Mutagenetix > Incidental Mutation

Incidental Mutation 'P0005:Casp6'

7628

Institutional Source

Beutler Lab

Gene Symbol

Casp6

Ensembl Gene

ENSMUSG00000027997

Gene Name

caspase 6

Synonyms

Mch2, mCASP-6

MMRRC Submission

038262-MU

Accession Numbers

Essential gene?

Possibly non essential (E-score: 0.422) question?

Stock #

P0005 (G1)

Quality Score

Status

Validated

Chromosome

Chromosomal Location

129695074-129707752 bp(+) (GRCm39)

Type of Mutation

missense

DNA Base Change (assembly)

T to C at 129705792 bp (GRCm39)

Zygosity

Heterozygous

Amino Acid Change

Valine to Alanine at position 153 (V153A)

Ref Sequence

ENSEMBL: ENSMUSP00000029626 (fasta)

Gene Model

predicted gene model for transcript(s): [ENSMUST00000029624] [ENSMUST00000029626] [ENSMUST00000153506]

AlphaFold

O08738

Predicted Effect

probably benign
Transcript: ENSMUST00000029624

SMART Domains

Protein: ENSMUSP00000029624
Gene: ENSMUSG00000027994

Domain	Start	End	E-Value	Type
Pfam:MCU	109	314	4.4e-68	PFAM
low complexity region	323	335	N/A	INTRINSIC

Predicted Effect

probably benign
Transcript: ENSMUST00000029626
AA Change: V153A

PolyPhen 2 Score 0.406 (Sensitivity: 0.89; Specificity: 0.90)

SMART Domains

Protein: ENSMUSP00000029626
Gene: ENSMUSG00000027997
AA Change: V153A

Domain	Start	End	E-Value	Type
CASc	19	272	6.84e-132	SMART

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000137314

Predicted Effect

probably benign
Transcript: ENSMUST00000146340

SMART Domains

Protein: ENSMUSP00000115224
Gene: ENSMUSG00000027994

Domain	Start	End	E-Value	Type
Pfam:MCU	34	149	2.4e-19	PFAM

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000152622

Predicted Effect

probably benign
Transcript: ENSMUST00000153506

SMART Domains

Protein: ENSMUSP00000118170
Gene: ENSMUSG00000027994

Domain	Start	End	E-Value	Type
low complexity region	178	202	N/A	INTRINSIC

Meta Mutation Damage Score

0.1283

Coding Region Coverage

1x: 85.5%
3x: 80.5%
10x: 66.1%
20x: 49.6%

Validation Efficiency

95% (104/109)

MGI Phenotype

FUNCTION: This gene encodes a member of the cysteine proteases that plays important roles in regulating apoptosis and neurodegeneration. The encoded protein is involved in the transmission of pain and axonal degeneration. Genetic deletion of this gene in mice results in the delay of axon pruning and protects from axon degeneration. [provided by RefSeq, Apr 2015]
PHENOTYPE: Mice homozygous for a knock-out allele exhibit failure to induce increased lysis of fluorogenic substrate VEID-AMC in staurosporine treated of lenses. Mice homozygous for a different knock-out allele exhibit resistance to excitotoxicity and axonal degeneration. [provided by MGI curators]

Allele List at MGI

All alleles(6) : Targeted(5) Gene trapped(1)

