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TWIST1
twist family bHLH transcription factor 1
The TWIST1 gene provides instructions for a protein crucial for embryonic development, influencing the formation of bone, muscle, and other tissues in the head, face, and limbs. The TWIST1 gene encodes a transcription factor that plays a significant role in early human development, particularly in bone and muscle formation.
TWIST1 is located on the short (p) arm of chromosome 7, at band 7p21.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The TWIST1 gene, also known as twist family bHLH transcription factor 1, is essential for normal embryonic growth and development. It produces a protein that acts as a transcription factor, controlling the activity of other genes involved in tissue formation. This gene is primarily recognised for its critical role in the development of cells that contribute to the skull, face, and limbs.
Pathogenic variants in the TWIST1 gene are linked to a spectrum of developmental disorders, including Saethre-Chotzen syndrome. Understanding the TWIST1 gene's function provides insights into the genetic basis of these conditions and the intricate processes of human development.
What the gene does
The protein encoded by the TWIST1 gene is a transcription factor, which means it attaches to specific regions of DNA and regulates the activity of particular genes. It belongs to the basic helix-loop-helix (bHLH) family of transcription factors, characterised by a distinctive bHLH domain that allows it to bind to specific DNA sequences.
During embryonic development, the TWIST1 protein is vital for the formation of tissues that will become bone, muscle, and other structures in the head and face. It also influences the early development of the arms and legs. Research suggests that the TWIST1 protein coordinates the activity of several genes, including FGFR2 and RUNX2, which are known to be key regulators of bone formation. By controlling these genes, TWIST1 helps ensure the proper development and patterning of various body parts before birth.
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Chromosome location
The TWIST1 gene is located on the short (p) arm of chromosome 7. Its specific position is 7p21.1. This genomic location is relevant for understanding its inheritance patterns and how variations within this region can contribute to developmental conditions.
Protein structure
The TWIST1 protein is composed of 202 amino acids. Its structural organisation includes several key regions. A Disordered region spans amino acids 1-105, which typically suggests flexibility and a role in molecular interactions. The protein also contains a bHLH (basic helix-loop-helix) domain, located from amino acids 108-159. This bHLH domain is critical for the protein's function, enabling it to bind to DNA and regulate gene expression. Additionally, a region from amino acids 161-191 is identified as sufficient for transactivation activity, indicating its importance in activating target genes.
Key variants
Variants in the TWIST1 gene can affect protein function, leading to various developmental conditions. These genetic changes can include insertions, deletions, or single-nucleotide changes within the gene's sequence. The specific location and nature of a variant can influence the resulting clinical presentation and severity. Genetic testing can identify these variants, aiding in diagnosis and management.
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.132_142del | p.Ser45fs | Pathogenic | ★★☆☆ | TWIST1-related craniosynostosis |
c.176del | p.Gly59fs | Pathogenic/Likely pathogenic | ★★☆☆ | TWIST1-related craniosynostosis |
c.211C>T | p.Gln71Ter | Pathogenic | ★★☆☆ | TWIST1-related craniosynostosis |
c.301C>T | p.Gln101Ter | Pathogenic/Likely pathogenic | ★★☆☆ | TWIST1-related disorder |
c.308dup | p.Tyr103Ter | Pathogenic | ★★☆☆ | Saethre-Chotzen syndrome |
c.309C>G | p.Tyr103Ter | Pathogenic | ★★☆☆ | Saethre-Chotzen syndrome |
c.358C>G | p.Arg120Gly | Pathogenic/Likely pathogenic | ★★☆☆ | Saethre-Chotzen syndrome |
c.376G>T | p.Glu126Ter | Pathogenic | ★★☆☆ | TWIST1-related craniosynostosis |
c.385_405dup | p.Ala129_Ile135dup | Pathogenic/Likely pathogenic | ★★☆☆ | TWIST1-related craniosynostosis |
c.396_416dup | p.Lys133_Pro139dup | Pathogenic | ★★☆☆ | TWIST1-related craniosynostosis |
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 TWIST1 gene are primarily associated with inherited developmental disorders. The most well-characterised condition linked to TWIST1 variants is Saethre-Chotzen syndrome. This syndrome is typically inherited in an autosomal dominant pattern and is characterised by premature fusion of certain skull bones and other skeletal abnormalities. Additionally, some specific variants in TWIST1 have been associated with a very rare condition known as Sweeney-Cox syndrome.
