Incidental Mutation 'P0042:Inpp5b'
| ID |
7782 |
| Institutional Source |
Beutler Lab
|
| Gene Symbol |
Inpp5b
|
| Ensembl Gene |
ENSMUSG00000028894 |
| Gene Name |
inositol polyphosphate-5-phosphatase B |
| Synonyms |
75kDa |
| MMRRC Submission |
038290-MU
|
| Accession Numbers |
|
| Essential gene? |
Probably non essential
(E-score: 0.175)
|
| Stock # |
P0042 (G1)
|
| Quality Score |
|
|
Status
|
Validated
|
| Chromosome |
4 |
| Chromosomal Location |
124635643-124695304 bp(+) (GRCm39) |
| Type of Mutation |
critical splice donor site (1 bp from exon) |
| DNA Base Change (assembly) |
G to A
at 124691703 bp (GRCm39)
|
| Zygosity |
Heterozygous |
| Amino Acid Change |
|
| Ref Sequence |
ENSEMBL: ENSMUSP00000092375
(fasta)
|
| Gene Model |
predicted gene model for transcript(s):
[ENSMUST00000030723]
[ENSMUST00000094782]
[ENSMUST00000094782]
[ENSMUST00000106193]
[ENSMUST00000138807]
[ENSMUST00000184454]
[ENSMUST00000175875]
|
| AlphaFold |
Q8K337 |
| PDB Structure |
A PH domain within OCRL bridges clathrin mediated membrane trafficking to phosphoinositide metabolism [SOLUTION NMR]
|
| Predicted Effect |
probably benign
Transcript: ENSMUST00000030723
|
| SMART Domains |
Protein: ENSMUSP00000030723
Gene: ENSMUSG00000028890
| Domain | Start | End | E-Value | Type |
|---|
|
ZnF_C2H2
|
139 |
163 |
1.22e-4 |
SMART |
|
ZnF_C2H2
|
169 |
193 |
6.42e-4 |
SMART |
|
ZnF_C2H2
|
199 |
223 |
2.4e-3 |
SMART |
|
ZnF_C2H2
|
228 |
252 |
2.57e-3 |
SMART |
|
ZnF_C2H2
|
258 |
282 |
2.57e-3 |
SMART |
|
ZnF_C2H2
|
288 |
312 |
7.37e-4 |
SMART |
|
low complexity region
|
429 |
456 |
N/A |
INTRINSIC |
|
low complexity region
|
500 |
526 |
N/A |
INTRINSIC |
|
low complexity region
|
545 |
558 |
N/A |
INTRINSIC |
|
low complexity region
|
628 |
638 |
N/A |
INTRINSIC |
|
low complexity region
|
656 |
669 |
N/A |
INTRINSIC |
|
| Predicted Effect |
probably null
Transcript: ENSMUST00000094782
|
| SMART Domains |
Protein: ENSMUSP00000092375
Gene: ENSMUSG00000028894
| Domain | Start | End | E-Value | Type |
|---|
|
Pfam:INPP5B_PH
|
1 |
150 |
4.3e-61 |
PFAM |
|
low complexity region
|
206 |
220 |
N/A |
INTRINSIC |
|
IPPc
|
343 |
644 |
6.29e-126 |
SMART |
|
Blast:RhoGAP
|
706 |
732 |
1e-7 |
BLAST |
|
Blast:RhoGAP
|
755 |
809 |
2e-24 |
BLAST |
|
RhoGAP
|
827 |
993 |
6.77e-37 |
SMART |
|
| Predicted Effect |
probably null
Transcript: ENSMUST00000094782
|
| SMART Domains |
Protein: ENSMUSP00000092375
Gene: ENSMUSG00000028894
| Domain | Start | End | E-Value | Type |
|---|
|
Pfam:INPP5B_PH
|
1 |
150 |
4.3e-61 |
PFAM |
|
low complexity region
|
206 |
220 |
N/A |
INTRINSIC |
|
IPPc
|
343 |
644 |
6.29e-126 |
SMART |
|
Blast:RhoGAP
|
706 |
732 |
1e-7 |
BLAST |
|
Blast:RhoGAP
|
755 |
809 |
2e-24 |
BLAST |
|
RhoGAP
|
827 |
993 |
6.77e-37 |
SMART |
|
| Predicted Effect |
probably benign
Transcript: ENSMUST00000106193
|
| SMART Domains |
Protein: ENSMUSP00000101799
Gene: ENSMUSG00000028890
| Domain | Start | End | E-Value | Type |
|---|
|
ZnF_C2H2
|
139 |
163 |
1.22e-4 |
SMART |
|
ZnF_C2H2
|
169 |
193 |
6.42e-4 |
SMART |
|
ZnF_C2H2
|
199 |
223 |
2.4e-3 |
SMART |
|
ZnF_C2H2
|
228 |
252 |
2.57e-3 |
SMART |
|
ZnF_C2H2
|
258 |
282 |
2.57e-3 |
SMART |
|
ZnF_C2H2
|
288 |
312 |
7.37e-4 |
SMART |
|
low complexity region
|
429 |
456 |
N/A |
INTRINSIC |
|
low complexity region
|
500 |
526 |
N/A |
INTRINSIC |
|
low complexity region
|
545 |
558 |
N/A |
INTRINSIC |
|