Other mutations in this stock

Total: 20 list
Gene	Ref	Var	Chr/Loc	Mutation	Predicted Effect	Zygosity
Atp13a1	T	C	8: 70,256,397 (GRCm39)	V845A	possibly damaging	Het
Col6a1	A	G	10: 76,553,163 (GRCm39)		probably benign	Het
Dars2	A	G	1: 160,881,509 (GRCm39)		probably null	Het
Hmgcll1	T	A	9: 75,982,041 (GRCm39)	M162K	possibly damaging	Het
Hydin	A	T	8: 111,220,921 (GRCm39)		probably null	Het
Ift74	A	G	4: 94,550,813 (GRCm39)		probably benign	Het
Itpr1	A	T	6: 108,358,218 (GRCm39)	I595F	probably damaging	Het
Mgat4f	T	A	1: 134,315,646 (GRCm39)	M15K	probably benign	Het
Mmp17	T	C	5: 129,673,695 (GRCm39)	V258A	probably benign	Het
Nek6	T	C	2: 38,459,749 (GRCm39)		probably null	Het
Nomo1	A	T	7: 45,686,981 (GRCm39)		probably null	Het
Nudt3	A	G	17: 27,815,689 (GRCm39)		probably benign	Het
Pramel32	A	G	4: 88,546,187 (GRCm39)	L385P	probably damaging	Het
Prkg2	A	C	5: 99,117,806 (GRCm39)	F512V	probably damaging	Het
Ptp4a3	T	A	15: 73,627,160 (GRCm39)	D72E	possibly damaging	Het
Rpgrip1l	A	T	8: 92,025,853 (GRCm39)		probably benign	Het
Rrp9	G	A	9: 106,358,376 (GRCm39)	R101H	probably benign	Het
Slc7a6os	T	C	8: 106,931,154 (GRCm39)	I161V	probably benign	Het
Tex15	T	C	8: 34,060,896 (GRCm39)	F109L	probably benign	Het
Tns2	A	G	15: 102,022,491 (GRCm39)	Q1188R	probably damaging	Het

Other mutations in Casp6

Allele	Source	Chr	Coord	Type	Predicted Effect	PPH Score
IGL02353:Casp6	APN	3	129,704,175 (GRCm39)	missense	probably damaging	1.00
IGL02360:Casp6	APN	3	129,704,175 (GRCm39)	missense	probably damaging	1.00
R0233:Casp6	UTSW	3	129,699,624 (GRCm39)	missense	probably damaging	1.00
R0233:Casp6	UTSW	3	129,699,624 (GRCm39)	missense	probably damaging	1.00
R0277:Casp6	UTSW	3	129,704,172 (GRCm39)	missense	probably benign	0.22
R4167:Casp6	UTSW	3	129,706,993 (GRCm39)	missense	probably damaging	1.00
R5297:Casp6	UTSW	3	129,704,204 (GRCm39)	missense	possibly damaging	0.83
R6662:Casp6	UTSW	3	129,705,875 (GRCm39)	missense	probably benign	0.22
R7605:Casp6	UTSW	3	129,705,812 (GRCm39)	missense	probably benign
R7653:Casp6	UTSW	3	129,705,872 (GRCm39)	missense	probably benign	0.00
R7750:Casp6	UTSW	3	129,705,858 (GRCm39)	missense	probably damaging	1.00
R9497:Casp6	UTSW	3	129,699,559 (GRCm39)	missense	probably benign

Protein Function and Prediction

Casp6 or MCH2 is a ced-3 apoptotic protease that is highly homologous to human CASP3 [OMIM #601532; (1)]. Casp6 functions downstream of the cell death inhibitors Bcl2 and BclXL (2). Casp6 is required for axonal degeneration (3;4). Casp6 was characterized as an effector caspase essential for the maturation of proinflammatory cytokines and lymphocyte development (5). Casp6 cleaves substrates involved in cell cycle, survival, or development (5). It has been proposed that Casp6 dysregulation is involved in the pathogenesis of gastrointestinal cancers, invasive melanomas, and other metastatic cancers [(6-8); reviewed in (5)].

Expression/Localization

Northern blot analysis identified a 1262 bp transcript found in all tissues with predominant expression in liver, lung, kidney, testis, and heart (1).

Background

KO information:

Casp6^tm1.2Xen;MGI:5426933

Genetic background: FVB.B6NTac-Casp6^tm1.2Xen

At 3 months, mice exhibit normal cortex volume, striatal volume, neuronal striatal counts, brain weight and cerebellum weight (4). However, at 8 months, they exhibit increased striatal and cortical volume, although the brain and cerebellum weight remains equivalent to wild-type (4). In the knockout animals, septal cholinergic neurons are protected from myelin-induced degeneration compared with wild-type cells and medium spiny neurons are protected from NMDA-mediated excitotoxicity compared with wild-type cells.

