Incidental Mutation 'R0104:Arhgap5'
ID |
16461 |
Institutional Source |
Beutler Lab
|
Gene Symbol |
Arhgap5
|
Ensembl Gene |
ENSMUSG00000035133 |
Gene Name |
Rho GTPase activating protein 5 |
Synonyms |
p190B, p190-B |
MMRRC Submission |
038390-MU
|
Accession Numbers |
|
Essential gene? |
Essential
(E-score: 1.000)
|
Stock # |
R0104 (G1)
|
Quality Score |
|
Status
|
Validated
|
Chromosome |
12 |
Chromosomal Location |
52550755-52618758 bp(+) (GRCm39) |
Type of Mutation |
missense |
DNA Base Change (assembly) |
A to T
at 52563500 bp (GRCm39)
|
Zygosity |
Heterozygous |
Amino Acid Change |
Aspartic acid to Valine
at position 157
(D157V)
|
Ref Sequence |
ENSEMBL: ENSMUSP00000151809
(fasta)
|
Gene Model |
predicted gene model for transcript(s):
[ENSMUST00000110725]
[ENSMUST00000217820]
[ENSMUST00000219443]
|
AlphaFold |
no structure available at present |
Predicted Effect |
probably damaging
Transcript: ENSMUST00000110725
AA Change: D157V
PolyPhen 2
Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)
|
SMART Domains |
Protein: ENSMUSP00000106353 Gene: ENSMUSG00000035133 AA Change: D157V
Domain | Start | End | E-Value | Type |
Pfam:Ras
|
142 |
248 |
5.3e-7 |
PFAM |
FF
|
269 |
325 |
6.03e-12 |
SMART |
FF
|
367 |
420 |
4.61e-8 |
SMART |
FF
|
427 |
482 |
2.22e-10 |
SMART |
FF
|
483 |
537 |
3.89e-6 |
SMART |
low complexity region
|
1035 |
1053 |
N/A |
INTRINSIC |
low complexity region
|
1224 |
1247 |
N/A |
INTRINSIC |
RhoGAP
|
1273 |
1447 |
1.03e-73 |
SMART |
low complexity region
|
1479 |
1496 |
N/A |
INTRINSIC |
|
Predicted Effect |
probably benign
Transcript: ENSMUST00000217820
|
Predicted Effect |
noncoding transcript
Transcript: ENSMUST00000218755
|
Predicted Effect |
noncoding transcript
Transcript: ENSMUST00000218869
|
Predicted Effect |
probably damaging
Transcript: ENSMUST00000219443
AA Change: D157V
PolyPhen 2
Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)
|
Meta Mutation Damage Score |
0.9592 |
Coding Region Coverage |
- 1x: 75.5%
- 3x: 52.6%
- 10x: 7.5%
- 20x: 3.0%
|
Validation Efficiency |
100% (37/37) |
MGI Phenotype |
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] Rho GTPase activating protein 5 negatively regulates RHO GTPases, a family which may mediate cytoskeleton changes by stimulating the hydrolysis of bound GTP. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008] PHENOTYPE: Homozygotes die at birth, are 30% smaller, do not inflate their lungs, and show a small thymus, abnormal adipocyte differentiation and brain defects in the corpus callosum, anterior commissure and lateral ventricles. Mutant MEFs show impaired adipogenesis but undergo myogenesis in response to IGF-1. [provided by MGI curators]
|
Allele List at MGI |
All alleles(4) : Targeted, knock-out(1) Gene trapped(3)
|
Other mutations in this stock |
