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Gene Review

HAPLN1  -  hyaluronan and proteoglycan link protein 1

Homo sapiens

Synonyms: CRTL1, Cartilage-link protein, Cartilage-linking protein 1, Hyaluronan and proteoglycan link protein 1, Proteoglycan link protein
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Disease relevance of HAPLN1

  • OBJECTIVE: To determine whether patients with osteoarthritis (OA) express cellular immunity to cartilage link protein (LP) and the G1 globular domain of proteoglycan (PG) aggrecan, and whether immunity to the G1 domain is influenced by the removal of keratan sulfate (KS) [1].
  • It has been established that suppression of uPA expression and invasiveness by UTI is mediated through inhibition of protein kinase C-dependent signaling pathways and that human chondrosarcoma cell line HCS-2/8 expresses two types of UTI-BPs; a 40-kDa UTI-BP (UTI-BP(40)), which is identical to link protein (LP), and a 45-kDa UTI-BP (UTI-BP(45)) [2].
  • Expression of the Myxococcus xanthus gene crtl is controlled by a light-inducible promoter [3].
  • Aberrations of the long arm of chromosome 5 (5q) were studied in 79 clear cell renal carcinomas (clear cell RCC) by LOH (loss of heterozygosity) method, using microsatellite markers D5S107, CRTL1, LNS-CA, IL-9.RP1, CFS1R and GeneScan analysis software [4].
  • This study used a cross-sectional comparison of endurance athletes (n=20; ATHL) exhibiting resting bradycardia and age-matched nonathletes (n=12; CRTL) to indirectly assess training effects on amplitude and timing characteristics of respiratory sinus arrhythmia (RSA) [5].
  • Proliferation, motility, invasion, and soft-agar colony formation assays on mesothelioma cells overexpressing full-length HAPLN1 or its functional domains strongly supported the protumorigenic role of HAPLN1 and its SP-IgV domain [6].

High impact information on HAPLN1


Biological context of HAPLN1

  • Two cis-acting enhancer elements resided in the 5'-untranslated region of CRTL1 [8].
  • Here, we investigated the regulation of CRTL1 by SOX9, a key regulator of cartilage matrix genes and chondrogenesis [8].
  • Subsequent refinement of the physical map allows ordering of known polymorphic microsatellites and excludes CRTL1 as a likely candidate for the disorder [9].
  • Refined genetic and physical localization of the Wagner disease (WGN1) locus and the genes CRTL1 and CSPG2 to a 2- to 2.5-cM region of chromosome 5q14.3 [9].
  • Complete amino acid sequence of human cartilage link protein (CRTL1) deduced from cDNA clones and chromosomal assignment of the gene [10].

Anatomical context of HAPLN1

  • METHODS: LP and the G1 globular domain of PG were isolated from human and/or bovine cartilage and used in proliferation assays with peripheral blood lymphocytes (PBL) from 42 patients with OA and 40 healthy control subjects [1].
  • Our results suggest that LP is involved in the stabilization of extracellular matrices of a wide variety of non-cartilaginous tissues [11].
  • Investigations on the interactions between LP and proteoglycans from skin and proventriculus demonstrate that LP can enhance the binding of proteoglycans from these tissues to HA [11].
  • LP is localized in the extracellular matrix of the mesoderm along the entire digestive tract and in the dermis of the embryonic skin as revealed by immunofluorescence analysis [11].
  • METHODS: Aggrecan and LP were prepared from fetal bovine epiphyseal cartilage, and PG aggregates were formed in the presence or absence of LP [12].

Associations of HAPLN1 with chemical compounds

  • Link protein (LP) is an abundant protein of cartilage which stabilizes the interaction of aggrecan with hyaluronic acid (HA) [11].
  • The concentration of LP was less than that of the G1-domain in all extracts of cartilage from individuals over 13 years, but this was particularly noticeable in the 1 M guanidinium chloride extracts, and it was surmised that a deficiency in LP produces unstable aggregates in situ [13].
  • Degradation of HA, aggrecan and LP were assessed by gel filtration chromatography and polyacrylamide gel electrophoresis [12].
  • The proteoglycan aggregate, including LP, is dissociated in the presence of chaotropes such as 4 M guanidine hydrochloride [14].
  • The proteoglycan aggregate, including LP, is dissociated in the presence of chaotropes such as 4 M guanidine hydrochloride [15].

Regulatory relationships of HAPLN1

  • RESULTS: Patients with RA (34%) and AS (71%) expressed a significantly higher prevalence of cellular immune responses to human LP compared with the healthy control group (13%) [16].

Other interactions of HAPLN1

  • Within the critical region lie genes encoding two extracellular macromolecules, link protein (CRTL1) and versican (CSPG2), which are important in binding hyaluronan, a significant component of the mammalian vitreous gel, and which therefore represent excellent candidates for Wagner syndrome [9].
  • Half the patients with RA responding to LP exhibited cellular immunity to both human and bovine protein [16].
  • The distribution of cartilage proteoglycan core protein (aggrecan) and cartilage proteoglycan link protein was investigated by in situ hybridization during different stages of human skeletal development [17].
  • We demonstrate, using RNase protection experiments, that the coding region of the LP mRNAs isolated from these tissues is identical to that present in cartilage [11].
  • Histological and immunohistochemical analysis of the TGF-beta 1-treated PLA/alginate amalgam and PLA constructs showed development of a cartilaginous phenotype from day 7 to day 21 as demonstrated by colocalization of Alcian blue staining with collagen type II and cartilage proteoglycan link protein [18].

