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FREM1
FRAS1 related extracellular matrix 1
The FREM1 gene encodes a protein crucial for the formation and organisation of basement membranes, which are vital for supporting cells and tissues during embryonic development. The FREM1 gene plays a key role in producing the FRAS1 related extracellular matrix 1 protein, an important component of basement membranes.
FREM1 is located on the short (p) arm of chromosome 9, at band 9p22.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The FREM1 gene, or FRAS1 related extracellular matrix 1, is instrumental in producing a protein that contributes to the structural integrity and organisation of basement membranes. These thin, sheet-like structures are fundamental for separating and supporting cell layers within numerous tissues.
During embryonic development, the FREM1 protein interacts with other proteins, including FRAS1 and FREM2, within basement membranes. This interaction is essential for anchoring epithelial cells, which line body surfaces and cavities, to other embryonic tissues that develop into connective tissues like skin, cartilage, and organs such as the kidneys. Disruptions to the FREM1 gene can affect normal foetal development, leading to a range of congenital conditions.
What the gene does
The FREM1 gene is responsible for synthesising the FRAS1 related extracellular matrix 1 protein, a critical component in the assembly and maintenance of basement membranes. Basement membranes are specialised extracellular matrices that provide structural support, compartmentalisation, and signalling cues to various tissues.
During early embryonic development, the FREM1 protein is vital for coordinating the attachment of different tissue layers. It facilitates the anchoring of epithelial cells to underlying mesenchymal tissues, which are precursors to connective tissues and organs. This function is particularly important for the proper development of structures such as the skin, kidneys, and eyes.
Interaction between FREM1 and other extracellular matrix proteins, like FRAS1 and FREM2, is crucial for establishing the robust adhesion required for tissue morphogenesis. The protein is thought to mediate cell-to-matrix interactions and play a role in signalling pathways that regulate cell proliferation, differentiation, and migration during development. Alterations in FREM1 function can compromise the integrity of basement membranes, leading to developmental anomalies affecting multiple organ systems.
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Chromosome location
The FREM1 gene is situated on the short arm of chromosome 9, specifically at position 9p22.3. Chromosome 9 contains approximately 145 million base pairs and represents between 4% and 4.5% of the total DNA in human cells. The precise location of FREM1 on this chromosome helps geneticists and clinicians understand its genetic context and how it might be inherited or affected by chromosomal rearrangements.
Protein structure
The FRAS1 related extracellular matrix 1 protein consists of 2179 amino acids. Its structure includes several important functional regions. There are two Cell attachment site motifs, one located at amino acids 199-201 and another at 1907-1909, which are likely involved in mediating cell adhesion.
The protein also contains numerous Chondroitin Sulphate Proteoglycan (CSPG) repeats, including CSPG 1 (amino acids 296-390), CSPG 2 (413-500), CSPG 3 (521-615), CSPG 4 (642-754), CSPG 5 (776-867), CSPG 6 (887-982), CSPG 7 (1024-1126), CSPG 8 (1147-1254), CSPG 9 (1275-1372), CSPG 10 (1393-1485), CSPG 11 (1506-1596), and CSPG 12 (1628-1724). These CSPG repeats are characteristic of proteoglycans, which are critical components of the extracellular matrix and play a role in tissue structure and cell signalling. Additionally, a Calx-beta domain is present between amino acids 1731-1830, indicating potential involvement in calcium-binding or related cellular processes.
Key variants
Variants within the FREM1 gene can lead to alterations in the FRAS1 related extracellular matrix 1 protein, impacting its ability to contribute to healthy basement membrane formation and function. These changes can range from small alterations in single protein building blocks (amino acids) to larger deletions of genetic material. Such variants can sometimes result in a shortened, non-functional protein or alter its interactions with other proteins. The potential impact of a FREM1 variant depends on its specific nature and location within the gene.
