On this page
FREM2
FRAS1 related extracellular matrix 2
The *FREM2* gene provides instructions for a protein that is a key component of the extracellular matrix, playing a vital role in tissue support and organ development. The *FREM2* gene encodes the FRAS1 related extracellular matrix 2 protein, an integral part of the extracellular matrix.
FREM2 is located on the long (q) arm of chromosome 13, at band 13q13.3. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 13 in the library →Available at Jeen Health
Clinical tests that include this
Overview
The *FREM2* gene, or FRAS1 related extracellular matrix 2, is involved in producing a protein that forms part of the extracellular matrix. This complex network provides structural support and helps regulate cellular interactions in tissues throughout the body. The *FREM2* protein is particularly important for the development and proper functioning of organs such as the kidneys and eyes.
Disruptions in the *FREM2* gene can lead to various developmental conditions, most notably Fraser syndrome, which affects development before birth. Understanding the function of *FREM2* is crucial for comprehending the genetic basis of these inherited disorders.
What the gene does
The protein encoded by the *FREM2* gene is found within the extracellular matrix, the intricate scaffold that provides structural support and organisation between cells. It is a constituent of the FRAS/FREM complex, and also helps regulate the formation of this complex. Within the extracellular matrix, this complex is active in the basement membrane, a thin, sheet-like structure that separates and supports cells in many tissues.
One significant role of the FRAS/FREM complex, involving the *FREM2* protein, is to anchor the basement membrane in the superficial layer of the skin to the layer beneath it. Beyond skin integrity, the FRAS/FREM complex is also involved in the proper organisation and development of other organs and tissues, including the kidneys. Additionally, the *FREM2* protein appears to play a role in programmed cell death (apoptosis), a process crucial for removing unneeded cells, although the precise mechanism is not yet fully understood.
Video: Genetics 101
Chromosome location
The *FREM2* gene is located on chromosome 13, specifically at position 13q13.3. This chromosomal address indicates its precise position on the long arm (q) of chromosome 13, within band 13.3.
Protein structure
The *FREM2* protein is composed of 3169 amino acids and features a complex domain organisation. It begins with a Disordered region at amino acids 1-24. Following this, there are twelve CSPG (Chondroitin Sulphate Proteoglycan) Repeats: CSPG 1 (319-413), CSPG 2 (438-537), CSPG 3 (560-675), CSPG 4 (700-807), CSPG 5 (828-919), CSPG 6 (945-1037), CSPG 7 (1066-1168), CSPG 8 (1189-1282), CSPG 9 (1303-1399), CSPG 10 (1420-1512), CSPG 11 (1532-1621), and CSPG 12 (1655-1752). The protein concludes with two Calx-beta domains: Calx-beta 1 (1759-1858) and Calx-beta 2 (1871-1982).
Key variants
Variants within the *FREM2* gene can alter the protein's structure and function, impacting its role in extracellular matrix formation and tissue development. Pathogenic variants are genetic changes that are known to cause disease. These changes can range from small alterations in the DNA sequence to larger deletions or duplications, potentially leading to conditions like Fraser syndrome or isolated eye abnormalities. The inheritance pattern for conditions associated with *FREM2* variants can vary.
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.2425C>T | p.Arg809Ter | Pathogenic | ★★☆☆ | Fraser syndrome 2 |
c.2833del | p.His945fs | Pathogenic/Likely pathogenic | ★★☆☆ | Fraser syndrome 2 |
c.3151C>T | p.Gln1051Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Fraser syndrome 2 |
c.3297dup | p.Asp1100Ter | Pathogenic | ★★☆☆ | Fraser syndrome 2 |
c.3569del | p.Gln1190fs | Pathogenic/Likely pathogenic | ★★☆☆ | Isolated cryptophthalmia |
c.5162dup | p.Phe1722fs | Pathogenic/Likely pathogenic | ★★☆☆ | Fraser syndrome 2 |
c.5982del | p.Ala1996fs | Pathogenic/Likely pathogenic | ★★☆☆ | Isolated cryptophthalmia |
c.6350_6351del | p.Thr2117fs | Pathogenic/Likely pathogenic | ★★☆☆ | Fraser syndrome 1 |
c.7477_7478del | p.Leu2493fs | Pathogenic/Likely pathogenic | ★★☆☆ | Fraser syndrome 2 |
c.750_751dup | p.Thr251fs | Pathogenic | ★★☆☆ | Fraser syndrome 2 |
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 *FREM2* gene are associated with a range of developmental conditions. The most well-known is Fraser syndrome, a rare genetic disorder affecting development before birth, typically characterised by eyes covered by skin (cryptophthalmos), fused skin between fingers and toes (cutaneous syndactyly), and kidney abnormalities. *FREM2* variants may also cause isolated cryptophthalmos or abnormally small and underdeveloped eyes (microphthalmia), which can affect one or both eyes.
No disease links recorded for this gene in our reference set.
UK clinical status
The *FREM2* gene is listed on several NHS Genomic Medicine Service clinical panels, indicating its recognised role in various inherited conditions within the UK. These panels include Anophthalmia or microphthalmia, CAKUT (Congenital Anomalies of Kidney and Urinary Tract), DDG2P (Developmental Disorders Genotype-Phenotype Database), 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. Inclusion on these panels signifies that genetic testing for *FREM2* variants may be considered in patients presenting with related clinical features.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the function of the *FREM2* gene?
The *FREM2* gene provides instructions for a protein that is a key component of the extracellular matrix. This protein helps provide structural support between cells and is crucial for the proper development and organisation of tissues and organs, including the kidneys and eyes.
Which conditions are associated with changes in the *FREM2* gene?
Pathogenic variants in the *FREM2* gene are associated with Fraser syndrome, a condition characterised by developmental abnormalities affecting the eyes, skin, and kidneys. It can also cause isolated eye abnormalities such as cryptophthalmos or microphthalmia.
How does the *FREM2* protein contribute to tissue development?
The *FREM2* protein is part of the FRAS/FREM complex, which helps anchor the basement membrane in various tissues. This anchoring role is essential for maintaining tissue structure and is critical for the proper formation and organisation of organs during development.
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
- Jadeja S, Smyth I, Pitera JE. Identification of a new gene mutated in Fraser syndrome and mouse myelencephalic blebs. Nature genetics. 2005. PMID: 15838507