Mutagenetix > Incidental Mutation

Incidental Mutation 'P0012:Adamtsl3'

7557

Institutional Source

Beutler Lab

Gene Symbol

Adamtsl3

Ensembl Gene

ENSMUSG00000070469

Gene Name

ADAMTS-like 3

Synonyms

9230119C12Rik, punctin-2

MMRRC Submission

038266-MU

Accession Numbers

Essential gene?

Non essential (E-score: 0.000) question?

Stock #

P0012 (G1)

Quality Score

Status

Validated

Chromosome

Chromosomal Location

81984902-82263658 bp(+) (GRCm39)

Type of Mutation

missense

DNA Base Change (assembly)

A to C at 82223465 bp (GRCm39)

Zygosity

Heterozygous

Amino Acid Change

Asparagine to Threonine at position 156 (N156T)

Ref Sequence

ENSEMBL: ENSMUSP00000133337 (fasta)

Gene Model

predicted gene model for transcript(s): [ENSMUST00000173287] [ENSMUST00000173828]

AlphaFold

G3UXC7

Predicted Effect

probably benign
Transcript: ENSMUST00000173287
AA Change: N1082T

PolyPhen 2 Score 0.027 (Sensitivity: 0.95; Specificity: 0.81)

SMART Domains

Protein: ENSMUSP00000133637
Gene: ENSMUSG00000070469
AA Change: N1082T

Domain	Start	End	E-Value	Type
signal peptide	1	38	N/A	INTRINSIC
TSP1	90	136	6.43e-8	SMART
TSP1	355	414	1.59e-1	SMART
TSP1	433	492	3.72e-4	SMART
TSP1	494	547	4.28e-4	SMART
TSP1	579	638	1.85e-2	SMART
TSP1	660	717	1.75e-2	SMART
TSP1	719	773	3.45e-8	SMART
TSP1	775	833	3.67e-3	SMART
TSP1	836	894	8.99e-2	SMART
IGc2	938	1002	7.59e-4	SMART
IG	1213	1296	4.87e0	SMART
IGc2	1326	1388	1.01e-13	SMART
TSP1	1441	1498	1.95e-2	SMART
TSP1	1500	1559	6.76e-2	SMART
TSP1	1616	1666	3.84e-1	SMART
Pfam:PLAC	1674	1704	2.4e-11	PFAM

Predicted Effect

probably benign
Transcript: ENSMUST00000173828
AA Change: N156T

PolyPhen 2 Score 0.269 (Sensitivity: 0.91; Specificity: 0.88)

SMART Domains

Protein: ENSMUSP00000133337
Gene: ENSMUSG00000070469
AA Change: N156T

Domain	Start	End	E-Value	Type
signal peptide	1	20	N/A	INTRINSIC
Blast:IG	22	79	1e-26	BLAST
SCOP:d1biha4	27	77	2e-5	SMART
IG	283	366	4.87e0	SMART
IGc2	396	458	1.01e-13	SMART
TSP1	511	568	1.95e-2	SMART
TSP1	570	629	6.76e-2	SMART
TSP1	686	736	3.84e-1	SMART

Meta Mutation Damage Score

0.0898

Coding Region Coverage

1x: 85.5%
3x: 81.0%
10x: 67.7%
20x: 52.2%

Validation Efficiency

85% (579/685)

Allele List at MGI

All alleles(10) : Targeted(7) Gene trapped(2) Spontaneous(1)

Other mutations in this stock

Total: 9 list
Gene	Ref	Var	Chr/Loc	Mutation	Predicted Effect	Zygosity
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
Tnfrsf11b	A	G	15: 54,123,194 (GRCm39)		probably benign	Het

