Paget's Disease

Paget's disease of bone is a medical condition that usually occurs after being 50 years old of age where the patient's bone density mass is decreasing. To increase the bone density mass, the osteoclast activation, which includes Nfr2 receptor, TNFRSF11A activator pathway, and a member of the tumor necrosis factor, needs to be inactive. There have been studies showing that the cytoplasmic and nuclear attachments are presented in the osteoclasts activity of PDB patients. With these attachments, there is a virus in the osteoclasts activity that increases PDB such as bone dysplasia due to an autosomal dominant inheritance. TNFRSF11A is the dominant mutant allele since there is a mutation of the signal peptide. So, PDB is caused by a mutation in the Nfr2 receptor for a growth factor, making it overactive. This is called a gain of function mutation. This leads to signaling that reduces bone growth.

Not only is the Paget's disease for osteoclast activity has autosomal dominant inheritance, the transmission of the mutation in the osteoclast activity of PDB has incomplete penetrance mutation due to environmental factors. Researchers Sparks & Wuyts figured out that there was a duplication of 75-101 bases on exon 1 in the TNFRSF11A gene and there were no mutations detected in PDB1 & PDB2 and on the other PDB family genes 3-8 yet (16 & 17). However, a gene called SQSTM1 is the first gene in the PDB3 region that has 9 mutations causing osteoporosis in patients that was discovered by a British scientist (19). The TNFRSF11B gene has mutations in several of the specific gene regions of the PDB. Researchers Lauren, Brown, and Morisette further discovered out that PDB is linked to the PDB3 and PDB8 genes, which both have a TNFRSF11B gene that has a missense mutation by substituting a lysine for arginine in the 3rd codon of exon 1 (21).

The SQSTMI gene, the long arm of chromosome 5, is the main gene that plays a role in the PDB3 region. It has 2870 nucleotides grouped into 8 exons and it has a co-enzyme ubiquitous that is expressed in tissues. It encodes for p62 protein, which has 440 amino acids from three domains. The three domains have a cysteine-rich base domain, G-protein binding site domain, and two short-lived proteins that are involved with ubiquitin-binding domain. Also, if we have a non-covalent binding interaction between the p62 protein and the ubiquitin binding domain at the C-terminus, then it will reduce the p62 protein. The p62 protein is a ligand to another protein tyrosine kinase, which is adding phosphate group to tyrosine, and is involved in the Nfr2 transcription process that regulates the osteoclast activity.

There are 9 mutations that affect ubiquitin-binding domain encoded by exon 7 and 8. The main mutation in SQSTMI gene for detection of PDB is a Cysteine to Thymine transition at exon 8 and gives us a methylated cytosine. This is a missense mutation because there is substitution of leucine for a proline at position 392 on the exon 8. There is a similar mutation in the CpG nucleotide as well. This P392L mutation is the most common mutation in osteoporosis patients around 46% of Americans. There is another mutation called S399P that has a complex interaction and a modifier effect on the P392L mutation, but this mutation is less severe causing osteoporosis. Johnson-Pais stated that the P392L mutation is found in the PDB2 region than in PDB3 region (26). There are other mutations that affect the ubiquitin-binding domain. There is a frame shift mutation, which is the insertion of base thymine that gives us a stop codon in in exon 8 at position 1224 (E396X). The other mutation (A390X) that affects ubiquitin-binding domain is splicing donor site in intron 7 and gives us a reduced protein of only 390 amino acids instead of 440 amino acids in the SQSTMI gene. There is a mutation (P387) that gives a Cysteine/Thymine transition in exon 7 at position 1200. Also, there are two deletions of cysteine at position 1215 and thymine at position 1210 in exon 8, which gives us the reduced amino-acid protein (L394X). The last four missense mutation on the SQSTM1 gene are S399P, G425R, M404T, and G411S. Overall, these are the nine main mutations of the SQSTMI that affects osteoporosis or the Paget's disease.

There are some consequences of the 9 mutations on the SQSTMI gene. The three SQSTMI mutations (A390X, L394X, and E396X) give us a reduced protein, which is going to lack all parts of the domain such as the main domain ubiquitin binding site. The other 6 missense mutations are P392L, P387L, M404V, G411S, G425R, and S399P, which leads to the production of the inherent protein p62. These mutations increase the inhibition of p62 protein substrate from binding to ubiquitin binding site domain and interfere with the protein-protein interactions. Researchers fail to study why the PDB is central and to show data upon the interactions between viral particles with the mutated p62 protein that increases osteoclast activity.

However, there are many genetic studies detecting PDB by seeing if the SQSTMI gene is mutated. First, scientists test if the most common P392L mutation in exon 8 is presented. If the test is negative, then the scientists take other genetic tests for detecting 8 other mutations in SQSTMI gene. The scientists want to detect for mutations before complications developed for osteoporosis patients. However, negative testing does not take out the rule for diagnosis or other possible mutations that cannot be seen on radiographic findings. The patients that are presented with a mutation or several mutations in the SQSTMI gene have a chance to inform their family to get genetic screening or counseling. However, genetic screening should only be done in adults and not in children before the age of 40 and having severe complications.

If the patient has a mutation in the SQSTMI gene that is genetically inherited, then testing should also be done in the patient's relatives to see if they have an inherited condition that is genetically heterozygous before complications are developed. PDB relatives with a mutation in the SQSTMI gene should have a bone scan for the detection of the disease, serum alkaline phosphatase assays should be done while doing the bone scan, and bisphosphonate drugs and therapy should be prescribed for the osteoporosis patients before the early stages of complications are seen. However, this is a big economic impact of doing the genetic testing on the patient and their relatives for detecting PDB and for buying the bisphosphonate prescribed drugs. In the end, there is not much of a cost and benefit analysis and genetic testing is a malpractice that should be done in a general population.

Michou L, Collet C, Laplanche J, Orcel P, Cornélis F. Genetics of Paget's disease of bone. Joint Bone Spine 2006 5;73(3):243-8.