low complexity region
|
628 |
638 |
N/A |
INTRINSIC |
|
low complexity region
|
656 |
669 |
N/A |
INTRINSIC |
|
| Predicted Effect |
noncoding transcript
Transcript: ENSMUST00000135971
|
| Predicted Effect |
probably benign
Transcript: ENSMUST00000138807
|
| Predicted Effect |
noncoding transcript
Transcript: ENSMUST00000142446
|
| Predicted Effect |
noncoding transcript
Transcript: ENSMUST00000147452
|
| Predicted Effect |
probably benign
Transcript: ENSMUST00000184454
|
| SMART Domains |
Protein: ENSMUSP00000139221
Gene: ENSMUSG00000028894
| Domain | Start | End | E-Value | Type |
|---|
|
PDB:2KIG|A
|
1 |
156 |
1e-105 |
PDB |
|
low complexity region
|
206 |
220 |
N/A |
INTRINSIC |
|
IPPc
|
343 |
644 |
6.29e-126 |
SMART |
|
PDB:3QBT|H
|
645 |
782 |
6e-49 |
PDB |
|
| Predicted Effect |
probably benign
Transcript: ENSMUST00000175875
|
| Meta Mutation Damage Score |
0.9587 |
| Coding Region Coverage |
- 1x: 81.5%
- 3x: 74.4%
- 10x: 52.2%
- 20x: 29.5%
|
| Validation Efficiency |
88% (87/99) |
| MGI Phenotype |
FUNCTION: This gene encodes a member of the inositol polyphosphate-5-phosphatase (INPP5) family. This protein hydrolyzes the 5' phosphate from phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol-1,4,5-trisphosphate, which results in changes to multiple signaling pathways. This protein may be involved in protein trafficking and secretion. Homozygous knockout mice exhibit impaired spermatogenesis and male sterility. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Nov 2014]
PHENOTYPE: Homozygous null male mice are infertile with a disruption in spermatogenesis and a defect in adherens junctions processing. [provided by MGI curators]
|
| Allele List at MGI |
All alleles(24) : Targeted(6) Gene trapped(18)
|
| Other mutations in this stock |
Total: 13 list
| Gene | Ref | Var | Chr/Loc | Mutation | Predicted Effect | Zygosity |
|---|
| Ackr3 |
A |
G |
1: 90,142,600 (GRCm39) |
E353G |
probably damaging |
Het |
| Cercam |
T |
A |
2: 29,771,095 (GRCm39) |
D497E |
probably damaging |
Het |
| Eif5a |
A |
T |
11: 69,808,728 (GRCm39) |
|
probably benign |
Het |
| Htr4 |
T |
A |
18: 62,546,748 (GRCm39) |
D100E |
probably damaging |
Het |
| Ift172 |
T |
C |
5: 31,418,799 (GRCm39) |
K1172E |
probably benign |
Het |
| Klc2 |
A |
G |
19: 5,163,805 (GRCm39) |
|
probably benign |
Het |
| Myh13 |
T |
A |
11: 67,225,817 (GRCm39) |
L332M |
probably benign |
Het |
| Naca |
T |
C |
10: 127,877,422 (GRCm39) |
|
probably benign |
Het |
| Oat |
A |
G |
7: 132,164,374 (GRCm39) |
V238A |
possibly damaging |
Het |
| Rabep1 |
A |
G |
11: 70,775,801 (GRCm39) |
|
probably benign |
Het |
| Snx13 |
A |
G |
12: 35,157,541 (GRCm39) |
D529G |
probably damaging |
Het |
| Urod |
T |
A |
4: 116,850,143 (GRCm39) |
L23F |
probably damaging |
Het |
| Zcchc2 |
C |
T |
1: 105,958,727 (GRCm39) |
T1066I |
possibly damaging |
Het |
|
| Other mutations in Inpp5b |
| Allele | Source | Chr | Coord | Type | Predicted Effect | PPH Score |
|---|
|
IGL00338:Inpp5b
|
APN |
4 |
124,678,168 (GRCm39) |
missense |
possibly damaging |
0.94 |
|
IGL00696:Inpp5b
|
APN |
4 |
124,636,328 (GRCm39) |
start codon destroyed |
probably null |
1.00 |
|
IGL00969:Inpp5b
|
APN |
4 |
124,677,787 (GRCm39) |
missense |
probably damaging |
1.00 |
|
IGL01401:Inpp5b
|
APN |
4 |
124,639,880 (GRCm39) |
missense |
probably damaging |
0.97 |
|
IGL01481:Inpp5b
|
APN |
4 |
