Incidental Mutation 'P0012:Tnfrsf11b'
ID |
7544 |
Institutional Source |
Beutler Lab
|
Gene Symbol |
Tnfrsf11b
|
Ensembl Gene |
ENSMUSG00000063727 |
Gene Name |
tumor necrosis factor receptor superfamily, member 11b (osteoprotegerin) |
Synonyms |
OPG, OCIF, TR1, osteoclastogenesis inhibitory factor, Opg |
MMRRC Submission |
038266-MU
|
Accession Numbers |
|
Essential gene? |
Probably non essential
(E-score: 0.133)
|
Stock # |
P0012 (G1)
|
Quality Score |
|
Status
|
Validated
|
Chromosome |
15 |
Chromosomal Location |
54114014-54141700 bp(-) (GRCm39) |
Type of Mutation |
splice site |
DNA Base Change (assembly) |
A to G
at 54123194 bp (GRCm39)
|
Zygosity |
Heterozygous |
Amino Acid Change |
|
Ref Sequence |
ENSEMBL: ENSMUSP00000078705
(fasta)
|
Gene Model |
predicted gene model for transcript(s):
[ENSMUST00000079772]
|
AlphaFold |
O08712 |
PDB Structure |
Crystal structure of mouse RANKL-OPG complex [X-RAY DIFFRACTION]
|
Predicted Effect |
probably benign
Transcript: ENSMUST00000079772
|
SMART Domains |
Protein: ENSMUSP00000078705 Gene: ENSMUSG00000063727
Domain | Start | End | E-Value | Type |
signal peptide
|
1 |
21 |
N/A |
INTRINSIC |
TNFR
|
24 |
62 |
1.04e-2 |
SMART |
TNFR
|
65 |
105 |
1.5e-8 |
SMART |
TNFR
|
107 |
142 |
2.19e-10 |
SMART |
TNFR
|
145 |
185 |
7.63e-1 |
SMART |
DEATH
|
270 |
365 |
1.01e-9 |
SMART |
|
Coding Region Coverage |
- 1x: 85.5%
- 3x: 81.0%
- 10x: 67.7%
- 20x: 52.2%
|
Validation Efficiency |
85% (579/685) |
MGI Phenotype |
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] The protein encoded by this gene is a member of the TNF-receptor superfamily. This protein is an osteoblast-secreted decoy receptor that functions as a negative regulator of bone resorption. This protein specifically binds to its ligand, osteoprotegerin ligand, both of which are key extracellular regulators of osteoclast development. Studies of the mouse counterpart also suggest that this protein and its ligand play a role in lymph-node organogenesis and vascular calcification. Alternatively spliced transcript variants of this gene have been reported, but their full length nature has not been determined. [provided by RefSeq, Jul 2008] PHENOTYPE: Homozygote null mice have abnormal bone remodeling that results in severe osteoperosis with increased risk of fractures and growth retardation. Progressive hearing loss also results due to abnormal remodeling of the otic capsule. [provided by MGI curators]
|
Allele List at MGI |
All alleles(4) : Targeted(4)
|
Other mutations in this stock |
Total: 9 list
Gene | Ref | Var | Chr/Loc | Mutation | Predicted Effect | Zygosity |
Adamtsl3 |
A |
C |
7: 82,223,465 (GRCm39) |
N156T |
probably benign |
Het |
Akap3 |
T |
C |
6: 126,841,564 (GRCm39) |
F61S |
possibly damaging |
Het |
Arhgap1 |
T |
C |
2: 91,500,608 (GRCm39) |
V379A |
probably benign |
Het |
Ces1h |
T |
C |
8: 94,080,138 (GRCm39) |
K459E |
unknown |
Het |
Fbn1 |
T |
C |
2: 125,211,241 (GRCm39) |
|
probably benign |
Het |
Hrh2 |
T |
C |
13: 54,368,447 (GRCm39) |
F141S |
probably benign |
Het |
Igkv3-4 |
A |
T |
6: 70,649,231 (GRCm39) |
N77Y |
probably benign |
Het |
Nup205 |
T |
C |
6: 35,173,478 (GRCm39) |
M496T |
possibly damaging |
Het |
Tas2r124 |
T |
C |
