On this page
GLI3
GLI family zinc finger 3
The GLI3 gene provides instructions for making a protein crucial for early foetal development, particularly in forming various tissues and organs. The GLI3 gene encodes a transcription factor that plays a fundamental role in embryonic patterning and development.
GLI3 is located on the short (p) arm of chromosome 7, at band 7p14.1. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 7 in the library →Available at Jeen Health
Clinical tests that include this
Overview
The GLI3 gene, or GLI family zinc finger 3, is a pivotal component in human development. It encodes a protein that acts as a transcription factor, meaning it binds to specific DNA regions to control whether particular genes are activated or repressed. This regulatory role is essential for the proper patterning and formation of numerous tissues and organs during the prenatal period.
The GLI3 protein is an integral part of the Sonic Hedgehog signalling pathway, a critical molecular route involved in cell growth, specialisation, and the development of key body structures. Depending on signals received, the GLI3 protein can either promote or inhibit gene expression, influencing the intricate processes of embryonic development.
What the gene does
The GLI3 gene produces a protein known as GLI3, which functions as a transcription factor. This protein's primary role is to regulate gene expression by binding to specific DNA sequences in the nucleus, thereby switching target genes on or off. This activity is vital for the precise patterning and development of numerous tissues and organs during early human development.
The GLI3 protein operates within the Sonic Hedgehog signalling pathway, a fundamental biological pathway. This pathway is crucial for processes such as cellular growth, cell differentiation, and the correct formation of structures like the brain and limbs. The ability of GLI3 to act as both an activator and a repressor of gene transcription allows for fine-tuned control over developmental pathways.
Depending on the specific cellular signals received from the Sonic Hedgehog pathway, the GLI3 protein can adopt different forms to either activate the expression of certain genes or repress others. This dual functionality ensures the precise genetic regulation necessary for complex developmental processes to unfold correctly.
Video: Genetics 101
Chromosome location
The GLI3 gene is located on the short arm of chromosome 7 at position 14.1, designated as 7p14.1. This specific genomic address signifies its precise place within the human genome. Knowing the chromosomal location helps in understanding inheritance patterns and contributes to genetic mapping efforts.
Protein structure
The GLI3 protein is composed of 1580 amino acids. Its structure includes several distinct functional regions and domains that are critical for its role as a transcription factor. At the N-terminus, there is a Repressor domain spanning amino acids 1-397. This region overlaps with two disordered regions, one from amino acids 1-79 and another from amino acids 368-475. A key feature of the GLI3 protein is its set of five C2H2-type zinc finger domains, which are crucial for DNA binding: C2H2-type 1 (480-505), C2H2-type 2 (513-540), C2H2-type 3 (546-570), C2H2-type 4 (576-601), and C2H2-type 5 (607-632). Another disordered region is found between amino acids 620-728. A specific region from amino acids 745-845 mediates interaction with the DZIP1 protein. The protein also contains an Activator domain spanning amino acids 827-1132, which is involved in promoting gene expression. This activator domain encompasses two additional disordered regions, from amino acids 863-918 and 981-1042.
Key variants
Genetic variations within the GLI3 gene can significantly impact the normal development of various body structures. These variants can include insertions, deletions, or single nucleotide changes in the DNA sequence. Depending on their nature and location, such variants can alter the structure or function of the GLI3 protein. This can lead to a range of developmental conditions, typically inherited in an autosomal dominant manner.
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.1028+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Pallister-Hall syndrome |
c.1096C>T | p.Arg366Ter | Pathogenic | ★★☆☆ | Pallister-Hall syndrome |
c.1497+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Pallister-Hall syndrome |
c.1873C>T | p.Arg625Trp | Pathogenic/Likely pathogenic | ★★☆☆ | Greig cephalopolysyndactyly syndrome |
c.1874G>A | p.Arg625Gln | Pathogenic | ★★☆☆ | Pallister-Hall syndrome |
c.1880_1881del | p.His627fs | Pathogenic | ★★☆☆ | Polydactyly, postaxial, type A1 |
c.1927C>T | p.Arg643Ter | Pathogenic | ★★☆☆ | Postaxial polydactyly, type A1/B |
c.1999C>T | p.Arg667Ter | Pathogenic | ★★☆☆ | GLI3-related disorder |
c.2374C>T | p.Arg792Ter | Pathogenic | ★★☆☆ | Greig cephalopolysyndactyly syndrome |
c.2594C>G | p.Ser865Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Polydactyly, postaxial, type A1 |
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 GLI3 gene are associated with several inherited conditions, primarily affecting development. These include Greig cephalopolysyndactyly, characterised by abnormalities of the head, face, and limbs, and Pallister-Hall syndrome, which also presents with limb abnormalities and specific organ malformations. These conditions are typically inherited in an autosomal dominant pattern.