Other mutations in Adamtsl3

Allele	Source	Chr	Coord	Type	Predicted Effect	PPH Score
IGL01549:Adamtsl3	APN	7	82,261,656 (GRCm39)	missense	probably damaging	1.00
IGL01936:Adamtsl3	APN	7	82,244,579 (GRCm39)	missense	possibly damaging	0.93
IGL02819:Adamtsl3	APN	7	82,223,329 (GRCm39)	missense	probably damaging	0.99
R0096:Adamtsl3	UTSW	7	82,114,907 (GRCm39)	intron	probably benign
R0096:Adamtsl3	UTSW	7	82,114,907 (GRCm39)	intron	probably benign
R0180:Adamtsl3	UTSW	7	82,225,198 (GRCm39)	missense	probably benign	0.00
R0270:Adamtsl3	UTSW	7	82,206,032 (GRCm39)	missense	probably damaging	1.00
R0295:Adamtsl3	UTSW	7	82,197,213 (GRCm39)	critical splice donor site	probably null
R0329:Adamtsl3	UTSW	7	82,171,198 (GRCm39)	missense	probably damaging	1.00
R0330:Adamtsl3	UTSW	7	82,171,198 (GRCm39)	missense	probably damaging	1.00
R0548:Adamtsl3	UTSW	7	82,178,191 (GRCm39)	critical splice donor site	probably null
R0611:Adamtsl3	UTSW	7	82,178,120 (GRCm39)	missense	probably damaging	1.00
R0671:Adamtsl3	UTSW	7	82,172,390 (GRCm39)	missense	probably damaging	1.00
R0711:Adamtsl3	UTSW	7	82,114,907 (GRCm39)	intron	probably benign
R0845:Adamtsl3	UTSW	7	82,225,204 (GRCm39)	missense	probably damaging	1.00
R1119:Adamtsl3	UTSW	7	82,189,525 (GRCm39)	missense	probably damaging	0.96
R1458:Adamtsl3	UTSW	7	82,172,528 (GRCm39)	missense	probably damaging	1.00
R1644:Adamtsl3	UTSW	7	82,099,298 (GRCm39)	missense	possibly damaging	0.87
R1691:Adamtsl3	UTSW	7	82,148,814 (GRCm39)	missense	probably damaging	1.00
R1838:Adamtsl3	UTSW	7	82,142,581 (GRCm39)	missense	probably damaging	1.00
R2131:Adamtsl3	UTSW	7	82,227,802 (GRCm39)	missense	probably damaging	1.00
R2245:Adamtsl3	UTSW	7	82,099,308 (GRCm39)	missense	probably damaging	1.00
R2274:Adamtsl3	UTSW	7	82,255,766 (GRCm39)	missense	probably benign	0.37
R2275:Adamtsl3	UTSW	7	82,255,766 (GRCm39)	missense	probably benign	0.37
R2448:Adamtsl3	UTSW	7	82,148,956 (GRCm39)	missense	probably damaging	1.00
R3725:Adamtsl3	UTSW	7	82,261,612 (GRCm39)	missense	possibly damaging	0.80
R3757:Adamtsl3	UTSW	7	81,986,415 (GRCm39)	missense	probably benign	0.01
R3821:Adamtsl3	UTSW	7	82,255,687 (GRCm39)	splice site	probably benign
R4618:Adamtsl3	UTSW	7	82,255,728 (GRCm39)	missense	probably benign	0.41
R4842:Adamtsl3	UTSW	7	82,178,069 (GRCm39)	missense	probably damaging	1.00
R4887:Adamtsl3	UTSW	7	82,223,822 (GRCm39)	missense	possibly damaging	0.87
R4888:Adamtsl3	UTSW	7	82,223,822 (GRCm39)	missense	possibly damaging	0.87
R4925:Adamtsl3	UTSW	7	82,251,507 (GRCm39)	critical splice donor site	probably null
R4960:Adamtsl3	UTSW	7	82,216,185 (GRCm39)	missense	probably damaging	0.99
R5026:Adamtsl3	UTSW	7	82,225,262 (GRCm39)	missense	probably benign	0.07
R5152:Adamtsl3	UTSW	7	82,223,752 (GRCm39)	missense	probably benign	0.11
R5198:Adamtsl3	UTSW	7	82,261,006 (GRCm39)	missense	possibly damaging	0.63
R5244:Adamtsl3	UTSW	7	82,247,277 (GRCm39)	missense	probably benign	0.02
R5281:Adamtsl3	UTSW	7	82,178,142 (GRCm39)	missense	probably damaging	1.00
R5323:Adamtsl3	UTSW	7	82,206,269 (GRCm39)	missense	probably damaging	1.00
R5523:Adamtsl3	UTSW	7	82,223,650 (GRCm39)	missense	possibly damaging	0.86
R5602:Adamtsl3	UTSW	7	82,206,447 (GRCm39)	missense	possibly damaging	0.89
R5638:Adamtsl3	UTSW	7	82,260,958 (GRCm39)	missense	probably damaging	0.99
R5682:Adamtsl3	UTSW	7	82,255,758 (GRCm39)	missense	probably damaging	0.99