6: 132,732,503 (GRCm39) |
Y271H |
possibly damaging |
Het |
|
Other mutations in Tnfrsf11b |
Allele | Source | Chr | Coord | Type | Predicted Effect | PPH Score |
IGL00094:Tnfrsf11b
|
APN |
15 |
54,123,238 (GRCm39) |
missense |
probably damaging |
1.00 |
IGL00770:Tnfrsf11b
|
APN |
15 |
54,117,468 (GRCm39) |
missense |
probably benign |
0.16 |
IGL00774:Tnfrsf11b
|
APN |
15 |
54,117,468 (GRCm39) |
missense |
probably benign |
0.16 |
IGL02355:Tnfrsf11b
|
APN |
15 |
54,115,778 (GRCm39) |
missense |
probably damaging |
0.96 |
IGL02362:Tnfrsf11b
|
APN |
15 |
54,115,778 (GRCm39) |
missense |
probably damaging |
0.96 |
IGL02711:Tnfrsf11b
|
APN |
15 |
54,119,532 (GRCm39) |
missense |
probably benign |
0.01 |
IGL02870:Tnfrsf11b
|
APN |
15 |
54,119,423 (GRCm39) |
missense |
probably benign |
0.05 |
IGL03219:Tnfrsf11b
|
APN |
15 |
54,117,574 (GRCm39) |
nonsense |
probably null |
|
R1550:Tnfrsf11b
|
UTSW |
15 |
54,117,454 (GRCm39) |
missense |
possibly damaging |
0.94 |
R1813:Tnfrsf11b
|
UTSW |
15 |
54,119,493 (GRCm39) |
nonsense |
probably null |
|
R3840:Tnfrsf11b
|
UTSW |
15 |
54,115,478 (GRCm39) |
missense |
probably damaging |
0.99 |
R3910:Tnfrsf11b
|
UTSW |
15 |
54,119,578 (GRCm39) |
splice site |
probably benign |
|
R3911:Tnfrsf11b
|
UTSW |
15 |
54,119,578 (GRCm39) |
splice site |
probably benign |
|
R3912:Tnfrsf11b
|
UTSW |
15 |
54,119,578 (GRCm39) |
splice site |
probably benign |
|
R4299:Tnfrsf11b
|
UTSW |
15 |
54,115,491 (GRCm39) |
missense |
probably benign |
|
R4362:Tnfrsf11b
|
UTSW |
15 |
54,119,555 (GRCm39) |
missense |
possibly damaging |
0.94 |
R4363:Tnfrsf11b
|
UTSW |
15 |
54,119,555 (GRCm39) |
missense |
possibly damaging |
0.94 |
R5288:Tnfrsf11b
|
UTSW |
15 |
54,141,622 (GRCm39) |
missense |
probably benign |
0.00 |
R5653:Tnfrsf11b
|
UTSW |
15 |
54,123,262 (GRCm39) |
missense |
probably damaging |
1.00 |
R5753:Tnfrsf11b
|
UTSW |
15 |
54,117,455 (GRCm39) |
missense |
possibly damaging |
0.90 |
R6881:Tnfrsf11b
|
UTSW |
15 |
54,117,539 (GRCm39) |
missense |
probably benign |
0.00 |
R6997:Tnfrsf11b
|
UTSW |
15 |
54,115,770 (GRCm39) |
missense |
probably damaging |
0.99 |
R7704:Tnfrsf11b
|
UTSW |
15 |
54,123,497 (GRCm39) |
missense |
probably benign |
0.30 |
R7730:Tnfrsf11b
|
UTSW |
15 |
54,117,470 (GRCm39) |
nonsense |
probably null |
|
R8017:Tnfrsf11b
|
UTSW |
15 |
54,117,598 (GRCm39) |
nonsense |
probably null |
|
R8052:Tnfrsf11b
|
UTSW |
15 |
54,115,502 (GRCm39) |
missense |
probably damaging |
1.00 |
R8060:Tnfrsf11b
|
UTSW |
15 |
54,117,505 (GRCm39) |
missense |
probably benign |
0.38 |
R8711:Tnfrsf11b
|
UTSW |
15 |
54,123,508 (GRCm39) |
missense |
possibly damaging |
0.81 |
R9224:Tnfrsf11b
|
UTSW |
15 |
54,115,556 (GRCm39) |
missense |
possibly damaging |
0.67 |
X0025:Tnfrsf11b
|
UTSW |
15 |
54,141,631 (GRCm39) |
missense |
probably benign |
0.22 |
|
Protein Function and Prediction |
Tumor necrosis factor receptor superfamily, member 11b [Tnfrsf11b; alternatively, osteoprotegerin (OPG) or osteoclastogenesis inhibitory factor (OCIF)], is a secreted protein that regulates bone resorption (1;2). It was determined that OPG regulates bone mass, osteoclast differentiation, inhibits the activation of mature osteoclasts, and stimulates osteoclast apoptosis (1).