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.2097_2100del | p.Lys699fs | Pathogenic | ★★☆☆ | Inborn genetic diseases |
c.3925del | p.Glu1309fs | Pathogenic/Likely pathogenic | ★★☆☆ | Oculotrichoanal syndrome |
c.631C>T | p.Gln211Ter | Pathogenic/Likely pathogenic | ★★☆☆ | BNAR syndrome |
GRCh37/hg19 9p22.3(chr9:14812846-14860436)x1 | - | Pathogenic | ★☆☆☆ | not specified |
c.1288C>T | p.Arg430Ter | Pathogenic | ★☆☆☆ | not provided |
c.2078+1G>A | - | Pathogenic | ★☆☆☆ | not provided |
c.2136_2143dup | p.Ala715fs | Pathogenic | ★☆☆☆ | not provided |
c.2557del | p.Asp853fs | Pathogenic | ★☆☆☆ | not provided |
c.2626del | p.Val876fs | Pathogenic | ★☆☆☆ | Oculotrichoanal syndrome |
c.5220G>A | p.Trp1740Ter | 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 FREM1 gene are associated with several inherited conditions, primarily affecting development. These include Manitoba oculotrichoanal syndrome, which presents with characteristic physical features impacting the eyes, hair, and anus. Another condition linked to FREM1 variants is bifid nose, renal agenesis, and anorectal malformations syndrome (BNAR).
Additionally, FREM1 gene variants have been identified in individuals with coloboma, a condition affecting eye structure, and congenital anomalies of the kidney and urinary tract (CAKUT). These conditions highlight the gene's widespread importance in normal foetal development across multiple organ systems.
No disease links recorded for this gene in our reference set.
UK clinical status
The FREM1 gene is recognised within the UK's National Health Service (NHS) Genomic Medicine Service, indicating its clinical relevance for diagnostic testing. It is currently listed as 'green' in PanelApp UK for several conditions, signifying that there is sufficient evidence for its inclusion on diagnostic panels. These include Anophthalmia or microphthalmia, CAKUT (Congenital Anomalies of the Kidney and Urinary Tract), DDG2P (Deciphering Developmental Disorders panel), Foetal anomalies (specifically under R21), Structural eye disease (under R36), Unexplained kidney failure in young people, and Unexplained young onset end-stage renal disease - additional genes. This green status means that variants in FREM1 are considered to be a likely cause of these conditions and are routinely analysed in relevant genetic tests.
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 choices can prevent conditions associated with FREM1 gene variants. General healthy lifestyle recommendations, such as maintaining a balanced diet, engaging in regular physical activity, and avoiding environmental toxins, are important for overall well-being. However, these are general health guidelines and are not known to directly mitigate the effects of genetic variants in FREM1.
Supplement considerations
There is no conclusive evidence from clinical studies to suggest that any specific dietary supplements can prevent, treat, or alleviate the symptoms of conditions associated with FREM1 gene variants. Individuals considering any supplements should consult with a healthcare professional to discuss potential benefits and risks, especially given the lack of specific research in this area for FREM1-related conditions.
Frequently asked questions
What is the primary function of the FREM1 gene?
The FREM1 gene provides instructions for making a protein that is crucial for the formation and organisation of basement membranes, which are thin, supportive structures in many tissues, particularly during embryonic development.
What conditions are associated with variants in the FREM1 gene?
Variants in the FREM1 gene are linked to several developmental conditions, including Manitoba oculotrichoanal syndrome, bifid nose, renal agenesis, and anorectal malformations syndrome (BNAR), coloboma, and congenital anomalies of the kidney and urinary tract (CAKUT).
How does the FREM1 protein contribute to embryonic development?
The FREM1 protein interacts with other proteins like FRAS1 and FREM2 within basement membranes to help anchor epithelial cells to other embryonic tissues, which is essential for the proper development of organs like the skin, kidneys, and eyes.
Can lifestyle changes prevent FREM1-related conditions?
There is no specific scientific evidence to suggest that lifestyle changes can prevent conditions directly caused by genetic variants in the FREM1 gene. General healthy living is always recommended for overall well-being.
Is the FREM1 gene part of genetic testing in the UK?
Yes, FREM1 is included on several diagnostic panels within the UK NHS Genomic Medicine Service, indicated by its 'green' status in PanelApp UK for conditions like Anophthalmia or microphthalmia and CAKUT.
References
- 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
- Slavotinek AM, Baranzini SE, Schanze D. Manitoba-oculo-tricho-anal (MOTA) syndrome is caused by mutations in FREM1. Journal of medical genetics. 2011. PMID: 21507892
- Alazami AM, Shaheen R, Alzahrani F. FREM1 mutations cause bifid nose, renal agenesis, and anorectal malformations syndrome. American journal of human genetics. 2009. PMID: 19732862