Total: 23 list
Gene | Ref | Var | Chr/Loc | Mutation | Predicted Effect | Zygosity |
3100002H09Rik |
C |
A |
4: 124,504,469 (GRCm39) |
A28S |
probably damaging |
Het |
Cfap54 |
G |
T |
10: 92,864,514 (GRCm39) |
H142N |
probably damaging |
Het |
Dpp10 |
A |
T |
1: 123,295,572 (GRCm39) |
M525K |
probably benign |
Het |
Fsip2 |
A |
T |
2: 82,809,317 (GRCm39) |
T1879S |
possibly damaging |
Het |
Gm14129 |
T |
C |
2: 148,773,493 (GRCm39) |
|
noncoding transcript |
Het |
Ighv2-7 |
A |
T |
12: 113,771,088 (GRCm39) |
W66R |
probably damaging |
Het |
Kif11 |
T |
A |
19: 37,401,663 (GRCm39) |
V880D |
probably benign |
Het |
Mcpt1 |
T |
A |
14: 56,256,888 (GRCm39) |
M142K |
possibly damaging |
Het |
Mlst8 |
T |
C |
17: 24,695,091 (GRCm39) |
N264S |
possibly damaging |
Het |
Nmrk1 |
T |
A |
19: 18,618,582 (GRCm39) |
S88R |
probably benign |
Het |
Or14j2 |
T |
A |
17: 37,885,817 (GRCm39) |
I166F |
probably damaging |
Het |
Or8d23 |
A |
G |
9: 38,842,261 (GRCm39) |
S265G |
possibly damaging |
Het |
Rtn1 |
A |
T |
12: 72,355,619 (GRCm39) |
I109N |
probably damaging |
Het |
Slc15a2 |
T |
A |
16: 36,594,997 (GRCm39) |
L156F |
possibly damaging |
Het |
Slc22a21 |
A |
C |
11: 53,842,635 (GRCm39) |
M498R |
probably null |
Het |
Ssc5d |
T |
C |
7: 4,939,285 (GRCm39) |
S574P |
probably benign |
Het |
Taf2 |
T |
C |
15: 54,901,734 (GRCm39) |
D820G |
probably benign |
Het |
Tas2r135 |
A |
T |
6: 42,383,258 (GRCm39) |
I266F |
possibly damaging |
Het |
Trgv4 |
C |
T |
13: 19,369,480 (GRCm39) |
H75Y |
probably damaging |
Het |
Vil1 |
A |
G |
1: 74,457,525 (GRCm39) |
K53E |
probably benign |
Het |
Zfc3h1 |
T |
A |
10: 115,251,192 (GRCm39) |
M1261K |
possibly damaging |
Het |
Zfp655 |
T |
C |
5: 145,180,825 (GRCm39) |
S228P |
probably damaging |
Het |
Zfyve9 |
C |
A |
4: 108,575,360 (GRCm39) |
D574Y |
probably damaging |
Het |
|
Other mutations in Arhgap5 |
Allele | Source | Chr | Coord | Type | Predicted Effect | PPH Score |
IGL00679:Arhgap5
|
APN |
12 |
52,564,064 (GRCm39) |
missense |
probably damaging |
0.98 |
IGL00823:Arhgap5
|
APN |
12 |
52,565,525 (GRCm39) |
missense |
possibly damaging |
0.84 |
IGL01161:Arhgap5
|
APN |
12 |
52,563,643 (GRCm39) |
missense |
probably damaging |
1.00 |
IGL01360:Arhgap5
|
APN |
12 |
52,565,023 (GRCm39) |
missense |
probably damaging |
1.00 |
IGL01910:Arhgap5
|
APN |
12 |
52,563,644 (GRCm39) |
missense |
probably benign |
0.33 |
IGL02417:Arhgap5
|
APN |
12 |
52,565,136 (GRCm39) |
missense |
probably damaging |
0.99 |
IGL02448:Arhgap5
|
APN |
12 |
52,609,123 (GRCm39) |
missense |
probably damaging |
0.97 |
IGL02813:Arhgap5
|
APN |
12 |
52,563,748 (GRCm39) |
missense |
probably benign |
0.20 |
IGL03398:Arhgap5
|
APN |
12 |
52,564,094 (GRCm39) |
missense |
probably damaging |
0.99 |
Decline
|
UTSW |
12 |
52,563,365 (GRCm39) |
nonsense |
