CHERUBISM – GENETICS AND BIOCHEMICAL PROCESSES
Novel Mutation of the Gene Encoding c-Abl-Binding Protein SH3BP2 Causes Cherubism , American Journal of Medical Genetics 121:37-40, 2003, Lo, Faiyaz-Ul-Haque, Kennedy, Aviv, Tsui & Teebi
This article describes the genetic basis for cherubism. It reviews the recently published findings that mapped cherubism to chromosome band 4p16 and to specific genes. The authors’ examination of genetic material from a Canadian family with cherubism led them to find a new mutation in the SH3BP2 gene. To date, they note that 13 ethnically diverse families with cherubism all show a mutation in a stretch of 6 amino acids on the 9th exon. They argue that cherubism is due to a de novo mutation.
Access Lo.2003
A New Mutation in the SH3BP2 Gene Showing Reduced Penetrance in a Family Associated with Cherubism, Oral Surgery, Oral medicine, Oral Pathology, Oral Radiology, and Endontology 103 (3): 378-381, 2007, Lange, Jan de; van Maarle, Merle C.; Akker, Hans P. van den and Redeker, Egbert J. W.
The authors genetically evaluated an 11 member Turkish family in tandem with a radiographic examination. They found a new amino acid change ( a point mutation) in the SH3BP2 gene, a known cherubism mutation hotspot in 5 members, of which 2 showed no clinical evidence of cherubism. The authors also discuss the theoretical connection between cherubism mutations and development of 2nd and 3rd molars. Unique in this study is a male with the cherubism mutation who exhibited no clinical signs of the disease, contrary to the frequently reported 100% penetrance of cherubism in boys/men.
Access Lange.2007A
The Gene for Cherubism Maps to Chromosome 4p16.3, American Journal of Human Genetics 65:151-157, 1999, Mangion, Jonathan, et al.
This article establishes a linkage between clinical, radiographic and histological evidence of cherubism and the genotyping data of two families in the UK (10 individuals). It locates the gene for cherubism on the 4p16.3 chromosome. Family A also appears in the Southgate article (1998).
Access Mangion.1999
The Gene for Cherubism Maps to Chromosome 4p16, American Journal of Human Genetics 65:158-166, 1999, Tiziani, Valdenize, et. al.
This article establishes a linkage between clinical, radiographic and histological evidence of cherubism and the genotyping data of three Brazilian and 1 German family (15 individuals). It locates the gene for cherubism on the 4p16 chromosome.
Access Tiziani.1999
Mutations in the Gene Encoding c-Abl-Binding Protein SH3BP2 Cause Cherubism, Nature Genetics 28: 125-126, 2001, Ueki, Yasuyoshi, et. al.
The authors studied 15 families: 66 individuals clinically diagnosed with cherubism, 4 “obligate carriers,” and 79 unaffected individuals. Using a linkage and haplotype analysis of 12 families, the authors defined the cherubism locus to a 1.5-megebase interval between D4S127 and D4S115. Sequencing genomic DNA from affected and unaffected family members, they detected point mutations causing amino acid substitutions in the SH3-binding protein SH3BP2 in 12 of the families. The authors conclude that a different genetic mutation other than SH3BP2 causes the cherubism symptoms in the remaining 3 families.
Access Ueki.2001
Jawing about TNF: New Hope for Cherubism, Cell 128, January 12, 2007, Deborah Veis Novack and Roberta Faccio.
This article provides background information about Cherubism. It includes previous research that has been conducted as well as an introduction to some of the most recent and promising research that has been carried out.
Novack and Faccio give some important basics concerning Cherubism: it is a dominantly inherited disease that is the result of a point mutation that codes for a proline to arginine substitution in the Sh3bp2 gene, which in turn results in a mutated Sh3bp2 protein. The protein Sh3pb2 is a scaffold protein, meaning that it is essential to mediating other proteins in a signaling pathway.
The authors summarize “Increased Myeloid Cell Responses to M-CSF and RANKL Cause Bone Loss and Inflammation in SH2BP2 ‘Cherubism’ Mice” written by Yasuyoshi Ueki, et al.. They explain the knock-in mouse experiment as well as the crossing experiments (please see article summary for Ueki et. al) and they give the general findings of the article, but more importantly they explain why the findings are significant:
- The crossing experiments show that myeloid cells, and not lymphocytes, are critical to the expression of the disease. Myeloid cells are cells which are derived from bone marrow, and osteoclasts are derived from the myeloid cells.
- Osteoclasts play a very important role in Cherubism—they are the cells that are responsible for the extensive bone resorption seen in the jaw.
- RANK is an activator protein that sits on the surface of osteoclasts and activates them upon being stimulated by its progenitor, RANKL. RANKL is a tumor necrosis factor (TNF) that is dependant on a number of stimulating and signaling pathways which require further experimentation to determine their exact role.
- Another tumor necrosis factor (TNF-α) is absolutely essential to the activation of the osteoclasts. When mutated mice with Cherubism-like characteristics were with a TNF-α lacking background, the offspring showed no bone loss or inflammation. Novack and Faccio point out that this is an extremely important discovery that needs to be explored further because there are already existing anti-TNF therapies in existence for arthritis patients. Further experimentation is needed to determine if this could potentially be an effective treatment for Cherubism patients. Access Novack.2007
Increased Myeloid Cell Responses to M-CSF and RANKL Cause Bone Loss and Inflammation in SH3BP2 ‘Cherubism’ Mice, Cell 128, 71–83, January 12, 2007, Yasuyoshi Ueki, Chin-Yu Lin, Makoto Senoo, Takeshi Ebihara, Naoki Agata, Masahiro Onji, Yasunori Saheki, Toshihisa Kawai, Padma M. Mukherjee, Ernst Reichenberger, and Bjorn R. Olsen
Previous to this 2007 article, Ueki and others had conducted experiments to determine where the causal mutation of Cherubism occurs. The gene for protein Sh3bp2 was mapped to chromosome 4p (the short arm of chromosome 4). The most common mutation that results in Cherubism in humans is a point mutation, that is, a single letter change in the genetic code, which leads to the amino acid arginine being produced in place of proline. In order to conduct experiments concerning the disease, Ueki et al. introduced the same point mutation into mice. This is referred to as a knock-in mouse experiment. Though the disease does not act in an autosomal dominant manner while in mice, as it does in humans, it still demonstrated some of the key components of Cherubism such as bone loss and inflammation. However, it was not limited to the face and jaw—instead it was spread throughout the skeleton. It is therefore necessary to recognize that the human form of the disease must depend on other factors as well.
