Normal Function
The FREM2 gene provides instructions for making a protein that is found within the extracellular matrix, which is the intricate lattice that forms in the space between cells and provides structural support. The FREM2 protein is part of a group of proteins called the FRAS/FREM complex. In addition to being part of the complex, the FREM2 protein helps regulate its formation.
Within the extracellular matrix, the FRAS/FREM complex is active in the basement membrane, which is the thin, sheet-like structure that separates and supports the cells in many tissues. One of the roles of the FRAS/FREM complex is to anchor the basement membrane in the top layer of skin to the layer of skin below. The FRAS/FREM complex is also involved in the proper organization and development of other organs and tissues, including the kidneys.
Through a mechanism that is not well understood, the FREM2 protein also appears to play a role in the self-destruction of cells that are no longer needed (apoptosis).
Health Conditions Related to Genetic Changes
Fraser syndrome
Genetic changes that cause disease are called pathogenic variants. Pathogenic variants in the FREM2 gene cause a small percentage of cases of Fraser syndrome. Fraser syndrome affects development before birth and is typically characterized by eyes that are covered by skin (cryptophthalmos), fusion of the skin between the fingers and toes (cutaneous syndactyly), and abnormalities of the kidneys and other organs and tissues.
The pathogenic variants in the FREM2 gene that are associated with Fraser syndrome likely cause cells to produce a version of the FREM2 protein that does not function properly. This disrupts the formation of the FRAS/FREM complex. Without enough FRAS/FREM complex in the basement membrane of the skin, the movement (migration) and communication of cells in the different skin layers is disrupted. This leads to the cryptophthalmos and cutaneous syndactyly seen in affected individuals.
The pathogenic variants in the FREM2 gene that cause Fraser syndrome likely also interfere with apoptosis, which may contribute to the additional abnormalities seen in people with Fraser syndrome.
More About This Health ConditionCongenital anomalies of kidney and urinary tract
MedlinePlus Genetics provides information about Congenital anomalies of kidney and urinary tract
More About This Health ConditionOther disorders
Pathogenic variants in the FREM2 gene may also cause cryptophthalmos without causing signs and symptoms in other parts of the body (isolated cryptophthalmos). Individuals may also have eyes that are abnormally small and underdeveloped (microphthalmia). The eye abnormalities can affect one eye (unilateral) or both eyes (bilateral).
Other Names for This Gene
- DKFZp686J0811
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
References
- Al-Hamed MH, Sayer JA, Alsahan N, Tulbah M, Kurdi W, Ambusaidi Q, Ali W, Imtiaz F. Novel loss of function variants in FRAS1 AND FREM2 underlie renal agenesis in consanguineous families. J Nephrol. 2021 Jun;34(3):893-900. doi: 10.1007/s40620-020-00795-0. Epub 2020 Jul 8. Citation on PubMed
- Ikeda S, Akamatsu C, Ijuin A, Nagashima A, Sasaki M, Mochizuki A, Nagase H, Enomoto Y, Kuroda Y, Kurosawa K, Ishikawa H. Prenatal diagnosis of Fraser syndrome caused by novel variants of FREM2. Hum Genome Var. 2020 Oct 2;7:32. doi: 10.1038/s41439-020-00119-5. eCollection 2020. Citation on PubMed
- Jadeja S, Smyth I, Pitera JE, Taylor MS, van Haelst M, Bentley E, McGregor L, Hopkins J, Chalepakis G, Philip N, Perez Aytes A, Watt FM, Darling SM, Jackson I, Woolf AS, Scambler PJ. Identification of a new gene mutated in Fraser syndrome and mouse myelencephalic blebs. Nat Genet. 2005 May;37(5):520-5. doi: 10.1038/ng1549. Epub 2005 Apr 17. Citation on PubMed
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- Pavlakis E, Chiotaki R, Chalepakis G. The role of Fras1/Frem proteins in the structure and function of basement membrane. Int J Biochem Cell Biol. 2011 Apr;43(4):487-95. doi: 10.1016/j.biocel.2010.12.016. Epub 2010 Dec 21. Citation on PubMed
- 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. Connect Tissue Res. 2008;49(3):277-82. doi: 10.1080/03008200802148025. Citation on PubMed
- Short K, Wiradjaja F, Smyth I. Let's stick together: the role of the Fras1 and Frem proteins in epidermal adhesion. IUBMB Life. 2007 Jul;59(7):427-35. doi: 10.1080/15216540701510581. Citation on PubMed
- Simikyan RG, Zhang X, Strelkova O, Li N, Zhu M, Eckhard A, Baranov PY, Wu X, Richey L, Indzhykulian AA. Frem2 Knockout Mice Exhibit Fraser Syndrome Phenotypes and Neonatal Lethality Due to Bilateral Renal Agenesis. bioRxiv [Preprint]. 2025 Aug 5:2024.10.28.620501. doi: 10.1101/2024.10.28.620501. Citation on PubMed
- van Haelst MM, Maiburg M, Baujat G, Jadeja S, Monti E, Bland E, Pearce K; Fraser Syndrome Collaboration Group; Hennekam RC, Scambler PJ. Molecular study of 33 families with Fraser syndrome new data and mutation review. Am J Med Genet A. 2008 Sep 1;146A(17):2252-7. doi: 10.1002/ajmg.a.32440. Citation on PubMed
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