R5782:Adamtsl3	UTSW	7	82,189,494 (GRCm39)	splice site	probably null
R5946:Adamtsl3	UTSW	7	82,225,265 (GRCm39)	missense	probably damaging	0.98
R6091:Adamtsl3	UTSW	7	82,114,829 (GRCm39)	missense	probably damaging	1.00
R6258:Adamtsl3	UTSW	7	82,178,191 (GRCm39)	critical splice donor site	probably null
R6500:Adamtsl3	UTSW	7	82,227,818 (GRCm39)	missense	probably benign	0.00
R6765:Adamtsl3	UTSW	7	82,216,232 (GRCm39)	missense	possibly damaging	0.60
R6785:Adamtsl3	UTSW	7	82,171,212 (GRCm39)	missense	probably damaging	0.99
R6982:Adamtsl3	UTSW	7	82,164,271 (GRCm39)	missense	probably damaging	1.00
R7109:Adamtsl3	UTSW	7	82,261,069 (GRCm39)	missense
R7341:Adamtsl3	UTSW	7	82,206,082 (GRCm39)	missense	probably damaging	1.00
R7402:Adamtsl3	UTSW	7	82,227,825 (GRCm39)	missense	probably damaging	0.96
R7506:Adamtsl3	UTSW	7	82,164,186 (GRCm39)	missense	probably damaging	1.00
R7549:Adamtsl3	UTSW	7	82,223,117 (GRCm39)	missense	probably damaging	1.00
R7575:Adamtsl3	UTSW	7	82,223,756 (GRCm39)	missense	possibly damaging	0.85
R7592:Adamtsl3	UTSW	7	81,986,459 (GRCm39)	missense	probably benign	0.00
R7617:Adamtsl3	UTSW	7	82,206,054 (GRCm39)	splice site	probably null
R7654:Adamtsl3	UTSW	7	82,223,702 (GRCm39)	missense	probably benign
R7721:Adamtsl3	UTSW	7	82,255,728 (GRCm39)	missense	possibly damaging	0.62
R7784:Adamtsl3	UTSW	7	82,223,197 (GRCm39)	missense	probably damaging	1.00
R7858:Adamtsl3	UTSW	7	82,099,371 (GRCm39)	missense	probably damaging	1.00
R8109:Adamtsl3	UTSW	7	82,251,487 (GRCm39)	missense	possibly damaging	0.94
R8125:Adamtsl3	UTSW	7	82,099,541 (GRCm39)	splice site	probably null
R8211:Adamtsl3	UTSW	7	82,172,371 (GRCm39)	missense	probably damaging	1.00
R8348:Adamtsl3	UTSW	7	82,253,007 (GRCm39)	missense	possibly damaging	0.89
R8360:Adamtsl3	UTSW	7	82,197,187 (GRCm39)	missense	probably damaging	1.00
R8448:Adamtsl3	UTSW	7	82,253,007 (GRCm39)	missense	possibly damaging	0.89
R8465:Adamtsl3	UTSW	7	82,247,330 (GRCm39)	missense	probably benign	0.43
R8547:Adamtsl3	UTSW	7	82,077,621 (GRCm39)	missense	probably damaging	1.00
R8551:Adamtsl3	UTSW	7	82,189,678 (GRCm39)	missense	probably benign	0.34
R8558:Adamtsl3	UTSW	7	82,077,600 (GRCm39)	missense	possibly damaging	0.59
R8709:Adamtsl3	UTSW	7	82,077,642 (GRCm39)	missense	possibly damaging	0.94
R8722:Adamtsl3	UTSW	7	82,244,745 (GRCm39)	critical splice donor site	probably null
R8930:Adamtsl3	UTSW	7	82,261,069 (GRCm39)	missense
R8932:Adamtsl3	UTSW	7	82,261,069 (GRCm39)	missense
R9131:Adamtsl3	UTSW	7	82,244,722 (GRCm39)	missense	probably benign	0.00
R9169:Adamtsl3	UTSW	7	82,223,188 (GRCm39)	missense	probably damaging	0.99
R9272:Adamtsl3	UTSW	7	82,189,753 (GRCm39)	missense	probably damaging	1.00
R9276:Adamtsl3	UTSW	7	82,206,710 (GRCm39)	intron	probably benign
R9351:Adamtsl3	UTSW	7	82,169,929 (GRCm39)	missense	possibly damaging	0.94
R9352:Adamtsl3	UTSW	7	82,091,656 (GRCm39)	missense	probably damaging	1.00
R9749:Adamtsl3	UTSW	7	82,099,394 (GRCm39)	missense	probably benign	0.04
R9750:Adamtsl3	UTSW	7	82,244,589 (GRCm39)	missense	probably benign	0.11
RF005:Adamtsl3	UTSW	7	82,261,603 (GRCm39)	missense
X0003:Adamtsl3	UTSW	7	82,260,967 (GRCm39)	nonsense	probably null
X0063:Adamtsl3	UTSW	7	82,223,365 (GRCm39)	missense	probably benign	0.25
Z1088:Adamtsl3	UTSW	7	82,189,533 (GRCm39)	missense	probably damaging	1.00
Z1088:Adamtsl3	UTSW	7	82,148,922 (GRCm39)	missense	probably damaging	1.00

