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Osteogenesis imperfecta gene identified

CRTAP affects prolyl 3-hydroxylation of fibrillar collagen

By | October 19, 2006

Researchers have identified a new gene linked to osteogenesis imperfecta, according to a report in Cell. Brendan Lee, a Howard Hughes Medical Institute investigator at Baylor College of Medicine, and colleagues report that mutation of CRTAP, an apparently non-enzymatic member of the family of prolyl 3-hydroxylases, causes a recessive form of OI - or brittle bone disease - in mice and humans. "It's a game-changer in a way," said Dan Cohn, director of the Skeletal Genetics Laboratory at Cedars Sinai Medical Center in Los Angeles. "It changes our thinking about the disease and counseling for the disease and testing for the disease." David Rimoin, director of Cedar Sinai's International Skeletal Dysplasia Registry agreed. "It's a whole new paradigm in OI," he told The Scientist. The classical description of OI is an autosomal dominant disease caused by mutations in the genes for type I collagen. About 90% of cases fit that description, with the remaining cases attributed either to germline mosaicism (in which the mutation arises in gametes) or to some currently unidentified autosomal recessive mutation. "It has been hypothesized that [post-translational] modifications should be important in the pathogenesis of these diseases also," said Lee. However, "until now, there have been no genetic mechanisms for these processes attributable to OI." Lee's group stumbled onto CRTAP, which is differentially expressed between hypertrophic and proliferating chondrocytes, in a search for proteins that are involved in skeletal development, he said. Unsure of its function, the team knocked the gene out in mice and found that the animals exhibited "a severe osteoporosis phenotype," with associated loss of 3-hydroxylation at a single amino acid in type I collagen fibers, Lee said. The team noted that CRTAP mapped to the same region of human chromosome 3 as the genetic lesion in a consanguineous Canadian family with recessive OI. An analysis of patients from the family identified several with lesions in the CRTAP locus and concomitant loss of prolyl 3-hydroxylation. A second, unrelated family with a more severe form of the disease was also shown to have defects in CRTAP. Disease severity correlated with protein levels: patients with reduced levels of CRTAP protein had milder disease than did patients with no CRTAP protein. "Finding the human patients was extremely exciting," Lee said. "Often, as a human geneticist, whenever you find a novel disease-causing mechanism or mutation in a gene, it is an insight into how nature works...It was a true eureka moment." Though CRTAP is not catalytically active, it forms a complex with prolyl 3-hydroxylase-1 (P3H1), which is catalytically active. At this month's American Society of Human Genetics national meeting in New Orleans, Joan Marini, chief of the Bone and Extracellular Matrix Branch of the National Institute of Child Health and Human Development, and colleagues presented data showing that mutations in either gene can lead to recessive OI. "We had 10 candidate patients [with recessive OI]," Marini said. "In the case of our screening, this P3H/CRTAP complex accounted for all of them." The identification of a new form of OI could impact both genetic counseling and testing, Cohn said. While classic OI is an autosomal dominant disease, CRTAP- and P3H1-induced OI is recessive. Couples in which both parents are carriers of mutations in either protein thus have a 25% chance of passing that trait on to additional children, as opposed to the relatively low risk of recurrence due to mosaicism in dominant OI, Cohn said. DNA testing should be used in the future to distinguish recessive from dominant OI, Lee said, noting that current clinical biochemical tests used to diagnose OI cannot distinguish CRTAP and type I collagen defects. Therapeutic options could also be affected. Most OI patients are treated with bisphosphonates to strengthen bone, Marini explained. "It's not clear whether defects in the hydroxylation pathway will also be benefited by treatment with these drugs," she said. Future enzyme-replacement or chaperone therapy might work in those cases, Rimoin suggested. Lee's team is now studying the post-translational modification in detail to determine, among other things, whether it serves a structural or regulatory role. In addition, they have begun to explore whether CRTAP, as an accessory protein, can interact with other prolyl hydroxylases and thus affect a wider range of substrates. "Maybe this regulation of prolyl 3-hydroxylase, by the enzyme or other proteins in the pathway, may contribute to connective tissue disease more broadly," Lee said. Meanwhile, Rimoin and his group are searching their skeletal dysplasia registry for all patients with possible recessive forms of the disease "to identify the clinical spectrum associated with this clinical lesion." Jeffrey M. Perkel jperkel@the-scientist.com Links within this article: R. Morello et al., "CRTAP is required for prolyl 3-hydroxylation and mutations cause recessive osteogenesis imperfecta," Cell, 127:291-304, Oct. 20, 2006 http://www.cell.com/content/article/abstract?uid=PIIS0092867406012153&highlight=crtap Brendan Lee http://www.hhmi.org/research/investigators/leebhl_bio.html Dan Cohn http://www.cedars-sinai.edu/3859.html David Rimoin http://www.cedars-sinai.edu/3858.html American Society of Human Genetics www.ashg.org Joan Marini http://nichddirsage.nichd.nih.gov:8080/ar2004/pages/bemb/bemb1.htm W.A. Cabral et al., "Deficiency of prolyl 3-hydroxylase (Leprecan) causes a novel recessive metabolic disorder of bone resembling lethal/severe osteogenesis imperfecta," American Society of Human Genetics annual meeting, New Orleans, LA, Oct. 9-13, 2006, abstract #279. http://www.ashg.org/genetics/ashg06s/index.shtml A.M. Barnes et al., "Recessive lethal form of osteogenesis imperfecta caused by null mutations in CRTAP," American Society of Human Genetics annual meeting, New Orleans, LA, Oct. 9-13, 2006, abstract #280. http://www.ashg.org/genetics/ashg06s/index.shtml J. King, "Genetic Counseling: The Human Side of Science," The Scientist, July 19, 1999 http://www.the-scientist.com/article/display/18651/ S. Bunk, "Chaperones to the Rescue," The Scientist, Nov. 11, 2002 http://www.the-scientist.com/article/display/13368/
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October 19, 2006

The Cell article can be found here:\n\nhttp://www.cell.com/content/article/abstract?uid=PIIS0092867406012153\n\nJeff Perkel
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anonymous poster

Posts: 1

July 31, 2008

I was just told that I may have a new gene mutation for OI. My DNA was tested at the University of Washington and I do have a faulty gene,but it does not fit the typical faulty gene for Type I OI, or any other type of OI. I was told by my endocrynologist that my parents would either need to have their DNA tested, or at least get more family history taken to clarify the results. The other option is to find others with the same faulty gene and basically hope someone will research it. I am looking for answers to why I am always hurt, and no one can ever tell me why. Now I am trying to get the actual results from U of W so I know the excact gene mutation myself, as my endocrynologist did not have the information at the office visit.\nAny information would be appreciated.\nThanks~Laura

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