probably null |
|
Pass
|
UTSW |
12 |
52,563,290 (GRCm39) |
missense |
possibly damaging |
0.82 |
3-1:Arhgap5
|
UTSW |
12 |
52,565,665 (GRCm39) |
missense |
possibly damaging |
0.54 |
R0039:Arhgap5
|
UTSW |
12 |
52,565,518 (GRCm39) |
nonsense |
probably null |
|
R0088:Arhgap5
|
UTSW |
12 |
52,563,331 (GRCm39) |
missense |
probably damaging |
1.00 |
R0111:Arhgap5
|
UTSW |
12 |
52,606,743 (GRCm39) |
splice site |
probably benign |
|
R0356:Arhgap5
|
UTSW |
12 |
52,563,091 (GRCm39) |
missense |
probably damaging |
1.00 |
R0616:Arhgap5
|
UTSW |
12 |
52,563,848 (GRCm39) |
missense |
possibly damaging |
0.79 |
R0707:Arhgap5
|
UTSW |
12 |
52,564,951 (GRCm39) |
missense |
probably damaging |
1.00 |
R0718:Arhgap5
|
UTSW |
12 |
52,563,290 (GRCm39) |
missense |
possibly damaging |
0.82 |
R0849:Arhgap5
|
UTSW |
12 |
52,566,406 (GRCm39) |
missense |
probably benign |
0.01 |
R0975:Arhgap5
|
UTSW |
12 |
52,563,927 (GRCm39) |
missense |
possibly damaging |
0.61 |
R1326:Arhgap5
|
UTSW |
12 |
52,565,153 (GRCm39) |
missense |
possibly damaging |
0.80 |
R1421:Arhgap5
|
UTSW |
12 |
52,563,631 (GRCm39) |
missense |
probably damaging |
1.00 |
R1422:Arhgap5
|
UTSW |
12 |
52,566,297 (GRCm39) |
missense |
probably damaging |
1.00 |
R1625:Arhgap5
|
UTSW |
12 |
52,564,159 (GRCm39) |
missense |
probably benign |
|
R1711:Arhgap5
|
UTSW |
12 |
52,566,128 (GRCm39) |
missense |
probably damaging |
1.00 |
R1970:Arhgap5
|
UTSW |
12 |
52,589,376 (GRCm39) |
missense |
probably damaging |
1.00 |
R2004:Arhgap5
|
UTSW |
12 |
52,564,817 (GRCm39) |
missense |
probably benign |
0.05 |
R2356:Arhgap5
|
UTSW |
12 |
52,565,930 (GRCm39) |
missense |
probably benign |
0.00 |
R3792:Arhgap5
|
UTSW |
12 |
52,566,671 (GRCm39) |
missense |
probably benign |
0.21 |
R3808:Arhgap5
|
UTSW |
12 |
52,613,970 (GRCm39) |
missense |
possibly damaging |
0.72 |
R4458:Arhgap5
|
UTSW |
12 |
52,564,740 (GRCm39) |
missense |
probably benign |
|
R4703:Arhgap5
|
UTSW |
12 |
52,564,366 (GRCm39) |
missense |
probably damaging |
0.99 |
R4736:Arhgap5
|
UTSW |
12 |
52,565,860 (GRCm39) |
missense |
probably benign |
0.00 |
R4737:Arhgap5
|
UTSW |
12 |
52,565,860 (GRCm39) |
missense |
probably benign |
0.00 |
R4740:Arhgap5
|
UTSW |
12 |
52,565,860 (GRCm39) |
missense |
probably benign |
0.00 |
R4768:Arhgap5
|
UTSW |
12 |
52,604,275 (GRCm39) |
missense |
probably damaging |
1.00 |
R4806:Arhgap5
|
UTSW |
12 |
52,565,486 (GRCm39) |
missense |
probably damaging |
0.99 |
R4817:Arhgap5
|
UTSW |
12 |
52,565,992 (GRCm39) |
missense |
possibly damaging |
0.71 |
R5586:Arhgap5
|
UTSW |
12 |
52,566,695 (GRCm39) |
missense |
possibly damaging |
0.95 |
R5681:Arhgap5
|
UTSW |
12 |
52,566,562 (GRCm39) |
missense |
probably benign |
0.21 |
R5683:Arhgap5
|
UTSW |
12 |
52,566,369 (GRCm39) |
missense |
probably benign |
|
R5911:Arhgap5
