159
- Ferjentsik Z, Hayashi S, Dale JK. Notch is a critical component of the mouse somitogenesis oscillator and is essential for the formation of the somites. PLoS genetics. 2009. PMID: 19779553
- Cornier AS, Staehling-Hampton K, Delventhal KM. Mutations in the MESP2 gene cause spondylothoracic dysostosis/Jarcho-Levin syndrome. American journal of human genetics. 2008. PMID: 18485326
- Sparrow DB, Chapman G, Turnpenny PD. Disruption of the somitic molecular clock causes abnormal vertebral segmentation. Birth defects research. Part C, Embryo today : reviews. 2007. PMID: 17600782
- Morimoto M, Takahashi Y, Endo M. The Mesp2 transcription factor establishes segmental borders by suppressing Notch activity. Nature. 2005. PMID: 15902259
- Whittock NV, Sparrow DB, Wouters MA. Mutated MESP2 causes spondylocostal dysostosis in humans. American journal of human genetics. 2004. PMID: 15122512
- Adam MP, Bick S, Mirzaa GM. Spondylocostal Dysostosis, Autosomal Recessive. 1993. PMID: 20301771