124,694,492 (GRCm39) |
splice site |
probably null |
|
|
IGL01517:Inpp5b
|
APN |
4 |
124,676,229 (GRCm39) |
missense |
probably benign |
0.00 |
|
IGL03085:Inpp5b
|
APN |
4 |
124,686,115 (GRCm39) |
missense |
probably benign |
0.01 |
|
IGL03178:Inpp5b
|
APN |
4 |
124,679,047 (GRCm39) |
missense |
probably benign |
0.02 |
|
reduced
|
UTSW |
4 |
124,686,045 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R0504:Inpp5b
|
UTSW |
4 |
124,676,201 (GRCm39) |
nonsense |
probably null |
|
|
R0531:Inpp5b
|
UTSW |
4 |
124,689,249 (GRCm39) |
missense |
probably damaging |
0.99 |
|
R1396:Inpp5b
|
UTSW |
4 |
124,682,873 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R1626:Inpp5b
|
UTSW |
4 |
124,677,696 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R1768:Inpp5b
|
UTSW |
4 |
124,687,069 (GRCm39) |
nonsense |
probably null |
|
|
R2037:Inpp5b
|
UTSW |
4 |
124,692,092 (GRCm39) |
missense |
probably damaging |
0.98 |
|
R2119:Inpp5b
|
UTSW |
4 |
124,691,662 (GRCm39) |
missense |
probably benign |
0.00 |
|
R2132:Inpp5b
|
UTSW |
4 |
124,678,961 (GRCm39) |
splice site |
probably benign |
|
|
R2190:Inpp5b
|
UTSW |
4 |
124,678,988 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R3237:Inpp5b
|
UTSW |
4 |
124,674,279 (GRCm39) |
missense |
probably benign |
0.04 |
|
R3800:Inpp5b
|
UTSW |
4 |
124,679,138 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R4735:Inpp5b
|
UTSW |
4 |
124,677,760 (GRCm39) |
missense |
probably damaging |
0.99 |
|
R4827:Inpp5b
|
UTSW |
4 |
124,637,643 (GRCm39) |
intron |
probably benign |
|
|
R4865:Inpp5b
|
UTSW |
4 |
124,645,288 (GRCm39) |
missense |
probably benign |
|
|
R4868:Inpp5b
|
UTSW |
4 |
124,645,203 (GRCm39) |
missense |
probably damaging |
0.99 |
|
R4913:Inpp5b
|
UTSW |
4 |
124,674,214 (GRCm39) |
missense |
probably benign |
0.09 |
|
R5055:Inpp5b
|
UTSW |
4 |
124,636,824 (GRCm39) |
critical splice donor site |
probably null |
|
|
R5068:Inpp5b
|
UTSW |
4 |
124,636,442 (GRCm39) |
splice site |
probably null |
|
|
R5208:Inpp5b
|
UTSW |
4 |
124,645,110 (GRCm39) |
missense |
possibly damaging |
0.62 |
|
R5642:Inpp5b
|
UTSW |
4 |
124,676,229 (GRCm39) |
missense |
probably benign |
0.00 |
|
R5875:Inpp5b
|
UTSW |
4 |
124,674,199 (GRCm39) |
missense |
possibly damaging |
0.66 |
|
R6015:Inpp5b
|
UTSW |
4 |
124,692,143 (GRCm39) |
missense |
possibly damaging |
0.94 |
|
R6288:Inpp5b
|
UTSW |
4 |
124,679,020 (GRCm39) |
missense |
probably benign |
0.00 |
|
R6450:Inpp5b
|
UTSW |
4 |
124,686,045 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R7138:Inpp5b
|
UTSW |
4 |
124,679,065 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R7235:Inpp5b
|
UTSW |
4 |
124,645,185 (GRCm39) |
missense |
probably benign |
0.04 |
|
R7382:Inpp5b
|
UTSW |
4 |
124,645,370 (GRCm39) |
missense |
probably benign |
0.00 |
|
R7659:Inpp5b
|
UTSW |
4 |
124,689,219 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R7806:Inpp5b
|
UTSW |
4 |
124,678,881 (GRCm39) |
splice site |
probably null |
|
|
R8348:Inpp5b
|
UTSW |
4 |
124,678,967 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R8509:Inpp5b
|
UTSW |
4 |
124,637,698 (GRCm39) |
critical splice donor site |
probably null |
|
|
R9430:Inpp5b
|
UTSW |
4 |
124,636,340 (GRCm39) |
missense |
possibly damaging |
0.84 |
|
R9794:Inpp5b
|
UTSW |
4 |
124,687,174 (GRCm39) |
missense |
probably damaging |
0.98 |
|
Z1176:Inpp5b
|
UTSW |
4 |
124,691,633 (GRCm39) |
frame shift |