- Saethre-Chotzen syndrome Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic TWIST1 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 TWIST1 gene is routinely assessed within the National Health Service (NHS) Genomic Medicine Service pathways. It is included on several PanelApp panels, demonstrating its clinical significance. These include the 'Common craniosynostosis syndromes', 'DDG2P', 'Foetal anomalies', 'Hydrocephalus', 'Intellectual disability', 'Limb disorders', 'Rare syndromic craniosynostosis or isolated multisuture synostosis', and 'Skeletal dysplasia' panels, all of which are rated 'green', indicating strong evidence for its gene-disease association in these contexts.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Currently, there is no specific evidence to suggest that particular lifestyle modifications can prevent or directly mitigate the effects of conditions caused by TWIST1 gene variants. These conditions are genetic in origin, meaning they are present from birth. However, maintaining a healthy lifestyle, including a balanced diet and appropriate physical activity, generally supports overall well-being and may help manage certain associated symptoms in affected individuals. Any individual health concerns should be discussed with a healthcare professional.
Supplement considerations
There is no conclusive evidence that any specific supplements can prevent or treat conditions associated with TWIST1 gene variants. Genetic conditions result from alterations in DNA and are not typically amenable to modification through dietary supplements. Individuals considering any supplements for health reasons should always consult with a doctor or other qualified healthcare provider, particularly those with a genetic condition, to avoid potential interactions or adverse effects.
Frequently asked questions
What is the main function of the TWIST1 gene?
The TWIST1 gene provides instructions for creating a transcription factor that is crucial for embryonic development. It controls the activity of other genes essential for the formation of bone, muscle, and other tissues, particularly in the head, face, and limbs.
What is Saethre-Chotzen syndrome?
Saethre-Chotzen syndrome is a genetic condition primarily characterised by the premature fusion of certain skull bones, known as craniosynostosis. This affects the shape of the head and face, and individuals may also have abnormalities of the hands and feet.
How is Saethre-Chotzen syndrome inherited?
Saethre-Chotzen syndrome is typically inherited in an autosomal dominant pattern. This means only one copy of the altered TWIST1 gene in each cell is sufficient to cause the condition.
Can lifestyle changes impact conditions associated with TWIST1?
Conditions caused by TWIST1 gene variants are genetic, so lifestyle changes cannot prevent or directly treat them. However, a healthy lifestyle can support overall well-being and help manage general health in affected individuals.
Are there other names for the TWIST1 gene?
Yes, the TWIST1 gene is also known by several other names including ACS3, B-HLH DNA binding protein, CRS1, H-twist, and SCS. Its full name is twist family bHLH transcription factor 1.
References
- Kim S, Twigg SRF, Scanlon VA. Localized TWIST1 and TWIST2 basic domain substitutions cause four distinct human diseases that can be modeled in Caenorhabditis elegans. Human molecular genetics. 2017. PMID: 28369379
- Seto ML, Hing AV, Chang J. Isolated sagittal and coronal craniosynostosis associated with TWIST box mutations. American journal of medical genetics. Part A. 2007. PMID: 17343269
- Kress W, Schropp C, Lieb G. Saethre-Chotzen syndrome caused by TWIST 1 gene mutations: functional differentiation from Muenke coronal synostosis syndrome. European journal of human genetics : EJHG. 2006. PMID: 16251895
- Guenou H, Kaabeche K, Mée SL. A role for fibroblast growth factor receptor-2 in the altered osteoblast phenotype induced by Twist haploinsufficiency in the Saethre-Chotzen syndrome. Human molecular genetics. 2005. PMID: 15829502
- de Heer IM, de Klein A, van den Ouweland AM. Clinical and genetic analysis of patients with Saethre-Chotzen syndrome. Plastic and reconstructive surgery. 2005. PMID: 15923834
- Cai J, Jabs EW. A twisted hand: bHLH protein phosphorylation and dimerization regulate limb development. BioEssays : news and reviews in molecular, cellular and developmental biology. 2005. PMID: 16237669
- Cai J, Goodman BK, Patel AS. Increased risk for developmental delay in Saethre-Chotzen syndrome is associated with TWIST deletions: an improved strategy for TWIST mutation screening. Human genetics. 2003. PMID: 14513358
- Chun K, Teebi AS, Jung JH. Genetic analysis of patients with the Saethre-Chotzen phenotype. American journal of medical genetics. 2002. PMID: 12116251
- Gripp KW, Zackai EH, Stolle CA. Mutations in the human TWIST gene. Human mutation. 2000. PMID: 10649491