|
Background |
Mutations in TNFRSF11B cause juvenile Paget disease (OMIM: #239000), an osteopathic disorder that is characterized by rapidly remodeling woven bone, osteopenia, fractures, and progressive skeletal deformity [(3-5) and OMIM: *602643)].
Tnfrsf11btm1Eac/tm1Eac; MGI:2179712
involves: 129S4/SvJaeSor
These mice exhibit fractured diaphyses of long bones often seen in older mice, increased outer diameter of long bones (6). These mice also have defective pro-B cell to pre-B cell transition, increased proliferative response to IL-7, increased number of peripheral B cells, and enhanced ability to stimulate T-cell proliferation (6).
Tnfrsf11btm1Khs/tm1Khs; MGI:2181227
B6.129P2-Tnfrsf11btm1Khs
This model has abnormal inner ear morphology and homozygotes display abnormal bone remodeling within the otic capsule with multiple foci showing osteoclastic bone resorption and formation of new bone, not observed in C57BL/6 control mice (7). These mice also have decreased brainstem auditory evoked potential and increased susceptibility to age-related hearing loss (7).
Tnfrsf11btm1Khs/tm1Khs; MGI:2181227
involves: 129P2/OlaHsd * C57BL/6
This model exhibits partial postnatal lethality and postnatal growth retardation (8) These animals also have abnormal bone structure, thinning in all three middle ear ossicles, and thinning of the incus body and the manubrium and processus brevis of the malleus (9). The animals have abnormal osteoclast differentiation and decreased bone mineral density (8;9). The animals also have increased osteoclast cell numbers in the metaphyseal region (10).
Tnfrsf11btm1Wss/tm1Wss; MGI:2183229
either: (involves: 129X1/SvJ * C57BL/6) or (involves: 129X1/SvJ * Black Swiss)
Approximately 15% of mice die prior to weaning likely from vertebral or endochondral bone fractures (11). The parietal bones of the skull are thin and have increased porosity (11). These mice exhibit decreased bone mineral density and osteoporotic by 1-2 months (11). The large arteries, including the aorta and in the kidney, exhibit some calcification as early as 2 weeks after birth and marked calcification by 2 months of age (11).
|
References |
1. Simonet, W. S., Lacey, D. L., Dunstan, C. R., Kelley, M., Chang, M. S., Luthy, R., Nguyen, H. Q., Wooden, S., Bennett, L., Boone, T., Shimamoto, G., DeRose, M., Elliott, R., Colombero, A., Tan, H. L., Trail, G., Sullivan, J., Davy, E., Bucay, N., Renshaw-Gegg, L., Hughes, T. M., Hill, D., Pattison, W., Campbell, P., Sander, S., Van, G., Tarpley, J., Derby, P., Lee, R., and Boyle, W. J. (1997) Osteoprotegerin: A Novel Secreted Protein Involved in the Regulation of Bone Density. Cell. 89, 309-319.
