Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: CILP
Cytogenetic location: 15q22.31 Genomic coordinates (GRCh38) : 15:65,194,760-65,211,473 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q22.31 | {Lumbar disc disease, susceptibility to} | 603932 | 3 |
Major alterations in the composition of the cartilage extracellular matrix occur in joint disease, such as osteoarthrosis (165720). The synthesis of cartilage intermediate layer protein (CILP), which was identified and purified from human articular cartilage (Lorenzo et al., 1998), increases in early osteoarthrosis cartilage. By RT-PCR using human articular cartilage RNA and degenerate primers based on the amino acid sequence of CILP, and by screening a human chondrocyte cDNA library, Lorenzo et al. (1998) isolated CILP cDNAs (GenBank AF035408). Northern blot analysis of human articular cartilage RNA detected a single transcript of approximately 4.2 kb. The deduced 1,184-amino acid protein has a calculated molecular mass of 132.5 kD, whereas biochemical characterization of CILP demonstrated an apparent molecular mass of 92 kD (Lorenzo et al., 1998). Sequence database searches indicated that the C-terminal 460 amino acids of the protein show 90% similarity to the pig ectonucleotide pyrophosphohydrolase NTPPHase; this region is preceded by a furin protease (FUR; 136950) consensus cleavage site. The authors concluded that the encoded protein is a precursor for 2 different proteins, namely CILP and a homolog of NTPPHase. CILP has 30 cysteines, 6 putative N-glycosylation sites, and a type-1 thrombospondin (e.g., 188060)-like repeat, and the homolog of NTPPHase contains 10 cysteine residues and 2 putative N-glycosylation sites. Expression of the full-length cDNA in a cell-free translation system and in COS-7 or EBNA cells indicated that the precursor protein, which contains a putative signal peptide, is synthesized as a single polypeptide chain that is processed into 2 polypeptides upon or preceding secretion. In medium from 293-EBNA cells expressing the full-length cDNA, Lorenzo et al. (1998) detected proteins of 92 kD and 60 kD, among others, using antibodies against CILP and the NTPPHase homolog, respectively.
Johnson et al. (2003) determined that both CILP1 and CILP2 (612419), which share 50.6% amino acid identity, contain a central furin endoprotease consensus cleavage site predicted to cause release of N- and C-terminal peptides. The N-terminal halves of CILP1 and CILP2 contain a thrombospondin type-1 repeat and an immunoglobulin C2-type domain, and the N-terminal half of CILP1 contains a putative aldehyde dehydrogenase (see 100640) cysteine active site and an ATP-binding site not found in CILP2. RT-PCR detected both CILP1 and CILP2 in cultured normal hyaline cartilage articular chondrocytes, but not in osteoblasts, fibroblasts, or vascular smooth muscle cells. Only CILP1 was detected in normal knee meniscal fibrocartilage chondrocytic cells. Western blot analysis showed that bovine knee articular chondrocytes transfected with full-length human CILP1 secreted N- and C-terminal CILP1 fragments with apparent molecular masses of about 60 kD.
Nakamura et al. (1999) determined that the CILP gene comprises 9 exons and spans approximately 15 kb of genomic DNA.
Using FISH, Nakamura et al. (1999) mapped the CILP gene to chromosome 15q22.
Seki et al. (2005) found that CILP is expressed abundantly in intervertebral discs and that its expression increases as degeneration progresses in individuals with lumbar disc disease (see 603932). CILP colocalizes with TGFB1 (190180) in clustering chondrocytes and their territorial matrices in intervertebral discs. CILP inhibited TGFB1-mediated induction of cartilage matrix genes through direct interaction with TGFB1 and inhibition of TGFB1 signaling. Therefore, Seki et al. (2005) concluded that the extracellular matrix protein CILP regulates TGF-beta signaling, and that this regulation has a crucial role in the etiology and pathogenesis of lumbar disc disease.
