HGNC Approved Gene Symbol: FMOD
Cytogenetic location: 1q32.1 Genomic coordinates (GRCh38): 1:203,340,628-203,351,122 (from NCBI)
Fibromodulin is a member of a family of small interstitial proteoglycans that also includes decorin (DCN; 125255), biglycan (BGN; 301870), and lumican (LDC; 600616). The core proteins of these proteoglycans are structurally related, consisting of a central region composed of leucine-rich repeats flanked by disulfide-bonded terminal domains, with that for fibromodulin possessing up to 4 keratan sulfate chains within its leucine-rich domain. Fibromodulin exhibits a wide tissue distribution, with the highest abundance observed in articular cartilage, tendon, and ligament. It has been suggested that fibromodulin participates in the assembly of the extracellular matrix by virtue of its ability to interact with type I and type II collagen fibrils and to inhibit fibrillogenesis in vitro. Sztrolovics et al. (1994) cloned the 3-prime untranslated region of the fibromodulin cDNA.
By RT-PCR, Mikaelsson et al. (2005) found fibromodulin expression in 75 patients with B-cell chronic lymphocytic leukemia (BCLL) and in 5 of 7 patients with mantle cell lymphoma (MCL). No mutations in the FMOD gene were detected. Western blot analysis detected fibromodulin in the cytoplasm of BCLL cells and in the medium of cultured BCLL cells, but not at the cell surface. Fibromodulin was not found in patients with several other leukemias, and it was not detected in normal T and B lymphocytes, monocytes, tonsil B cells, or granulocytes. Phorbol ester activation of normal T and B lymphocytes induced weak FMOD expression, but not to the extent seen in freshly isolated BCLL cells. Mikaelsson et al. (2005) concluded that FMOD is involved in the pathobiology of BCLL and MCL.
By fluorescence in situ hybridization, Sztrolovics et al. (1994) mapped the FMOD gene to 1q32. Secondary signals were detected at 9q34.1; however, PCR analysis of somatic cell hybrids confirmed the localization to chromosome 1.
Svensson et al. (1999) found that Fmod -/- mice had an altered morphologic phenotype in tail tendon with fewer and abnormal collagen fiber bundles. In heterozygotes, about 10 to 20% of bundles were similarly abnormal. Immunohistochemical and electron microscopic analysis demonstrated irregular and thinner collagen fibrils in Achilles tendons of Fmod -/- mice. Expression of lumican protein was increased, in spite of a decrease in lumican mRNA, whereas decorin protein levels were unchanged. Svensson et al. (1999) concluded that FMOD has a role in collagen fibrillogenesis.
Lumican (600616) and fibromodulin regulate the assembly of collagens into higher-order fibrils in connective tissues. Jepsen et al. (2002) found that mice in which the genes encoding both of these proteoglycans had been knocked out manifest several clinical features of Ehlers-Danlos syndrome (see 130000). Fibromodulin deficiency alone led to significant reduction in tendon stiffness, with further loss in stiffness in a Lum gene dose-dependent way. At the protein level, Jepsen et al. (2002) showed marked increase of lumican in Fmod -/- tendons, which may indicated partial rescue of the tendon phenotype in this genotype. These results established fibromodulin as a key regulator and lumican as a modulator of tendon strength. A disproportionate increase in small diameter immature collagen fibrils and a lack of progression to mature, large diameter fibrils in the Fmod -/- background constitute the underlying cause of tendon weakness and suggest that fibromodulin aids fibril maturation. Jepsen et al. (2002) concluded that lumican and fibromodulin are candidate genes and key players in the pathogenesis of certain types of Ehlers-Danlos syndrome and other connective tissue disorders.
Jepsen, K. J., Wu, F., Peragallo, J. H., Paul, J., Roberts, L., Ezura, Y., Oldberg, A., Birk, D. E., Chakravarti, S. A syndrome of joint laxity and impaired tendon integrity in lumican- and fibromodulin-deficient mice. J. Biol. Chem. 277: 35532-35540, 2002. [PubMed: 12089156] [Full Text: https://doi.org/10.1074/jbc.M205398200]
Mikaelsson, E., Danesh-Manesh, A. H., Luppert, A., Jeddi-Tehrani, M., Rezvany, M.-R., Sharifian, R. A., Safaie, R., Roohi, A., Osterborg, A., Shokri, F., Mellstedt, H., Rabbani, H. Fibromodulin, an extracellular matrix protein: characterization of its unique gene and protein expression in B-cell lymphocytic leukemia and mantle cell lymphoma. Blood 105: 4828-4835, 2005. [PubMed: 15741214] [Full Text: https://doi.org/10.1182/blood-2004-10-3941]
Svensson, L., Aszodi, A., Reinholt, F. P., Fassler, R., Heinegard, D., Oldberg, A. Fibromodulin-null mice have abnormal collagen fibrils, tissue organization, and altered lumican deposition in tendon. J. Biol. Chem. 274: 9636-9647, 1999. [PubMed: 10092650] [Full Text: https://doi.org/10.1074/jbc.274.14.9636]
Sztrolovics, R., Chen, X.-N., Grover, J., Roughley, P. J., Korenberg, J. R. Localization of the human fibromodulin gene (FMOD) to chromosome 1q32 and completion of the cDNA sequence. Genomics 23: 715-717, 1994. [PubMed: 7851907] [Full Text: https://doi.org/10.1006/geno.1994.1567]