Protein Function and Prediction

Adamts13 cleaves von Willebrand factor (vWF), a factor necessary for linking circulating blood platelets to the sites of vascular injury (1).

Background

Mutations in Adamts13 can cause thrombotic thrombocytopenic purpura, familial [TTP; OMIM: #274150; (2-4)]. In addition, autoantibodies to Adamts13 can cause acquired TTP (5;6). Patients with TTP have hemolytic anemia with fragmentation of erythrocytes, thrombocytopenia, diffuse and nonfocal neurologic findings, decreased renal function, and fever.

Adamts13^{tm1Dgi/tm1Dgi}; MGI:3605825

B6.129X1-Adamts13^tm1Dgi

In this genetic background, these Adamts13-deficient mice exhibited a reduced time to clot formation and vessel occlusion compared with similarly treated wild-type mice (7).

Adamts13^{tm1Dgi/tm1Dgi}; MGI:3605825

involves: 129X1/SvJ * C57BL/6J

In one study, researchers examined the Adamts13-deficient mice in two genetic backgrounds (see next entry). In this background, mice exhibit normal development, fertility, survival, blood smears and a similar response to shiga toxin as wildtype, even though von Willebrand Factor (vWF)-cleaving activity is lost, unlike on a background that contains CASA/Rk (1).

Adamts13^{tm1Dgi/tm1Dgi}; MGI:3605825

involves: 129X1/SvJ * C57BL/6J * CASA/Rk

Mice in this genetic background exhibit a significant decrease in survival than wildtype (1). Furthermore, the mice exhibited fragmented red blood cells, a decrease in platelet count in the peripheral blood, and the platelets had significantly prolonged adhesion to endothelial cells (1). Shiga toxin injection causes increased mortality, thrombocytopenia, microangiopathic hemolytic anemia and widespread vWF-rich and fibrin-poor hyaline thrombi in the small vessels of multiple organs and results in a syndrome closely resembling human thrombotic thrombocytopenic purpura (1).

Adamts13^{tm1Myta/tm1Myta}; MGI:3763820

involves: 129S6/SvEvTac

In this model, homozygous mice had abnormal platelet activation, blood coagulation, and thrombosis (8).

Adamts13^s/s; MGI:3579136

129.B6-Adamts13^s

This spontaneous mutation results in thrombosis (9).

References

1. Motto, D. G., Chauhan, A. K., Zhu, G., Homeister, J., Lamb, C. B., Desch, K. C., Zhang, W., Tsai, H. M., Wagner, D. D., and Ginsburg, D. (2005) Shigatoxin Triggers Thrombotic Thrombocytopenic Purpura in Genetically Susceptible ADAMTS13-Deficient Mice. J Clin Invest. 115, 2752-2761.

2. Levy, G. G., Nichols, W. C., Lian, E. C., Foroud, T., McClintick, J. N., McGee, B. M., Yang, A. Y., Siemieniak, D. R., Stark, K. R., Gruppo, R., Sarode, R., Shurin, S. B., Chandrasekaran, V., Stabler, S. P., Sabio, H., Bouhassira, E. E., Upshaw, J. D.,Jr, Ginsburg, D., and Tsai, H. M. (2001) Mutations in a Member of the ADAMTS Gene Family Cause Thrombotic Thrombocytopenic Purpura. Nature. 413, 488-494.

3. Kokame, K., Matsumoto, M., Soejima, K., Yagi, H., Ishizashi, H., Funato, M., Tamai, H., Konno, M., Kamide, K., Kawano, Y., Miyata, T., and Fujimura, Y. (2002) Mutations and Common Polymorphisms in ADAMTS13 Gene Responsible for Von Willebrand Factor-Cleaving Protease Activity. Proc Natl Acad Sci U S A. 99, 11902-11907.

4. Veyradier, A., Lavergne, J. M., Ribba, A. S., Obert, B., Loirat, C., Meyer, D., and Girma, J. P. (2004) Ten Candidate ADAMTS13 Mutations in Six French Families with Congenital Thrombotic Thrombocytopenic Purpura (Upshaw-Schulman Syndrome). J Thromb Haemost. 2, 424-429.

5. Furlan, M., Robles, R., Solenthaler, M., Wassmer, M., Sandoz, P., and Lammle, B. (1997) Deficient Activity of Von Willebrand Factor-Cleaving Protease in Chronic Relapsing Thrombotic Thrombocytopenic Purpura. Blood. 89, 3097-3103.