|
UTSW |
12 |
52,565,525 (GRCm39) |
missense |
possibly damaging |
0.84 |
R6448:Arhgap5
|
UTSW |
12 |
52,564,446 (GRCm39) |
missense |
probably benign |
0.11 |
R6887:Arhgap5
|
UTSW |
12 |
52,565,927 (GRCm39) |
missense |
probably benign |
|
R6988:Arhgap5
|
UTSW |
12 |
52,564,908 (GRCm39) |
missense |
possibly damaging |
0.94 |
R7009:Arhgap5
|
UTSW |
12 |
52,566,422 (GRCm39) |
missense |
probably benign |
0.03 |
R7013:Arhgap5
|
UTSW |
12 |
52,565,109 (GRCm39) |
missense |
probably benign |
0.05 |
R7239:Arhgap5
|
UTSW |
12 |
52,564,159 (GRCm39) |
missense |
probably benign |
|
R7310:Arhgap5
|
UTSW |
12 |
52,589,270 (GRCm39) |
critical splice acceptor site |
probably null |
|
R7339:Arhgap5
|
UTSW |
12 |
52,564,481 (GRCm39) |
missense |
possibly damaging |
0.64 |
R7375:Arhgap5
|
UTSW |
12 |
52,563,365 (GRCm39) |
nonsense |
probably null |
|
R7421:Arhgap5
|
UTSW |
12 |
52,564,783 (GRCm39) |
missense |
probably benign |
0.42 |
R7442:Arhgap5
|
UTSW |
12 |
52,563,739 (GRCm39) |
missense |
probably benign |
0.25 |
R7842:Arhgap5
|
UTSW |
12 |
52,565,480 (GRCm39) |
missense |
possibly damaging |
0.78 |
R8079:Arhgap5
|
UTSW |
12 |
52,613,988 (GRCm39) |
missense |
probably benign |
|
R8241:Arhgap5
|
UTSW |
12 |
52,565,098 (GRCm39) |
missense |
probably benign |
0.00 |
R8419:Arhgap5
|
UTSW |
12 |
52,565,572 (GRCm39) |
missense |
probably damaging |
1.00 |
R9138:Arhgap5
|
UTSW |
12 |
52,609,146 (GRCm39) |
missense |
probably benign |
0.05 |
X0018:Arhgap5
|
UTSW |
12 |
52,565,180 (GRCm39) |
missense |
probably damaging |
1.00 |
Z1176:Arhgap5
|
UTSW |
12 |
52,565,246 (GRCm39) |
missense |
possibly damaging |
0.94 |
|
Nature of Mutation |
Two transcripts of the Arhgap5 gene are displayed on Ensembl.
|
Protein Function and Prediction |
The Arhgap5 gene encodes a 1503 amino acid GTPase-activating protein for Rho family members. The protein contains 4 FF domains, and a Rho-GAP domain at residues 1261-1448 (Uniprot P97393). Arhgap5 (alternatively, p190B) is a cytosolic Rho family GTPase-activating protein that is co-localized with the alpha 5 beta 1 integrin receptor for fibronectin in fibrillar patterns (1;2). P190B functions to regulate actin stress fiber dynamics through the hydrolysis of Rho-GTP (2-4). Through its function in hydrolyzing Rho-GTP, p190B also regulates cell cycle progression (3). The GAP domain is crucial for the regulation of actin cytoskeletal rearrangements in axonal pathfinding and stability (5-8) and in response to integrin engagement (9;10), growth factor stimulation (4), and v-Src transformation (11). When p190B heterozygous mice mated to a MMTV-Neu breast cancer model, tumor penetrance was reduced and tumor onset was delayed (12). Further studies determined that p190B regulates chromosome segregation and apoptosis in cancer cells (13).