probably null |
|
|
| Protein Function and Prediction |
Inpp5b is a ubiquitously expressed endosomal enzyme that converts inositol-1,4,5-trisphosphate (IP3) to inositol-1,4-bisphosphate (IP2) (1). In mice Inpp5b and Ocrl1, another phosphatase, have overlapping functions. Inpp5b functions in sperm maturation and is involved in the acrosome reaction (i.e., phosphoinositides facilitate a signal transduction cascade that leads to exocytosis of the acrosome (2)) (3). Further studies determined that Inpp5b regulates cell adhesion in the testis and is necessary to form junctional complexes with neighboring cells (4). Inpp5b has been shown to be localized to the early secretory pathway and binds RAB proteins necessary for Inpp5b targeting to the Golgi (5). It has been proposed that Inpp5b can function in retrograde ER-to-Golgi intermediate compartment to ER transport (5).
|
| Background |
Inpp5btm1Nbm/tm1Nbm; MGI:2159609
129S6/SvEvTac
Homozygous males are infertile; sperm have reduced motility and ability to fertilize eggs (3;4). Capacitation and acrosome exocytosis are normal (3). Proteolytic processing of a sperm surface protein involved in sperm-egg membrane interactions, fertilin beta, is reduced (3). In the Sertoli cell cytosol of homozygous males there is an accumulation of swollen, actin-coated, endosome-like structures that contain intact adherens junctions by P13 (4). Also at P13, there is a disruption at meiosis I during spermatogenesis (4). Another study found that loss of Inpp5b expression led to a reduction in the ability of their sperm to bind to and fuse with the egg plasma membrane. The mice also had variable deficiencies in ADAM2 and ADAM3 cleavage (6).
Inpp5btm1Nbm/tm1Nbm; MGI:2159609
either: (involves: 129S6/SvEvTac * C57BL/6) or (involves: 129S6/SvEvTac * NIH Black Swiss)
Similar to the genetic background above, males in this background are infertile (7). Testicular degeneration was observed (7).
Inpp5btm2.1Nbm/tm2.1Nbm; MGI:2159620
involves: 129S6/SvEvTac * FVB/N
About half of the males on a mixed 129S6/SvEvTac and FVB/N background are infertile (3). Infertile males are unable to process Adam2 while males with reduced fertility are able to process Adam2 (3).
|
| References |
1. Matzaris, M., Jackson, S. P., Laxminarayan, K. M., Speed, C. J., and Mitchell, C. A. (1994) Identification and Characterization of the Phosphatidylinositol-(4, 5)-Bisphosphate 5-Phosphatase in Human Platelets. J Biol Chem. 269, 3397-3402.
3. Hellsten, E., Evans, J. P., Bernard, D. J., Janne, P. A., and Nussbaum, R. L. (2001) Disrupted Sperm Function and Fertilin Beta Processing in Mice Deficient in the Inositol Polyphosphate 5-Phosphatase Inpp5b. Dev Biol. 240, 641-653.
4. Hellsten, E., Bernard, D. J., Owens, J. W., Eckhaus, M., Suchy, S. F., and Nussbaum, R. L. (2002) Sertoli Cell Vacuolization and Abnormal Germ Cell Adhesion in Mice Deficient in an Inositol Polyphosphate 5-Phosphatase. Biol Reprod. 66, 1522-1530.
7. Janne, P. A., Suchy, S. F., Bernard, D., MacDonald, M., Crawley, J., Grinberg, A., Wynshaw-Boris, A., Westphal, H., and Nussbaum, R. L. (1998) Functional Overlap between Murine Inpp5b and Ocrl1 may Explain Why Deficiency of the Murine Ortholog for OCRL1 does Not Cause Lowe Syndrome in Mice. J Clin Invest. 101, 2042-2053. |
| Posted On |
2012-10-29 |
| Science Writer |
Anne Murray |
Incidental Mutation