Juvenile Paget's Disease: The Second Reported, Oldest Patient Is Homozygous for the <i>TNFRSF11B</i> “Balkan” Mutation (966_969delTGACinsCTT), Which Elevates Circulating Immunoreactive Osteoprotegerin Levels

Whyte, Michael P.; Singhellakis, P.N.; Petersen, Michael B.; Davies, M.; Totty, William G.; Mumm, Steven

doi:10.1359/jbmr.070307

Cited by 37 publications

(38 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another frameshift mutation (D323FfsX4), resulting in deletion of the HBD, has been reported in a relatively mild juvenile Paget disease patient. (46) RANKL coexpressed with OPG-DHBD mutant tends to accumulate in the Golgi apparatus and is not transported to either lysosomes or the cell surface, as is shown in the experiments using HeLa cells. Considering this, the D323FfsX4 mutation might result in the retention of RANKL in the Golgi apparatus, and the increase in the amount of RANKL transported to the cell surface is rather small compared with that in the case of the D198RfsX7 mutation.…”

Section: Discussionsupporting

confidence: 55%

Function of OPG as a traffic regulator for RANKL is crucial for controlled osteoclastogenesis

Aoki

Honma

Kariya

et al. 2010

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

The amount of the receptor activator of NF-kB ligand (RANKL) on the osteoblastic cell surface is considered to determine the magnitude of the signal input to osteoclast precursors and the degree of osteoclastogenesis. Previously, we have shown that RANKL is localized predominantly in lysosomal organelles, but little is found on the osteoblastic cell surface, and consequently, the regulated subcellular trafficking of RANKL in osteoblastic cells is important for controlled osteoclastogenesis. Here we have examined the involvement of osteoprotegerin (OPG), which is currently recognized as a decoy receptor for RANKL, in the regulation of RANKL behavior. It was suggested that OPG already makes a complex with RANKL in the Golgi apparatus and that the complex formation is necessary for RANKL sorting to the secretory lysosomes. It was also shown that each structural domain of OPG is indispensable for exerting OPG function as a traffic regulator. In particular, the latter domains of OPG, whose physiologic functions have been unclear, were indicated to sort RANKL molecules to lysosomes from the Golgi apparatus. In addition, the overexpression of RANK-OPG chimeric protein, which retained OPG function as a decoy receptor but lost the function as a traffic regulator, inhibited endogenous OPG function as a traffic regulator selectively in osteoblastic cells and resulted in the upregulation of osteoclastogenic ability despite the increased number of decoy receptor molecules. Conclusively, OPG function as a traffic regulator for RANKL is crucial for regulating osteoclastogenesis at least as well as that as a decoy receptor. ß

show abstract

Section: Discussionsupporting

confidence: 55%

Function of OPG as a traffic regulator for RANKL is crucial for controlled osteoclastogenesis

Aoki

Honma

Kariya

et al. 2010

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

show abstract

“…(11) Other JPD1 patients present in childhood with somewhat more mild skeletal disease. (4, 16) This range in JPD expressivity is now understood to reflect the variety of mutations identified within the different functional domains of TNFRSF11B . (13, 38, 39) …”

Section: V) Discussionmentioning

confidence: 99%

“…(13) This OPG deficiency form of JPD uniquely leads to vascular microcalcification (VMC) (14) that perhaps explains carotid aneurysms in childhood (15) and retinopathy with blindness in adult life. (16, 17) A genetic basis for other instances of JPD remains presumptive. (4) …”

Section: Ii) Introductionmentioning

confidence: 99%

Juvenile Paget's disease with heterozygous duplication within TNFRSF11A encoding RANK