Analytical, diagnostic and therapeutic context of HAPLN1


  1. Immune responses to cartilage link protein and the G1 domain of proteoglycan aggrecan in patients with osteoarthritis. Guerassimov, A., Zhang, Y., Cartman, A., Rosenberg, L.C., Esdaile, J., Fitzcharles, M.A., Poole, A.R. Arthritis Rheum. (1999) [Pubmed]
  2. Characterization of binding properties of urinary trypsin inhibitor to cell-associated binding sites on human chondrosarcoma cell line HCS-2/8. Hirashima, Y., Kobayashi, H., Suzuki, M., Tanaka, Y., Kanayama, N., Fujie, M., Nishida, T., Takigawa, M., Terao, T. J. Biol. Chem. (2001) [Pubmed]
  3. The structure of an ECF-sigma-dependent, light-inducible promoter from the bacterium Myxococcus xanthus. Martínez-Argudo, I., Ruiz-Vázquez, R.M., Murillo, F.J. Mol. Microbiol. (1998) [Pubmed]
  4. Abnormalities of chromosome 5q correlate with morphologic features of better prognosis in clear cell renal carcinomas. Podolski, J., Huzarski, T., Byrski, T., Tołoczko, A., Wrzecion, S., Sikorski, A., Mahoy, P., Huebner, K., Rabbitts, P., Lubiński, J. Polish journal of pathology : official journal of the Polish Society of Pathologists. (1995) [Pubmed]
  5. Enhanced cardiac vagal efferent activity does not explain training-induced bradycardia. Scott, A.S., Eberhard, A., Ofir, D., Benchetrit, G., Dinh, T.P., Calabrese, P., Lesiuk, V., Perrault, H. Autonomic neuroscience : basic & clinical. (2004) [Pubmed]
  6. Protumorigenic role of HAPLN1 and its IgV domain in malignant pleural mesothelioma. Ivanova, A.V., Goparaju, C.M., Ivanov, S.V., Nonaka, D., Cruz, C., Beck, A., Lonardo, F., Wali, A., Pass, H.I. Clin. Cancer Res. (2009) [Pubmed]
  7. The tandemly repeated sequences of cartilage link protein contain the sites for interaction with hyaluronic acid. Goetinck, P.F., Stirpe, N.S., Tsonis, P.A., Carlone, D. J. Cell Biol. (1987) [Pubmed]
  8. SOX9-dependent and -independent transcriptional regulation of human cartilage link protein. Kou, I., Ikegawa, S. J. Biol. Chem. (2004) [Pubmed]
  9. Refined genetic and physical localization of the Wagner disease (WGN1) locus and the genes CRTL1 and CSPG2 to a 2- to 2.5-cM region of chromosome 5q14.3. Perveen, R., Hart-Holden, N., Dixon, M.J., Wiszniewski, W., Fryer, A.E., Brunner, H.G., Pinkners, A.J., van Beersum, S.E., Black, G.C. Genomics (1999) [Pubmed]
  10. Complete amino acid sequence of human cartilage link protein (CRTL1) deduced from cDNA clones and chromosomal assignment of the gene. Osborne-Lawrence, S.L., Sinclair, A.K., Hicks, R.C., Lacey, S.W., Eddy, R.L., Byers, M.G., Shows, T.B., Duby, A.D. Genomics (1990) [Pubmed]
  11. Link protein is ubiquitously expressed in non-cartilaginous tissues where it enhances and stabilizes the interaction of proteoglycans with hyaluronic acid. Binette, F., Cravens, J., Kahoussi, B., Haudenschild, D.R., Goetinck, P.F. J. Biol. Chem. (1994) [Pubmed]
  12. Link protein can retard the degradation of hyaluronan in proteoglycan aggregates. Rodriguez, E., Roughley, P. Osteoarthr. Cartil. (2006) [Pubmed]
  13. Age-related changes in the composition, the molecular stoichiometry and the stability of proteoglycan aggregates extracted from human articular cartilage. Wells, T., Davidson, C., Mörgelin, M., Bird, J.L., Bayliss, M.T., Dudhia, J. Biochem. J. (2003) [Pubmed]
  14. The link proteins. Neame, P.J., Barry, F.P. Experientia (1993) [Pubmed]
  15. The link proteins. Neame, P.J., Barry, F.P. EXS. (1994) [Pubmed]
  16. Autoimmunity to cartilage link protein in patients with rheumatoid arthritis and ankylosing spondylitis. Guerassimov, A., Zhang, Y., Banerjee, S., Cartman, A., Webber, C., Esdaile, J., Fitzcharles, M.A., Poole, A.R. J. Rheumatol. (1998) [Pubmed]
  17. Distribution of cartilage proteoglycan (aggrecan) core protein and link protein gene expression during human skeletal development. Mundlos, S., Meyer, R., Yamada, Y., Zabel, B. Matrix (1991) [Pubmed]
  18. Three-dimensional cartilage formation by bone marrow-derived cells seeded in polylactide/alginate amalgam. Caterson, E.J., Nesti, L.J., Li, W.J., Danielson, K.G., Albert, T.J., Vaccaro, A.R., Tuan, R.S. J. Biomed. Mater. Res. (2001) [Pubmed]
  19. Humoral immunity to link protein in patients with inflammatory joint disease, osteoarthritis, and in non-arthritic controls. Austin, A.K., Hobbs, R.N., Anderson, J.C., Butler, R.C., Ashton, B.A. Ann. Rheum. Dis. (1988) [Pubmed]
  20. Feasibility of a cost-effective approach to evaluate short tandem repeat markers suitable for chimerism follow-up. Fundia, A.F., De Brasi, C., Larripa, I. Mol. Diagn. (2004) [Pubmed]
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