Mutagenetix > Incidental Mutation

Incidental Mutation 'R0070:Hipk2'

17084

Institutional Source

Beutler Lab

Gene Symbol

Hipk2

Ensembl Gene

ENSMUSG00000061436

Gene Name

homeodomain interacting protein kinase 2

Synonyms

B230339E18Rik, 1110014O20Rik, Stank

MMRRC Submission

038361-MU

Accession Numbers

Essential gene?

Probably essential (E-score: 0.960) question?

Stock #

R0070 (G1)

Quality Score

Status

Validated

Chromosome

Chromosomal Location

38671325-38853099 bp(-) (GRCm39)

Type of Mutation

nonsense

DNA Base Change (assembly)

G to A at 38795919 bp (GRCm39)

Zygosity

Heterozygous

Amino Acid Change

Arginine to Stop codon at position 117 (R117*)

Ref Sequence

ENSEMBL: ENSMUSP00000125150 (fasta)

Gene Model

predicted gene model for transcript(s): [ENSMUST00000160360] [ENSMUST00000160962] [ENSMUST00000161779] [ENSMUST00000162359]

AlphaFold

Q9QZR5

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000114855

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000159894

Predicted Effect

probably null
Transcript: ENSMUST00000160360
AA Change: R117*

SMART Domains

Protein: ENSMUSP00000125500
Gene: ENSMUSG00000061436
AA Change: R117*

Domain	Start	End	E-Value	Type
low complexity region	94	104	N/A	INTRINSIC
low complexity region	156	180	N/A	INTRINSIC
S_TKc	199	527	3.05e-78	SMART
low complexity region	895	909	N/A	INTRINSIC
low complexity region	963	992	N/A	INTRINSIC
low complexity region	998	1018	N/A	INTRINSIC
low complexity region	1057	1072	N/A	INTRINSIC

Predicted Effect

probably null
Transcript: ENSMUST00000160962
AA Change: R110*

SMART Domains

Protein: ENSMUSP00000125572
Gene: ENSMUSG00000061436
AA Change: R110*

Domain	Start	End	E-Value	Type
low complexity region	87	97	N/A	INTRINSIC
low complexity region	149	173	N/A	INTRINSIC
S_TKc	192	520	3.05e-78	SMART
low complexity region	888	902	N/A	INTRINSIC
low complexity region	956	985	N/A	INTRINSIC
low complexity region	991	1011	N/A	INTRINSIC
low complexity region	1050	1065	N/A	INTRINSIC

Predicted Effect

probably null
Transcript: ENSMUST00000161779
AA Change: R117*

SMART Domains

Protein: ENSMUSP00000124133
Gene: ENSMUSG00000061436
AA Change: R117*

Domain	Start	End	E-Value	Type
low complexity region	94	104	N/A	INTRINSIC
low complexity region	156	180	N/A	INTRINSIC
S_TKc	199	527	3.05e-78	SMART
low complexity region	923	937	N/A	INTRINSIC
low complexity region	991	1020	N/A	INTRINSIC
low complexity region	1026	1046	N/A	INTRINSIC
low complexity region	1085	1100	N/A	INTRINSIC

Predicted Effect

probably null
Transcript: ENSMUST00000162359
AA Change: R117*

SMART Domains

Protein: ENSMUSP00000125150
Gene: ENSMUSG00000061436
AA Change: R117*

Domain	Start	End	E-Value	Type
low complexity region	94	104	N/A	INTRINSIC
low complexity region	156	180	N/A	INTRINSIC
S_TKc	199	527	3.05e-78	SMART
low complexity region	896	910	N/A	INTRINSIC
low complexity region	964	993	N/A	INTRINSIC
low complexity region	999	1019	N/A	INTRINSIC
low complexity region	1058	1073	N/A	INTRINSIC

Meta Mutation Damage Score

0.9755

Coding Region Coverage

1x: 88.0%
3x: 83.9%
10x: 69.3%
20x: 41.9%

Validation Efficiency

88% (67/76)

