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FGD1
FYVE, RhoGEF and PH domain containing 1
The FGD1 gene provides instructions for a protein that acts as a guanine nucleotide exchange factor, playing a key role in cellular signalling pathways critical for development, particularly bone formation. The FGD1 gene encodes a protein essential for cell signalling, specifically by activating the Cdc42 GTPase.
FGD1 is located on the short (p) arm of chromosome X, at band Xp11.22. Arm ratio per GRCh38 - banding schematic.
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Overview
The FGD1 gene, also known as FYVE, RhoGEF and PH domain containing 1, produces a protein that acts as a guanine nucleotide exchange factor (GEF). This protein is integral to intracellular signalling, primarily by activating a protein called Cdc42. Correct functioning of the FGD1 protein is vital for typical embryonic and postnatal development, particularly the formation of bones.
Disruptions to the FGD1 gene's function are primarily linked to Aarskog-Scott syndrome, a rare genetic condition that affects skeletal development and other bodily systems.
What the gene does
The FGD1 protein functions as a guanine nucleotide exchange factor (GEF). GEFs are responsible for activating small GTPase proteins, which are central to various cellular signalling pathways. Specifically, FGD1 activates Cdc42, a GTPase involved in transmitting crucial signals for developmental processes. This activation occurs when FGD1 stimulates the exchange of guanosine diphosphate (GDP) for guanosine triphosphate (GTP) on the Cdc42 protein, effectively switching it to its active state.
Activated Cdc42 then orchestrates signals vital for many aspects of development, particularly bone formation. Beyond its role in bone development, the FGD1 protein may also contribute to the remodelling of the extracellular matrix, which is the network of molecules surrounding cells. This involvement suggests a broader role in processes like cell movement and the structural organisation of blood vessels.
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Chromosome location
The FGD1 gene is located on the short (p) arm of the X chromosome at position 11.22, specifically at Xp11.22. This chromosomal location indicates that the gene follows an X-linked inheritance pattern.
Protein structure
The FGD1 protein comprises 961 amino acids and features several distinct functional domains. The N-terminal region, spanning amino acids 1-353, is characterised as a Disordered region. Within this initial segment, an SH3-binding Motif is found between amino acids 171 and 187. Further along the protein, a Dbl homology (DH) Domain is situated from amino acids 373 to 561, followed by a Pleckstrin homology (PH) 1 Domain from 590 to 689. Another Disordered region is present between amino acids 702 and 726. A FYVE-type Zinc finger domain occupies positions 730 to 790, and a second PH 2 Domain is located from 821 to 921. The protein concludes with a C-terminal Disordered region from amino acids 925 to 961.
Key variants
Genetic variants within the FGD1 gene can alter the protein's structure or function, leading to various health implications. Over 40 different variants in FGD1 have been identified as causing Aarskog-Scott syndrome. These changes typically result in a non-functional or abnormally functioning FGD1 protein, disrupting its crucial role in cell signalling and 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.1565G>A | p.Arg522His | Pathogenic/Likely pathogenic | ★★☆☆ | Aarskog syndrome |
c.1699C>T | p.Arg567Ter | Pathogenic | ★★☆☆ | Intellectual disability |
c.1829G>A | p.Arg610Gln | Pathogenic | ★★☆☆ | not provided |
c.1966C>T | p.Arg656Ter | Pathogenic | ★★☆☆ | Aarskog syndrome |
c.26dup | p.Ala10fs | Pathogenic | ★★☆☆ | Inborn genetic diseases |
c.277dup | p.Tyr93fs | Pathogenic/Likely pathogenic | ★★☆☆ | Aarskog syndrome |
c.527del | p.Pro176fs | Pathogenic/Likely pathogenic | ★★☆☆ | Inborn genetic diseases |
c.527dup | p.Leu177fs | Pathogenic/Likely pathogenic | ★★☆☆ | FGD1-related disorder |
c.577C>T | p.Arg193Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Aarskog syndrome |
c.918del | p.Ser307fs | 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
Variants in the FGD1 gene are primarily associated with Aarskog-Scott syndrome. This rare inherited condition mainly affects males and is characterised by distinctive facial features, genital abnormalities, short stature during childhood, and other skeletal anomalies. The specific features and their severity can vary among affected individuals.
UK clinical status
The FGD1 gene is included on several UK National Health Service (NHS) national genomic testing panels. It is listed with a 'green' status, indicating strong evidence for its association with conditions on panels such as Clefting, DDG2P, Foetal anomalies (specifically under R21), Intellectual disability, IUGR and IGF abnormalities, and Limb disorders. This inclusion highlights its clinical significance within the UK healthcare system.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the FGD1 gene?
The FGD1 gene provides instructions for making a protein that acts as a guanine nucleotide exchange factor (GEF). This protein activates Cdc42, a small GTPase, which is vital for transmitting signals important for development, particularly bone formation.
What condition is associated with variants in the FGD1 gene?
Variants in the FGD1 gene are primarily associated with Aarskog-Scott syndrome. This condition is characterised by distinctive facial features, genital abnormalities, and skeletal issues, predominantly affecting males.
How does the FGD1 gene relate to bone development?
The FGD1 protein activates Cdc42, which then sends signals critical for proper bone development both before and after birth. When the FGD1 protein is not functioning correctly, these developmental signals can be disrupted, leading to skeletal abnormalities seen in conditions like Aarskog-Scott syndrome.
References
- Pedigo NG, Van Delden D, Walters L. Minireview: Role of genetic changes of faciogenital dysplasia protein 1 in human disease. Physiological genomics. 2016. PMID: 27199457
- Oshima T, Fujino T, Ando K. Role of FGD1, a Cdc42 guanine nucleotide exchange factor, in epidermal growth factor-stimulated c-Jun NH2-terminal kinase activation and cell migration. Biological & pharmaceutical bulletin. 2011. PMID: 21212517
- Gao L, Gorski JL, Chen CS. The Cdc42 guanine nucleotide exchange factor FGD1 regulates osteogenesis in human mesenchymal stem cells. The American journal of pathology. 2011. PMID: 21356349
- Daubon T, Buccione R, Génot E. The Aarskog-Scott syndrome protein Fgd1 regulates podosome formation and extracellular matrix remodeling in transforming growth factor β-stimulated aortic endothelial cells. Molecular and cellular biology. 2011. PMID: 21911474
- Orrico A, Galli L, Cavaliere ML. Phenotypic and molecular characterisation of the Aarskog-Scott syndrome: a survey of the clinical variability in light of FGD1 mutation analysis in 46 patients. European journal of human genetics : EJHG. 2004. PMID: 14560308
- Hou P, Estrada L, Kinley AW. Fgd1, the Cdc42 GEF responsible for Faciogenital Dysplasia, directly interacts with cortactin and mAbp1 to modulate cell shape. Human molecular genetics. 2003. PMID: 12913069
- Estrada L, Caron E, Gorski JL. Fgd1, the Cdc42 guanine nucleotide exchange factor responsible for faciogenital dysplasia, is localized to the subcortical actin cytoskeleton and Golgi membrane. Human molecular genetics. 2001. PMID: 11181572
- Gorski JL, Estrada L, Hu C. Skeletal-specific expression of Fgd1 during bone formation and skeletal defects in faciogenital dysplasia (FGDY; Aarskog syndrome). Developmental dynamics : an official publication of the American Association of Anatomists. 2000. PMID: 10906777