Casp6^tm1Flv; MGI: 3603318

Genetic background not specified

In this model, the lenses appear grossly normal, althoughstaurosporine treatment of lenses fails to induce increased lysis of fluorogenic substrate VEID-AMC as it does in wild-type lenses (9). Also, thymocytes treated with dexamthasone display normal phosphatidyl serine flip-flop (10).

References

1. Van de Craen, M., Vandenabeele, P., Declercq, W., Van den Brande, I., Van Loo, G., Molemans, F., Schotte, P., Van Criekinge, W., Beyaert, R., and Fiers, W. (1997) Characterization of Seven Murine Caspase Family Members. FEBS Lett. 403, 61-69.

2. Orth, K., Chinnaiyan, A. M., Garg, M., Froelich, C. J., and Dixit, V. M. (1996) The CED-3/ICE-Like Protease Mch2 is Activated during Apoptosis and Cleaves the Death Substrate Lamin A. J Biol Chem. 271, 16443-16446.

3. Nikolaev, A., McLaughlin, T., O'Leary, D. D., and Tessier-Lavigne, M. (2009) APP Binds DR6 to Trigger Axon Pruning and Neuron Death Via Distinct Caspases. Nature. 457, 981-989.

4. Uribe, V., Wong, B. K., Graham, R. K., Cusack, C. L., Skotte, N. H., Pouladi, M. A., Xie, Y., Feinberg, K., Ou, Y., Ouyang, Y., Deng, Y., Franciosi, S., Bissada, N., Spreeuw, A., Zhang, W., Ehrnhoefer, D. E., Vaid, K., Miller, F. D., Deshmukh, M., Howland, D., and Hayden, M. R. (2012) Rescue from Excitotoxicity and Axonal Degeneration Accompanied by Age-Dependent Behavioral and Neuroanatomical Alterations in Caspase-6-Deficient Mice. Hum Mol Genet. 21, 1954-1967.

5. Watanabe, C., Shu, G. L., Zheng, T. S., Flavell, R. A., and Clark, E. A. (2008) Caspase 6 Regulates B Cell Activation and Differentiation into Plasma Cells. J Immunol. 181, 6810-6819.

6. Lee, J. W., Kim, M. R., Soung, Y. H., Nam, S. W., Kim, S. H., Lee, J. Y., Yoo, N. J., and Lee, S. H. (2006) Mutational Analysis of the CASP6 Gene in Colorectal and Gastric Carcinomas. APMIS. 114, 646-650.

7. Lee, J. W., Soung, Y. H., Kim, S. Y., Park, W. S., Nam, S. W., Lee, J. Y., Yoo, N. J., and Lee, S. H. (2006) Somatic Mutation of Pro-Apoptosis Caspase-6 Gene is Rare in Breast and Lung Carcinomas. Pathology. 38, 358-359.

8. Woenckhaus, C., Giebel, J., Failing, K., Fenic, I., Dittberner, T., and Poetsch, M. (2003) Expression of AP-2alpha, c-Kit, and Cleaved Caspase-6 and -3 in Naevi and Malignant Melanomas of the Skin. A Possible Role for Caspases in Melanoma Progression? J Pathol. 201, 278-287.

9. Zandy, A. J., Lakhani, S., Zheng, T., Flavell, R. A., and Bassnett, S. (2005) Role of the Executioner Caspases during Lens Development. J Biol Chem. 280, 30263-30272.

10. Zheng, T. S., Hunot, S., Kuida, K., and Flavell, R. A. (1999) Caspase Knockouts: Matters of Life and Death. Cell Death Differ. 6, 1043-1053.

Posted On

2012-10-05

Science Writer

Anne Murray