MGI Phenotype

FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes a conserved serine/threonine kinase that is a member of the homeodomain-interacting protein kinase family. The encoded protein interacts with homeodomain transcription factors and many other transcription factors such as p53, and can function as both a corepressor and a coactivator depending on the transcription factor and its subcellular localization. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011]
PHENOTYPE: Homozygous null mice display decreased apoptosis and increased neuron numbers in the trigeminal ganglion. [provided by MGI curators]

Allele List at MGI

All alleles(10) : Targeted(7) Gene trapped(3)

Other mutations in this stock

Total: 40 list
Gene	Ref	Var	Chr/Loc	Mutation	Predicted Effect	Zygosity
Adgre4	T	C	17: 56,109,154 (GRCm39)	I387T	probably damaging	Het
Ankfn1	A	T	11: 89,283,128 (GRCm39)	L173Q	probably damaging	Het
Atp2a1	T	C	7: 126,046,624 (GRCm39)	E892G	probably benign	Het
AU018091	T	C	7: 3,208,738 (GRCm39)		probably null	Het
Capn12	T	C	7: 28,588,551 (GRCm39)		probably benign	Het
Capn2	C	A	1: 182,301,434 (GRCm39)		probably benign	Het
Cd79b	A	G	11: 106,202,744 (GRCm39)		probably benign	Het
Cdh20	C	T	1: 110,026,102 (GRCm39)	A446V	probably benign	Het
Ciapin1	T	C	8: 95,551,847 (GRCm39)	N246S	possibly damaging	Het
Flt3	A	G	5: 147,309,536 (GRCm39)		probably benign	Het
Gm2027	T	A	12: 44,269,145 (GRCm39)		probably benign	Het
Hycc1	T	C	5: 24,169,997 (GRCm39)	S451G	probably damaging	Het
Hykk	T	A	9: 54,829,632 (GRCm39)		probably benign	Het
Kansl1l	T	C	1: 66,840,262 (GRCm39)	D346G	probably damaging	Het
Kcnt1	T	C	2: 25,782,374 (GRCm39)	V191A	probably benign	Het
Lcorl	G	A	5: 45,891,043 (GRCm39)	R437C	probably damaging	Het
Mtch1	T	A	17: 29,559,033 (GRCm39)		probably benign	Het
Myo1c	A	G	11: 75,551,076 (GRCm39)	N217S	probably benign	Het
Nav2	A	G	7: 49,220,462 (GRCm39)	E1669G	probably damaging	Het
Or2h15	A	G	17: 38,441,780 (GRCm39)	L101P	probably damaging	Het
Or2w4	T	C	13: 21,795,431 (GRCm39)	K236R	possibly damaging	Het
Or5p51	T	G	7: 107,444,124 (GRCm39)	D272A	probably damaging	Het
Phf20l1	T	G	15: 66,511,840 (GRCm39)	W940G	probably damaging	Het
Pi4k2b	A	C	5: 52,914,260 (GRCm39)	D309A	probably damaging	Het
Pkd2	T	C	5: 104,614,856 (GRCm39)	C233R	probably damaging	Het
Prkd3	A	G	17: 79,261,939 (GRCm39)	Y792H	probably damaging	Het
Pxdn	T	C	12: 30,032,726 (GRCm39)	L146S	probably damaging	Het
Serpinh1	A	T	7: 98,998,521 (GRCm39)	S36R	probably damaging	Het
Setx	A	T	2: 29,051,537 (GRCm39)	T2030S	probably benign	Het
Sin3b	T	A	8: 73,452,210 (GRCm39)	H105Q	probably damaging	Het
Slx4	A	T	16: 3,805,880 (GRCm39)	D557E	possibly damaging	Het
Stag1	C	T	9: 100,838,461 (GRCm39)	P1238S	probably null	Het
Stra6	C	T	9: 58,059,898 (GRCm39)		probably benign	Het
Taok1	T	A	11: 77,444,543 (GRCm39)	M511L	probably benign	Het
Tmem127	T	C	2: 127,098,979 (GRCm39)	V171A	probably damaging	Het
Tmem147	T	C	7: 30,427,526 (GRCm39)	Y97C	probably damaging	Het
Tmem150a	A	G	6: 72,335,742 (GRCm39)		probably null	Het
Top2a	C	G	11: 98,905,886 (GRCm39)		probably null	Het
Zc3hav1l	A	T	6: 38,272,125 (GRCm39)	S215T	probably damaging	Het
Zscan20	C	T	4: 128,479,675 (GRCm39)	V939I	possibly damaging	Het