Whyte

Tau

McAlister

et al. 2014

Bone

Self Cite

View full text Add to dashboard Cite

Mendelian disorders of RANKL/OPG/RANK signaling feature the extremes of aberrant osteoclastogenesis and cause either osteopetrosis or rapid turnover skeletal disease. The patients with autosomal dominant accelerated bone remodeling have familial expansile osteolysis, early-onset Paget’s disease of bone, expansile skeletal hyperphosphatasia, or panostotic expansile bone disease due to heterozygous 18-, 27-, 15-, and 12-bp insertional duplications, respectively, within exon 1 of TNFRSF11A that encodes the signal peptide of RANK. Juvenile Paget’s disease (JPD), an autosomal recessive disorder, manifests extremely fast skeletal remodeling, and is usually caused by loss-of-function mutations within TNFRSF11B that encodes OPG. These disorders are ultra-rare. A 13-year-old Bolivian girl was referred at age 3 years. One femur was congenitally short and curved. Then, both bowed. Deafness at age 2 years involved missing ossicles and eroded cochleas. Teeth often had absorbed roots, broke, and were lost. Radiographs had revealed acquired tubular bone widening, cortical thickening, and coarse trabeculation. Biochemical markers indicated rapid skeletal turnover. Histopathology showed accelerated remodeling with abundant osteoclasts. JPD was diagnosed. Immobilization from a femur fracture caused severe hypercalcemia that responded rapidly to pamidronate treatment followed by bone turnover marker and radiographic improvement. No TNFRSF11B mutation was found. Instead, a unique heterozygous 15-bp insertional tandem duplication (87dup15) within exon 1 of TNFRSF11A predicted the same pentapeptide extension of RANK that causes expansile skeletal hyperphosphatasia (84dup15). Single nucleotide polymorphisms in TNFRSF11A and TNFRSF11B possibly impacted her phenotype. Our findings: i) reveal that JPD can be associated with an activating mutation within TNFRSF11A, ii) expand the range and overlap of phenotypes among the mendelian disorders of RANK activation, and iii) call for mutation analysis to improve diagnosis, prognostication, recurrence risk assessment, and perhaps treatment selection among the monogenic disorders of RANKL/OPG/RANK activation.

show abstract

“…TNFRSF11B is identified by molecular function of receptor, and it is involved in biological process of developmental processes, skeletal development, and mesoderm development (DAVID). TNFRSF11B's relational study also can be presented in these articles [28][29][30][31][32][33]. NFAT5 is relevant to molecular function of transcription factor, and biological process of nucleoside, nucleotide and nucleic acid metabolism, mRNA transcription, mRNA transcription regulation, signal transduction, immunity and defense, stress response, developmental processes, mesoderm development, cytokine/chemokine mediated immunity (DAVID).…”

Section: Discussionmentioning

confidence: 99%

CREB5 Computational Regulation Network Construction and Analysis Between Frontal Cortex of HIV Encephalitis (HIVE) and HIVE-Control Patients

Wang

Huang

Jiang

2010

Cell Biochem Biophys

View full text Add to dashboard Cite

CREB5 computational regulation network construction and analysis of frontal cortex of HIV encephalitis (HIVE) is very useful to identify novel markers and potential targets for prognosis and therapy. By integration of gene regulatory network infer and the database for annotation, visualization and integrated discovery we identified and constructed significant molecule CREB5 regulation network from 12 frontal cortex of HIVE-control patients and 16 HIVE in the same GEO Dataset GDS1726. Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition), whereas in the upstream of frontal cortex of HIVE (BST2, CFB, LCAT, TNFRSF11B activation; CFHR1, LY96 inhibition) and downstream (GAS1, LCAT, LGALS3BP, NFAT5, VEZF1, ZNF652 activation; DGKG, IFITM1, LY96, TNFRSF11B inhibition). Importantly, we datamined that CREB5 regulation cluster of HIVE was involved in inflammatory response, proteolysis, biological adhesion, and negative regulation of biological process (only in HIVE terms) without positive regulation of cellular process, phosphotransferase, kinase, post-translational protein modification, ATP binding, transmembrane protein, calcium ion binding, acetylation, and hydrolase activity (only in HIVE-control patients terms), the condition was vital to inflammation and cognition impairment of HIVE. Our result demonstrated that common terms in both HIVE-control patients and HIVE included biological regulation, phosphoprotein, metabolic process, zinc, biosynthetic process, organelle, signal transduction, defense response, membrane, secreted, signal peptide, and glycoprotein, and these terms were more relative to inflammation and cognition impairment, therefore we deduced the stronger CREB5 regulation network in HIVE consistent with our number computation. It would be necessary of the stronger CREB5 regulation function to inflammation and cognition impairment of HIVE.

show abstract

Juvenile Paget's Disease: The Second Reported, Oldest Patient Is Homozygous for the TNFRSF11B “Balkan” Mutation (966_969delTGACinsCTT), Which Elevates Circulating Immunoreactive Osteoprotegerin Levels

Cited by 37 publications

References 33 publications

Function of OPG as a traffic regulator for RANKL is crucial for controlled osteoclastogenesis

Function of OPG as a traffic regulator for RANKL is crucial for controlled osteoclastogenesis

Juvenile Paget's disease with heterozygous duplication within TNFRSF11A encoding RANK

CREB5 Computational Regulation Network Construction and Analysis Between Frontal Cortex of HIV Encephalitis (HIVE) and HIVE-Control Patients

Contact Info

Product

Resources

About