2. Yasuda, H., Shima, N., Nakagawa, N., Mochizuki, S. I., Yano, K., Fujise, N., Sato, Y., Goto, M., Yamaguchi, K., Kuriyama, M., Kanno, T., Murakami, A., Tsuda, E., Morinaga, T., and Higashio, K. (1998) Identity of Osteoclastogenesis Inhibitory Factor (OCIF) and Osteoprotegerin (OPG): A Mechanism by which OPG/OCIF Inhibits Osteoclastogenesis in Vitro. Endocrinology. 139, 1329-1337.
3. Whyte, M. P., Obrecht, S. E., Finnegan, P. M., Jones, J. L., Podgornik, M. N., McAlister, W. H., and Mumm, S. (2002) Osteoprotegerin Deficiency and Juvenile Paget's Disease. N Engl J Med. 347, 175-184.
4. Cundy, T., Hegde, M., Naot, D., Chong, B., King, A., Wallace, R., Mulley, J., Love, D. R., Seidel, J., Fawkner, M., Banovic, T., Callon, K. E., Grey, A. B., Reid, I. R., Middleton-Hardie, C. A., and Cornish, J. (2002) A Mutation in the Gene TNFRSF11B Encoding Osteoprotegerin Causes an Idiopathic Hyperphosphatasia Phenotype. Hum Mol Genet. 11, 2119-2127.
5. Chong, B., Hegde, M., Fawkner, M., Simonet, S., Cassinelli, H., Coker, M., Kanis, J., Seidel, J., Tau, C., Tuysuz, B., Yuksel, B., Love, D., and International Hyperphosphatasia Collaborative Group. (2003) Idiopathic Hyperphosphatasia and TNFRSF11B Mutations: Relationships between Phenotype and Genotype. J Bone Miner Res. 18, 2095-2104.
6. Yun, T. J., Tallquist, M. D., Aicher, A., Rafferty, K. L., Marshall, A. J., Moon, J. J., Ewings, M. E., Mohaupt, M., Herring, S. W., and Clark, E. A. (2001) Osteoprotegerin, a Crucial Regulator of Bone Metabolism, also Regulates B Cell Development and Function. J Immunol. 166, 1482-1491.
7. Zehnder, A. F., Kristiansen, A. G., Adams, J. C., Kujawa, S. G., Merchant, S. N., and McKenna, M. J. (2006) Osteoprotegrin Knockout Mice Demonstrate Abnormal Remodeling of the Otic Capsule and Progressive Hearing Loss. Laryngoscope. 116, 201-206.
8. Mizuno, A., Amizuka, N., Irie, K., Murakami, A., Fujise, N., Kanno, T., Sato, Y., Nakagawa, N., Yasuda, H., Mochizuki, S., Gomibuchi, T., Yano, K., Shima, N., Washida, N., Tsuda, E., Morinaga, T., Higashio, K., and Ozawa, H. (1998) Severe Osteoporosis in Mice Lacking Osteoclastogenesis Inhibitory factor/osteoprotegerin. Biochem Biophys Res Commun. 247, 610-615.
9. Kanzaki, S., Ito, M., Takada, Y., Ogawa, K., and Matsuo, K. (2006) Resorption of Auditory Ossicles and Hearing Loss in Mice Lacking Osteoprotegerin. Bone. 39, 414-419.
10. Yamashita, T., Okada, S., Higashio, K., Nabeshima, Y., and Noda, M. (2002) Double Mutations in Klotho and Osteoprotegerin Gene Loci Rescued Osteopetrotic Phenotype. Endocrinology. 143, 4711-4717.
11. Bucay, N., Sarosi, I., Dunstan, C. R., Morony, S., Tarpley, J., Capparelli, C., Scully, S., Tan, H. L., Xu, W., Lacey, D. L., Boyle, W. J., and Simonet, W. S. (1998) Osteoprotegerin-Deficient Mice Develop Early Onset Osteoporosis and Arterial Calcification. Genes Dev. 12, 1260-1268.
|
Posted On |
2012-10-04 |
Science Writer |
Anne Murray |