Other mutations in Hipk2

Allele	Source	Chr	Coord	Type	Predicted Effect	PPH Score
IGL00582:Hipk2	APN	6	38,796,257 (GRCm39)	splice site	probably benign
IGL00814:Hipk2	APN	6	38,795,484 (GRCm39)	missense	probably damaging	1.00
IGL00907:Hipk2	APN	6	38,795,208 (GRCm39)	missense	probably damaging	1.00
IGL01350:Hipk2	APN	6	38,795,250 (GRCm39)	missense	probably damaging	1.00
IGL01714:Hipk2	APN	6	38,796,117 (GRCm39)	missense	probably damaging	1.00
IGL01893:Hipk2	APN	6	38,795,330 (GRCm39)	missense	probably benign	0.05
IGL02028:Hipk2	APN	6	38,795,691 (GRCm39)	missense	possibly damaging	0.67
IGL02133:Hipk2	APN	6	38,796,069 (GRCm39)	missense	probably benign
IGL02135:Hipk2	APN	6	38,795,934 (GRCm39)	missense	possibly damaging	0.90
IGL02543:Hipk2	APN	6	38,680,436 (GRCm39)	missense	possibly damaging	0.95
IGL02630:Hipk2	APN	6	38,795,456 (GRCm39)	missense	possibly damaging	0.48
IGL02896:Hipk2	APN	6	38,675,382 (GRCm39)	missense	probably damaging	1.00
IGL02900:Hipk2	APN	6	38,706,879 (GRCm39)	missense	probably damaging	0.96
IGL03345:Hipk2	APN	6	38,724,937 (GRCm39)	splice site	probably benign
R0070:Hipk2	UTSW	6	38,795,919 (GRCm39)	nonsense	probably null
R0092:Hipk2	UTSW	6	38,720,164 (GRCm39)	missense	probably damaging	0.97
R0184:Hipk2	UTSW	6	38,695,866 (GRCm39)	missense	possibly damaging	0.77
R0494:Hipk2	UTSW	6	38,706,924 (GRCm39)	missense	probably benign	0.03
R0617:Hipk2	UTSW	6	38,724,420 (GRCm39)	missense	possibly damaging	0.70
R0720:Hipk2	UTSW	6	38,675,491 (GRCm39)	missense	probably damaging	1.00
R1812:Hipk2	UTSW	6	38,675,098 (GRCm39)	missense	probably benign	0.14
R1864:Hipk2	UTSW	6	38,695,870 (GRCm39)	critical splice acceptor site	probably null
R1919:Hipk2	UTSW	6	38,795,919 (GRCm39)	nonsense	probably null
R1995:Hipk2	UTSW	6	38,692,909 (GRCm39)	missense	probably damaging	1.00
R2079:Hipk2	UTSW	6	38,795,720 (GRCm39)	missense	probably damaging	1.00
R2238:Hipk2	UTSW	6	38,706,850 (GRCm39)	splice site	probably benign
R2384:Hipk2	UTSW	6	38,795,306 (GRCm39)	missense	probably damaging	0.99
R3775:Hipk2	UTSW	6	38,720,029 (GRCm39)	missense	probably damaging	0.99
R3792:Hipk2	UTSW	6	38,675,491 (GRCm39)	missense	probably damaging	1.00