|
Expression/Localization |
p190B localizes to centrosomes during interphase and mitosis (13).
|
Background |
Arhgap5tm1Jset/tm1Jset; MGI:2179998
involves: 129S2/SvPas * C57BL/6J
Homozygotes die at birth, are 30% smaller, do not inflate their lungs, and show a small thymus, abnormal adipocyte differentiation and brain defects in the corpus callosum, anterior commissure and lateral ventricles (14). Mutant MEFs show impaired adipogenesis but undergo myogenesis in response to IGF-1 (14). Also depletion in Arhgap5 leads to decreased incidence of mammary ductal morphogenesis (15).
|
References |
1. Burbelo, P. D., Miyamoto, S., Utani, A., Brill, S., Yamada, K. M., Hall, A., and Yamada, Y. (1995) P190-B, a New Member of the Rho GAP Family, and Rho are Induced to Cluster After Integrin Cross-Linking. J Biol Chem. 270, 30919-30926.
2. Ridley, A. J., Self, A. J., Kasmi, F., Paterson, H. F., Hall, A., Marshall, C. J., and Ellis, C. (1993) Rho Family GTPase Activating Proteins p190, Bcr and rhoGAP show Distinct Specificities in Vitro and in Vivo. EMBO J. 12, 5151-5160.
4. Chang, J. H., Gill, S., Settleman, J., and Parsons, S. J. (1995) C-Src Regulates the Simultaneous Rearrangement of Actin Cytoskeleton, p190RhoGAP, and p120RasGAP Following Epidermal Growth Factor Stimulation. J Cell Biol. 130, 355-368.
5. Brouns, M. R., Matheson, S. F., Hu, K. Q., Delalle, I., Caviness, V. S., Silver, J., Bronson, R. T., and Settleman, J. (2000) The Adhesion Signaling Molecule p190 RhoGAP is Required for Morphogenetic Processes in Neural Development. Development. 127, 4891-4903.
7. Billuart, P., Winter, C. G., Maresh, A., Zhao, X., and Luo, L. (2001) Regulating Axon Branch Stability: The Role of p190 RhoGAP in Repressing a Retraction Signaling Pathway. Cell. 107, 195-207.
10. Nakahara, H., Mueller, S. C., Nomizu, M., Yamada, Y., Yeh, Y., and Chen, W. T. (1998) Activation of beta1 Integrin Signaling Stimulates Tyrosine Phosphorylation of p190RhoGAP and Membrane-Protrusive Activities at Invadopodia. J Biol Chem. 273, 9-12.
12. Heckman-Stoddard, B. M., Vargo-Gogola, T., McHenry, P. R., Jiang, V., Herrick, M. P., Hilsenbeck, S. G., Settleman, J., and Rosen, J. M. (2009) Haploinsufficiency for p190B RhoGAP Inhibits MMTV-Neu Tumor Progression. Breast Cancer Res. 11, R61.
13. Hwang, M., Peddibhotla, S., McHenry, P., Chang, P., Yochum, Z., Park, K. U., Sears, J. C., and Vargo-Gogola, T. (2012) P190B RhoGAP Regulates Chromosome Segregation in Cancer Cells. Cancers (Basel). 4, 475-489.
14. Sordella, R., Classon, M., Hu, K. Q., Matheson, S. F., Brouns, M. R., Fine, B., Zhang, L., Takami, H., Yamada, Y., and Settleman, J. (2002) Modulation of CREB Activity by the Rho GTPase Regulates Cell and Organism Size during Mouse Embryonic Development. Dev Cell. 2, 553-565.
15. Chakravarty, G., Hadsell, D., Buitrago, W., Settleman, J., and Rosen, J. M. (2003) P190-B RhoGAP Regulates Mammary Ductal Morphogenesis. Mol Endocrinol. 17, 1054-1065.
|
Posted On |
2013-01-20 |
Science Writer |
Anne Murray |