The recent identification of novel gene mutations in seven Saudi Arabian children with camptodactyly-arthropathy-coxa vara-pericarditis syndrome has implications beyond the rare autosomal recessive joint condition, as it provides researchers with more pieces to fit into the genetic puzzle of pediatric rheumatic disease, Dr. Matthew Warman of Case Western Reserve University, in Cleveland, said in an interview.
Currently, because camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome mimics juvenile idiopathic arthritis, it is often mistakenly diagnosed and treated as such. However, “the management of the two conditions is very different,” said Amaka C. Offiah, Ph.D., of the Great Ormond Street Hospital for Children in London in an interview. While juvenile idiopathic arthritis is treated with anti-inflammatory medications, often in association with corticosteroids and methotrexate, “CACP does not respond to those therapies because it is not an inflammatory disorder,” she said. The estimated incidence of the syndrome is one case per 1–2 million individuals.
Previously, Dr. Warman and colleagues identified the CACP gene as proteoglycan, or PRG4, which maps to human chromosome 1. The PRG4 gene is switched on in human synovial cells and encodes for lubricin, which is a large, highly glycosylated secreted protein that has been identified as a key joint lubricant.
“Our studies have shown that most patients with CACP syndrome are missing lubricin from their synovial fluid,” said Dr. Warman. The PRG4 mutations in CACP patients suggest not only that inherited lubricin defects could lead to joint damage, he said, “but also that lubricin has an important role in healthy joints.”
In the aforementioned Saudi Arabian study, Anas M. Alazami, Ph.D., and colleagues at the King Faisal Specialist Hospital and Research Centre in Riyadh discovered five novel PRG4 mutations in seven children from four unrelated families (Human Mutation 2006;27:213). The new findings confirm Dr. Warman's observation that CACP may result from a loss of lubricin function.
In addition, “our paper suggests that PRG4 mutations are not uncommon, and that there may be a mutation hot spot within the gene, because each of the four families we examined in this fairly consanguineous population had a distinct mutation,” Dr. Alazami said in an interview.
Perhaps the most important conclusion from the new data “is that CACP syndrome is most likely based on a null phenotype, in other words, no synthesis of PRG4 protein at all,” said Dr. Alazami. This is because all of the mutations published thus far “predict a prematurely truncated protein and because the PRG4 gene appears to be under the control of the nonsense mediated mRNA decay pathway,” he said. “This suggests strongly that missense mutations, or in-frame deletions, may be associated with a less severe phenotype, perhaps one of the more common forms of arthropathy.”
Given that the disorder is associated with a null phenotype, “the obvious potential treatment target would be the injection of active PRG4 protein, or a synthetic substitute, into affected joints,” said Dr. Alazami. “But, from a genetic standpoint, the data are concerned more closely with prevention—in other words, the ability to identify carriers and offer genetic counseling—rather than treatment” at this juncture.
Toward this end, antibodies against lubricin could potentially be used to test synovial fluid from individuals suspected of having the disease for the protein's presence, said Dr. Warman. “The data also suggest that antibodies could be used to look for transient deficiency of lubricin, as might occur when an individual sustains a joint injury that abrades the cartilage surface or has inflammation in the joint that results in degradation of lubricin.”
Because the mounting evidence of the genetic deficiency of lubricin in CACP points to this protein's importance in maintaining human joint function, said Dr. Warman, “we can now ask specific questions about how this protein works within the joint. For example, what other proteins does it interact with? What leads to its synthesis and degradation? What happens if we find a way to replace the protein, for example, through gene therapy or protein replacement therapy? When do we need to give lubricin back to a joint? Can lubricin reverse damage that may have already occurred in the presence of other joint-damaging diseases such as rheumatoid arthritis?”
To begin answering these questions, Dr. Warman and colleagues have genetically engineered mice that lack lubricin and are studying the consequences of this deficiency on joint development. While the joints of the genetically altered mice appear normal in the newborn period, abnormal protein deposits appear on the cartilage surface and underlying superficial zone chondrocytes disappear as the mice age, leading to joint damage.
“In addition to cartilage surface changes and subsequent cartilage deterioration, intimal cells in the synovium surrounding the joint space became hyperplastic, which further contributes to joint failure,” said Dr. Warman. The investigators hypothesize that, in the absence of lubricin, the synovial cells become much more aggressive, potentially invading the cartilage surface, in a process similar to that seen in rheumatoid arthritis, he said.