R3841:Hipk2	UTSW	6	38,795,861 (GRCm39)	missense	probably damaging	1.00
R3883:Hipk2	UTSW	6	38,676,200 (GRCm39)	missense	probably damaging	1.00
R4471:Hipk2	UTSW	6	38,713,857 (GRCm39)	intron	probably benign
R4724:Hipk2	UTSW	6	38,675,327 (GRCm39)	missense	probably benign	0.10
R4838:Hipk2	UTSW	6	38,795,339 (GRCm39)	missense	possibly damaging	0.94
R4843:Hipk2	UTSW	6	38,796,192 (GRCm39)	missense	possibly damaging	0.94
R5040:Hipk2	UTSW	6	38,707,816 (GRCm39)	missense	possibly damaging	0.82
R5044:Hipk2	UTSW	6	38,795,814 (GRCm39)	missense	probably benign	0.06
R5320:Hipk2	UTSW	6	38,795,212 (GRCm39)	missense	probably damaging	1.00
R5409:Hipk2	UTSW	6	38,706,977 (GRCm39)	missense	probably damaging	1.00
R5682:Hipk2	UTSW	6	38,714,408 (GRCm39)	missense	possibly damaging	0.50
R5695:Hipk2	UTSW	6	38,795,810 (GRCm39)	missense	possibly damaging	0.64
R5876:Hipk2	UTSW	6	38,707,802 (GRCm39)	critical splice donor site	probably null
R6309:Hipk2	UTSW	6	38,675,446 (GRCm39)	missense	probably damaging	1.00
R6612:Hipk2	UTSW	6	38,795,808 (GRCm39)	missense	probably benign	0.04
R6815:Hipk2	UTSW	6	38,795,777 (GRCm39)	missense	probably damaging	1.00
R7104:Hipk2	UTSW	6	38,795,579 (GRCm39)	missense	probably damaging	0.98
R7124:Hipk2	UTSW	6	38,795,413 (GRCm39)	nonsense	probably null
R7238:Hipk2	UTSW	6	38,692,992 (GRCm39)	missense	probably benign	0.45
R7712:Hipk2	UTSW	6	38,680,569 (GRCm39)	missense	probably benign	0.02
R7994:Hipk2	UTSW	6	38,795,403 (GRCm39)	missense	possibly damaging	0.94
R8190:Hipk2	UTSW	6	38,795,728 (GRCm39)	missense	possibly damaging	0.88
R8388:Hipk2	UTSW	6	38,722,630 (GRCm39)	missense	probably damaging	1.00
R8796:Hipk2	UTSW	6	38,675,158 (GRCm39)	missense	probably damaging	0.99
R9041:Hipk2	UTSW	6	38,724,909 (GRCm39)	nonsense	probably null
R9388:Hipk2	UTSW	6	38,707,956 (GRCm39)	missense	probably damaging	1.00
R9480:Hipk2	UTSW	6	38,680,377 (GRCm39)	missense	probably benign	0.37
R9485:Hipk2	UTSW	6	38,680,445 (GRCm39)	missense	possibly damaging	0.94
R9562:Hipk2	UTSW	6	38,724,390 (GRCm39)	missense	probably damaging	0.99
R9565:Hipk2	UTSW	6	38,724,390 (GRCm39)	missense	probably damaging	0.99

