Alternative titles; symbols
HGNC Approved Gene Symbol: LUM
Cytogenetic location: 12q21.33 Genomic coordinates (GRCh38): 12:91,102,629-91,111,494 (from NCBI)
Lumican, a member of the small interstitial proteoglycan gene (SIPG) family, is a keratan sulfate proteoglycan present in large quantities in the corneal stroma and in interstitial collagenous matrices of the heart, aorta, skeletal muscle, skin, and intervertebral discs (Chakravarti and Magnuson, 1995). Other SIPG members are decorin (125255), biglycan (301870), and fibromodulin (600245).
Chakravarti et al. (1995) derived the primary structure of lumican from cDNA sequencing of chicken, bovine, and human clones and demonstrated that lumican shows all the characteristic features of the SIPG family, namely, 4 and 2 cysteines in the N- and C-terminal globular domains, I and III, and a central, cysteine-free domain II, with 9 beta sheet-forming leucine motifs. This human core protein contains 4 putative N-glycosylation sites in the central domains, all or some of which are substituted with keratan sulfate side chains. At the amino acid level, it is 90% identical with the bovine and 72% identical with the chicken core protein. By immunohistochemical staining, Chakravarti et al. (1995) showed that lumican is present not only in the corneal stroma but also in the dermal area of the skin.
Grover et al. (1995) used PCR techniques to derive a human lumican cDNA sequence from RNA obtained from intestine, placenta, and articular cartilage. The deduced lumican protein sequence had 338 amino acids, including a putative 18-residue signal peptide. The lumican message is expressed at high levels in adult articular chondrocytes, but at low levels in the young juvenile. It is present in the extracellular matrix of human articular cartilage at all ages, although its abundance is far greater in the adult. In adult cartilage, lumican exists predominantly in a glycoprotein form lacking keratan sulfate, whereas the juvenile form of the molecule is a proteoglycan.
Yeh et al. (2010) found that zebrafish Lum existed as a keratan sulfate proteoglycan in corneal stroma and as an unglycanated glycoprotein in sclera.
Grover et al. (1995) showed that the LDC gene is spread over about 7.5 kb of genomic DNA and consists of 3 exons separated by introns of 2.2 and 3.5 kb.
Chakravarti and Magnuson (1995) localized the mouse lumican gene to distal chromosome 10 by segregation analysis of restriction fragment length variants (RFLVs) in recombinant inbred (RI) strains of mice.
Chakravarti et al. (1995) localized the lumican gene to human chromosome 12 by hybridizing a cDNA probe to a Southern blot containing a human/hamster monochromosomal mapping panel DNA. Sublocalization to 12q21.3-q22 was performed by fluorescence in situ hybridization.
By PCR analysis of human/hamster somatic cell hybrids Grover et al. (1995) mapped the LDC gene to chromosome 12 and regionalized it to chromosome 12q22 by fluorescence in situ hybridization.
Like decorin, lumican interacts with collagen and limits growth of fibrils in diameter (Chakravarti and Magnuson, 1995). In the cornea, lumican not only interacts with collagen molecules to limit fibril growth, but by virtue of its keratan sulfate-containing glycosaminoglycan side chains LDC plays a critical role in the regular spacing of fibrils and acquisition of corneal transparency.
Association with Myopia
For discussion of a possible association between variation in the LUM gene and myopia, see MYP3 (603221).
Lumican and fibromodulin (600245) regulate the assembly of collagens into higher-order fibrils in connective tissues. Jepsen et al. (2002) showed that mice deficient in both of these proteoglycans manifest several clinical features of Ehlers-Danlos syndrome (see 130000). Double-null Lum -/- Fmod -/- mice were smaller than their wildtype littermates and displayed gait abnormality, joint laxity, and age-dependent osteoarthritis. Misaligned patellae, severe knee dysmorphogenesis, and extreme tendon weakness were the likely causes for joint laxity in the double-nulls. 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 partially rescue 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. The study suggested that lumican and fibromodulin may be key players in the pathogenesis of certain types of Ehlers-Danlos syndrome and other connective tissue disorders.
Yeh et al. (2010) found that knockdown of zebrafish Lum by antisense morpholinos resulted in ocular enlargement resembling axial myopia. Mutant zebrafish also showed enlarged pericardium and deformed body shape. Ocular enlargement was due to disruption of the collagen fibril arrangement in the sclera and resulted in scleral thinning. Administration of muscarinic receptor antagonists subdued ocular enlargement.
Chakravarti, S., Magnuson, T. Localization of mouse lumican (keratan sulfate proteoglycan) to distal chromosome 10. Mammalian Genome 6: 367-368, 1995. [PubMed: 7626890] [Full Text: https://doi.org/10.1007/BF00364803]
Chakravarti, S., Stallings, R. L., SundarRaj, N., Cornuet, P. K., Hassell, J. R. Primary structure of human lumican (Keratan sulfate proteoglycan) and localization of the gene (LUM) to chromosome 12q21.3-q22. Genomics 27: 481-488, 1995. [PubMed: 7558030] [Full Text: https://doi.org/10.1006/geno.1995.1080]
Grover, J., Chen, X.-N., Korenberg, J. R., Roughley, P. J. The human lumican gene: organization, chromosomal location, and expression in articular cartilage. J. Biol. Chem. 270: 21942-21949, 1995. [PubMed: 7665616] [Full Text: https://doi.org/10.1074/jbc.270.37.21942]
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]
Yeh, L.-K., Liu, C.-Y., Kao, W. W.-Y., Huang, C.-J., Hu, F.-R., Chien, C.-L., Wang, I.-J. Knockdown of zebrafish lumican gene (zlum) causes scleral thinning and increased size of scleral coats. J. Biol. Chem. 285: 28141-28155, 2010. [PubMed: 20551313] [Full Text: https://doi.org/10.1074/jbc.M109.043679]