Inheritance pattern
Conditions caused by pathogenic GLI3 variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
The GLI3 gene is well-recognised within the UK's National Health Service (NHS) Genomic Medicine Service. It is included on numerous NHS England National Genomic Test Directory panels, indicating its established role in diagnosing a variety of conditions. These panels cover diverse clinical areas, such as CAKUT, Clefting, DDG2P, Foetal anomalies, Hydrocephalus, IUGR and IGF abnormalities, Limb disorders, Neurological ciliopathies, Non-syndromic familial congenital anorectal malformations, Ophthalmological ciliopathies, Pituitary hormone deficiency, Rare multisystem ciliopathy disorders, Rare syndromic craniosynostosis or isolated multisuture synostosis, Skeletal ciliopathies, Skeletal dysplasia, Unexplained kidney failure in young people, and Unexplained young onset end-stage renal disease - additional genes, reflecting the broad impact of GLI3 variants on development and health.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Research suggests that a balanced lifestyle, including a nutritious diet and avoiding known teratogens during pregnancy, generally supports healthy foetal development. While lifestyle choices do not alter an individual's genetic predisposition to conditions linked to GLI3, maintaining overall health is broadly beneficial. Pregnant individuals are advised to discuss any lifestyle concerns with their healthcare provider.
Supplement considerations
Currently, there is no conclusive scientific evidence to suggest that specific dietary supplements can prevent or treat conditions associated with GLI3 gene variants. Individuals considering any supplements, especially during pregnancy, should consult a healthcare professional. A balanced diet generally provides sufficient nutrients for most people.
Frequently asked questions
What is the primary function of the GLI3 gene?
The GLI3 gene provides instructions for making the GLI3 protein, which acts as a transcription factor. It helps regulate the expression of other genes, playing a crucial role in the normal patterning and development of various tissues and organs during early foetal life.
Which conditions are associated with variants in the GLI3 gene?
Variants in the GLI3 gene are associated with several developmental conditions, including Greig cephalopolysyndactyly and Pallister-Hall syndrome. These conditions typically affect the limbs, face, and other body systems.
How are GLI3-related conditions inherited?
Conditions associated with GLI3 gene variants are generally inherited in an autosomal dominant pattern. This means that only one copy of the altered gene in each cell is sufficient to cause the condition.
What is the Sonic Hedgehog pathway, and how does GLI3 relate to it?
The Sonic Hedgehog pathway is a fundamental molecular signalling route essential for embryonic development. The GLI3 protein is a key component of this pathway, acting to either activate or repress other genes depending on the signals received from Sonic Hedgehog, thereby controlling cell growth and differentiation.
Is GLI3 included in routine genetic testing in the UK?
Yes, the GLI3 gene is included on multiple NHS England National Genomic Test Directory panels, covering a wide range of developmental and syndromic conditions. This indicates its clinical relevance for diagnostic testing in the UK.
References
- Démurger F, Ichkou A, Mougou-Zerelli S. New insights into genotype-phenotype correlation for GLI3 mutations. European journal of human genetics : EJHG. 2015. PMID: 24736735
- Speksnijder L, Cohen-Overbeek TE, Knapen MF. A de novo GLI3 mutation in a patient with acrocallosal syndrome. American journal of medical genetics. Part A. 2013. PMID: 23633388
- Johnston JJ, Sapp JC, Turner JT. Molecular analysis expands the spectrum of phenotypes associated with GLI3 mutations. Human mutation. 2010. PMID: 20672375
- Johnston JJ, Olivos-Glander I, Killoran C. Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations. American journal of human genetics. 2005. PMID: 15739154
- Biesecker LG, Johnston J. Syndromic and non-syndromic GLI3 phenotypes. Clinical genetics. 2005. PMID: 16098019
- Elson E, Perveen R, Donnai D. De novo GLI3 mutation in acrocallosal syndrome: broadening the phenotypic spectrum of GLI3 defects and overlap with murine models. Journal of medical genetics. 2002. PMID: 12414818
- Radhakrishna U, Bornholdt D, Scott HS. The phenotypic spectrum of GLI3 morphopathies includes autosomal dominant preaxial polydactyly type-IV and postaxial polydactyly type-A/B; No phenotype prediction from the position of GLI3 mutations. American journal of human genetics. 1999. PMID: 10441570
- Kang S, Graham JM Jr, Olney AH. GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome. Nature genetics. 1997. PMID: 9054938
- Wild A, Kalff-Suske M, Vortkamp A. Point mutations in human GLI3 cause Greig syndrome. Human molecular genetics. 1997. PMID: 9302279
- Kang S, Rosenberg M, Ko VD. Gene structure and allelic expression assay of the human GLI3 gene. Human genetics. 1997. PMID: 9402960
- Adam MP, Bick S, Mirzaa GM. GLI3-Related Greig Cephalopolysyndactyly Syndrome. 1993. PMID: 20301619
- Adam MP, Bick S, Mirzaa GM. GLI3-Related Pallister-Hall Syndrome. 1993. PMID: 20301638