On this page
FRAS1
Fraser extracellular matrix complex subunit 1
The FRAS1 gene provides instructions for a protein crucial to the extracellular matrix, particularly in the basement membrane, influencing embryonic development and organ formation. The FRAS1 gene encodes a protein that is a key component of the extracellular matrix, a network providing structural support between cells.
FRAS1 is located on the long (q) arm of chromosome 4, at band 4q21.21. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 4 in the library →Available at Jeen Health
Clinical tests that include this
Overview
The FRAS1 gene, or Fraser extracellular matrix complex subunit 1, is instrumental in producing a protein that forms part of the intricate lattice-like structure known as the extracellular matrix. This matrix provides critical structural support and organisation to tissues throughout the body. The FRAS1 protein is particularly active within the basement membrane, a thin, supportive layer found in many tissues, and is involved in anchoring cell layers.
Changes within the FRAS1 gene are most commonly associated with Fraser syndrome, a rare genetic disorder affecting development before birth. The gene's role extends to the proper organisation and development of various organs, including the kidneys, highlighting its broad importance in embryogenesis.
What the gene does
The FRAS1 protein functions as a critical component of the extracellular matrix, the complex network that supports and separates cells in many tissues. Specifically, it is part of the FRAS/FREM complex, which is active in the basement membrane. This thin, sheet-like structure separates and supports cell layers in numerous tissues, and the FRAS/FREM complex helps to anchor the basement membrane, for instance, between layers of skin.
Beyond its structural roles, the FRAS1 protein is essential for the proper organisation and development of various organs and tissues during foetal development, including the kidneys. Additionally, research suggests the FRAS1 protein may be involved in the programmed self-destruction of cells (apoptosis) that are no longer required, though the exact mechanism for this role is not yet fully understood.
Video: Genetics 101
Chromosome location
The FRAS1 gene is situated on chromosome 4, specifically at position 4q21.21. This location refers to the long (q) arm of chromosome 4, within region 2, band 1, sub-band 21.
Protein structure
The FRAS1 protein is a large protein, consisting of 4008 amino acids. It features a complex arrangement of domains, including multiple VWFC (von Willebrand factor type C) domains and FU (FRAS1-related extracellular matrix) repeats. Specific VWFC domains are found at amino acid positions 27-88 (VWFC 1), 93-153 (VWFC 2), 157-217 (VWFC 3), 219-279 (VWFC 4), 283-343 (VWFC 5), and 347-417 (VWFC 6). Following these are a series of FU repeats, located at positions 409-460 (FU 1), 462-505 (FU 2), 507-553 (FU 3), 555-599 (FU 4), 602-647 (FU 5), 649-705 (FU 6), 708-753 (FU 7), 755-800 (FU 8), and 803-852 (FU 9). These domains and repeats are crucial for the protein's interactions within the extracellular matrix.
Key variants
Genetic changes, known as variants, in the FRAS1 gene can disrupt its normal function, potentially leading to developmental conditions. These variants can alter the protein's structure or reduce its production, impacting the integrity of the extracellular matrix and proper organ development. Pathogenic variants in FRAS1 are recognised as the most frequent cause of Fraser syndrome.
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.1253C>G | p.Ser418Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Fraser syndrome 1 |
c.1346G>A | p.Trp449Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Fraser syndrome 1 |
c.3204_3205del | p.Cys1068_Asp1069delinsTer | Pathogenic/Likely pathogenic | ★★☆☆ | Fraser syndrome 1 |
c.3563+1G>A | - | Pathogenic | ★★☆☆ | Fraser syndrome 1 |
c.382del | p.Gln128fs | Pathogenic/Likely pathogenic | ★★☆☆ | Fraser syndrome 1 |
c.3911_3918del | p.Val1304fs | Pathogenic | ★★☆☆ | Fraser syndrome 1 |
c.5989_5990del | p.Leu1997fs | Pathogenic/Likely pathogenic | ★★☆☆ | Fraser syndrome 1 |
c.6445C>T | p.Gln2149Ter | Pathogenic | ★★☆☆ | Fraser syndrome 1 |
c.79_103dup | p.Leu35fs | Pathogenic/Likely pathogenic | ★★☆☆ | Fraser syndrome 1 |
c.988G>T | p.Glu330Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Fraser syndrome 1 |
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 FRAS1 gene are primarily associated with Fraser syndrome, a rare genetic condition that affects development before birth. This syndrome typically presents with distinct features such as cryptophthalmos (eyes covered by skin), cutaneous syndactyly (fusion of skin between fingers and toes), and abnormalities of the kidneys and other organs. The FRAS1 gene is also implicated in conditions like anophthalmia/microphthalmia, coloboma, and congenital anomalies of the kidney and urinary tract.
No disease links recorded for this gene in our reference set.
UK clinical status
The FRAS1 gene is recognised within the NHS Genomic Medicine Service due to its association with several conditions. It is listed on several Green-status panels in NHS England's National Genomic Test Directory, including those for Anophthalmia or microphthalmia, CAKUT, Clefting, Deafness and congenital structural abnormalities, Foetal anomalies (R21), Limb disorders, Structural eye disease (R36), Unexplained kidney failure in young people, and Unexplained young onset end-stage renal disease - additional genes. A Green status indicates that there is strong evidence for the gene's association with these conditions and it is routinely tested.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the function of the FRAS1 gene?
The FRAS1 gene provides instructions for making a protein that is a vital component of the extracellular matrix, particularly within the basement membrane. It helps provide structural support and is essential for the proper development and organisation of various organs and tissues during embryonic growth.
What is Fraser syndrome?
Fraser syndrome is a rare genetic disorder predominantly caused by variants in the FRAS1 gene. It affects development before birth and is characterised by features such as eyes covered by skin (cryptophthalmos), fused digits (cutaneous syndactyly), and kidney abnormalities.
How can genetic variants in FRAS1 affect health?
Variants in the FRAS1 gene can lead to disruptions in the formation and integrity of the extracellular matrix and basement membrane. This can impair normal embryonic development, resulting in congenital anomalies affecting multiple organ systems, as seen in Fraser syndrome.
References
- Kohl S, Hwang DY, Dworschak GC. Mild recessive mutations in six Fraser syndrome-related genes cause isolated congenital anomalies of the kidney and urinary tract. Journal of the American Society of Nephrology : JASN. 2014. PMID: 24700879
- Pavlakis E, Chiotaki R, Chalepakis G. The role of Fras1/Frem proteins in the structure and function of basement membrane. The international journal of biochemistry & cell biology. 2011. PMID: 21182980
- Petrou P, Makrygiannis AK, Chalepakis G. The Fras1/Frem family of extracellular matrix proteins: structure, function, and association with Fraser syndrome and the mouse bleb phenotype. Connective tissue research. 2008. PMID: 18661360
- van Haelst MM, Maiburg M, Baujat G. Molecular study of 33 families with Fraser syndrome new data and mutation review. American journal of medical genetics. Part A. 2008. PMID: 18671281
- Short K, Wiradjaja F, Smyth I. Let's stick together: the role of the Fras1 and Frem proteins in epidermal adhesion. IUBMB life. 2007. PMID: 17654118