To determine the dependence of the disease on different types of cells present, the mutant mice were crossed with mice deficient in Rag-1 (meaning that they had non-functional lymphocytes) and also op-deficient mice (which are lacking in myeloid cells). The disease was only apparent in those that lacked lymphocytes (Rag-1 deficient). This implies that the disease depends on myeloid cells, and not lymphocytes, to function. Osteoclasts are derived from myeloid cells (that is cells that are derived from bone marrow).
Not only did knock-in mice bones showing signs of deterioration, but there was also a marked increase in the number of osteoclasts—multinucleated cells that are responsible for the extensive bone resorption seen in Cherubism patients—in them. The researchers found that mutant mice also had osteoclasts with an increased number of nuclei. They found that when incubated with activators M-CSF and RANKL (M-CSF influences hemopoietic cells like osteoclasts to differentiate while RANKL activates osteoclasts) osteoclasts became even larger with more nuclei, and with less RANKL than is required for wild-type (non-mutant) cultures of osteoclasts. This implies that the mutant osteoclasts will resorb an abnormal amount of bone.
Researchers measured the levels of TNF-α in serum of wild-type and knock-in mice with the Cherubism mutation. Tumor necrosis factor- alpha (TNF-α) is meant to regulate immune cells, however when it is overproduced it has been implicated as the cause of a number of diseases, including cancers. It was found that there was an increased level of TNF-α was found in the serum of those mice that had the Cherubism characteristics. To determine how much TNF-α influences the expression of Cherubism symptoms the researchers crossed the mutant mice with TNF-α null mice—that is mice that lack TNF-α. The result was that all of the offspring were void of the lymph node abnormalities, systemic inflammation, as well as bone loss. Basically all of the symptoms of Cherubism disapated when the TNF-α was removed. This shows that Cherubism is entirely dependent on TNF-α.
It is clear that Cherubism depends on both myeloid cells and TNF-α. More research needs to be done in both areas to better understand their pathways and why it is that they induce the symptoms of Cherubism. This does bring a great deal of hope to people who have Cherubism—anti- TNF-α therapies have the potential to be used as treatment of the disease. Anti- TNF-α therapies have already proved as useful for other bone disorders such as rheumatoid arthritis.
Access Ueki.2007
Adaptor Protein 3BP2 and Cherubism, Current Medicinal Chemistry 15: 549-554, 2008, Hatani, Tomoko and Sada, Kiyonao
The authors synthesize current genetic and microbiological studies on cherubism. They first review the structure and function of 3BP2, identifying the consequences of deletions and mutations in different zones of the gene (PH, PR1, PR2, PR3, SH2). In this section, they summarize the 11 mutations in Arg, Pro, Asp and Gly and one deletion of Arg that researchers have associated with cherubism. The second section describes the physiological function of 3PP2 on T cells, B cells, NK cells and Mast cells. The third and forth sections discuss the “implications of 3BP2 mutations in the pathogenesis of cherubism” and the possibility of intervention in the disease cycle through selective inhibition of 3BP2.
No link available.
Cherubism – New Hypotheses on Pathogenesis and therapeutic Consequences, Journal of Cranio-Maxillofacial Surgery, 33: 61-68, 2005, Hyckel, Peter; Berndt, Alexander; Schleier, Peter; Clement, Joachim; Beensen, Volkmar; Peters, Harmut; Kosmehl, Hartwig
The authors note the close association between clinical aspects of cherubism and tooth formation: (1) the visible development of lesions and the normal development of 2nd and3rd molars; (2) the coincidence of regression with the “conclusion of molar odontogenesis: and (3) the skyward gaze (orbital involvement) and excessive tissue formation associated with highly placed dental germs of 2nd molars at 2-3 years. They hypothesize “the underlying genetic defect of cherubism [ mutations in the SH3BP2 gene] disturbing normal development of these teeth and disregulating the associated bone formation.” Specifically, “SH3BP2- dependent signal transduction chains interact with regulatory pathways temporarily determining jaw morphogenesis.” This hypothesis accounts for the development of large cell granuloma, root resorption and lymph node swelling.
Access Hyckel.2005
Identification of a Novel Mutation of SH3BP2 in Cherubism and Demonstation that SH3PB2 Mutations Lead to increased NFAT Activation, Human Mutation in Brief #904, 2006, Lietman, Steven; Kalinchinko, Natasha; Deng, Xichao; Kohanski, Roland; Levine, Michael A.
No summary.
Access Leitman.2006
SH3PB2 is an Activator of NFAT Activity and Osteoclastogenesis, Biochemical and Biophysical Research Communications. 371: 644-648, 2008, Lietman, Steven; Yin, Lihong; Levine, Michael A.
No summary.
Access Leitman.2008
NFATc1 in mice represses osteoprotegerin during osteoclastogenesis and dissociates systemic osteopenia from inflammation in cherubism, The Journal of Clinical Investigation http://www.jci.org 2008, Allprantis.et. al.
No summary
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