Johnson et al. (2003) noted that human CILP had been expected to increase inorganic pyrophosphate (PPi) levels via nucleotide pyrophosphatase phosphodiesterase (NPP) activity, since Cilp peptides were associated with NPP activity secreted by porcine articular chondrocytes. However, they showed that neither human CILP1 nor CILP2 exhibited NPP activity. Full-length CILP1 and the CILP1 N-terminal domain blocked the ability of IGF1 (147440) to lower extracellular PPi levels in resting primary bovine chondrocytes. Full-length CILP1 and the CILP1 N-terminal domain inhibited IGF1-stimulated proteoglycan synthesis, IGF1 receptor tyrosine autophosphorylation, and proliferation of bovine chondrocytes.
Using a case-control association study, Seki et al. (2005) identified a functional SNP (I395T; 603489.0001) in the CILP gene that acts as a modulator of susceptibility to lumbar disc disease.
Virtanen et al. (2007) analyzed the I395T SNP and flanking SNPs in the CILP gene in 243 Finnish patients with symptoms of lumbar disc disease and 259 controls, and in 348 Chinese individuals with MRI-defined lumbar disc disease and 343 controls. The authors found no evidence of association in the Finnish or Chinese samples and suggested that the CILP gene is not a major risk factor for symptoms of lumbar disc disease in Caucasians or in the general population.
Through genotyping 30 sequence variants in 20 candidate genes in 188 individuals with lumbar disc disease (see 603932) and 376 controls, Seki et al. (2005) identified a functional SNP in the CILP gene, 1184T-C, resulting in the amino acid change ile395 to thr (I395T), that was significantly associated with the phenotype. They confirmed the association in an additional 279 cases and 278 controls. The susceptibility-associated 1184C allele showed increased binding and inhibition of TGFB1 (190180).
Johnson, K., Farley, D., Hu, S.-I., Terkeltaub, R. One of two chondrocyte-expressed isoforms of cartilage intermediate-layer protein functions as an insulin-like growth factor 1 antagonist. Arthritis Rheum. 48: 1302-1314, 2003. [PubMed: 12746903] [Full Text: https://doi.org/10.1002/art.10927]
Lorenzo, P., Bayliss, M. T., Heinegard, D. A novel cartilage protein (CILP) present in the mid-zone of human articular cartilage increases with age. J. Biol. Chem. 273: 23463-23468, 1998. [PubMed: 9722583] [Full Text: https://doi.org/10.1074/jbc.273.36.23463]
Lorenzo, P., Neame, P., Sommarin, Y., Heinegard, D. Cloning and deduced amino acid sequence of a novel cartilage protein (CILP) identifies a proform including a nucleotide pyrophosphohydrolase. J. Biol. Chem. 273: 23469-23475, 1998. [PubMed: 9722584] [Full Text: https://doi.org/10.1074/jbc.273.36.23469]
Nakamura, I., Okawa, A., Ikegawa, S., Takaoka, K., Nakamura, Y. Genomic organization, mapping, and polymorphisms of the gene encoding human cartilage intermediate layer protein. J. Hum. Genet. 44: 203-205, 1999. [PubMed: 10319588] [Full Text: https://doi.org/10.1007/s100380050143]
Seki, S., Kawaguchi, Y., Chiba, K., Mikami, Y., Kizawa, H., Oya, T., Mio, F., Mori, M., Miyamoto, Y., Masuda, I., Tsunoda, T., Kamata, M., Kubo, T., Toyama, Y., Kimura, T., Nakamura, Y., Ikegawa, S. A functional SNP in CILP, encoding cartilage intermediate layer protein, is associated with susceptibility to lumbar disc disease. Nature Genet. 37: 607-612, 2005. [PubMed: 15864306] [Full Text: https://doi.org/10.1038/ng1557]
Virtanen, I. M., Song, Y. Q., Cheung, K. M. C., Ala-Kokko, L., Karppinen, J., Ho, D. W. H., Luk, K. D. K., Yip, S. P., Leong, J. C. Y., Cheah, K. S. E., Sham, P., Chan, D. Phenotypic and population differences in the association between CILP and lumbar disc disease. (Letter) J. Med. Genet. 44: 285-288, 2007. [PubMed: 17220213] [Full Text: https://doi.org/10.1136/jmg.2006.047076]