Protein Function and Prediction

Homeodomain interacting protein kinase 2 (Hipk2) is a conserved serine/threonine kinase that interacts with and phosphorylates homeodomain transcription factors to regulate transcription during development and in response to DNA damage (1). Hipk2 has a conserved N-terminal kinase domain with a DYRK motif, a nuclear localization sequence, a PEST domain, and C-terminal region that contains speckle-retention signal, an autoinhibitory domain, and a ubiquitylation site (1;2).

Northern blot analysis detected ubiquitous expression of a 11.0-kb HIPK2 transcript, with strongest expression in human neuronal tissue; a 7.8-kb transcript was detected in the uterus and a 1.4-kb transcript was detected in the pancreas (3). Hipk2 is detectable in postnatal day (P) 15 mouse embryos and is strong by P17 (4). In situ hybridization detected expression in neural retina, telencephalon, and muscle at P16.5 (4). Similar to human HIPK2, mouse Hipk2 is ubiquitously expressed in the adult, Pierantoni et al. detected highest expression in the heart, muscle and kidney by RT-PCR (4).

Hipk2^{tm1Hko/tm1Hko}; MGI:3624127

involves: C57BL/6

Embyronic fibroblasts from null mice are slightly resistant to UV radiation (5). Also, there are more frequent instances of neural tube defects in these mice (5).

Hipk2^{tm1Ejh/tm1Ejh}; MGI:3487301

involves: 129X1/SvJ * C57BL/6

Homozygous mice exhibit diminished locomotor activity response to amphetamine compared with wild-type mice as well as abnormal limb grasping, impaired coordination, abnormal voluntary movement, and abnormal gait (6). There is also decreased neuron apoptosis in dopaminergic neurons at E17.5 and P0 (6). Homozygotes have decreased dopaminergic neuron number throughout life (6).

Hipk2^{tm1Ejh/tm1Ejh}; MGI:3487301

involves: 129X1/SvJ * C57BL/6J

In this genetic background, homozygotes have more neurons in the trigeminal ganglion at E13.5 and P0 due to a reduction in apoptotic neurons (7).

Hipk2^{tm1Afus/tm1Afus}; MGI:4429497

involves: 129X1/SvJ * C57BL/6

Homozygotes in this model have abnormal motor capabilities/coordination/movement as well as an increase in the number of mouse embryonic fibroblasts in the G0/G1 phase of the cell cycle and reduced proliferation (8). Homozygotes have decreased birth and body weight over their life (8).

References

1. Rinaldo, C., Prodosmo, A., Siepi, F., and Soddu, S. (2007) HIPK2: A Multitalented Partner for Transcription Factors in DNA Damage Response and Development. Biochem Cell Biol. 85, 411-418.

2. Hofmann, T. G., Mincheva, A., Lichter, P., Droge, W., and Schmitz, M. L. (2000) Human Homeodomain-Interacting Protein Kinase-2 (HIPK2) is a Member of the DYRK Family of Protein Kinases and Maps to Chromosome 7q32-q34. Biochimie. 82, 1123-1127.

3. Wang, Y., Hofmann, T. G., Runkel, L., Haaf, T., Schaller, H., Debatin, K., and Hug, H. (2001) Isolation and Characterization of cDNAs for the Protein Kinase HIPK2. Biochim Biophys Acta. 1518, 168-172.

4. Pierantoni, G. M., Bulfone, A., Pentimalli, F., Fedele, M., Iuliano, R., Santoro, M., Chiariotti, L., Ballabio, A., and Fusco, A. (2002) The Homeodomain-Interacting Protein Kinase 2 Gene is Expressed Late in Embryogenesis and Preferentially in Retina, Muscle, and Neural Tissues. Biochem Biophys Res Commun. 290, 942-947.

5. Isono, K., Nemoto, K., Li, Y., Takada, Y., Suzuki, R., Katsuki, M., Nakagawara, A., and Koseki, H. (2006) Overlapping Roles for Homeodomain-Interacting Protein Kinases hipk1 and hipk2 in the Mediation of Cell Growth in Response to Morphogenetic and Genotoxic Signals. Mol Cell Biol. 26, 2758-2771.

6. Zhang, J., Pho, V., Bonasera, S. J., Holtzman, J., Tang, A. T., Hellmuth, J., Tang, S., Janak, P. H., Tecott, L. H., and Huang, E. J. (2007) Essential Function of HIPK2 in TGFbeta-Dependent Survival of Midbrain Dopamine Neurons. Nat Neurosci. 10, 77-86.

7. Wiggins, A. K., Wei, G., Doxakis, E., Wong, C., Tang, A. A., Zang, K., Luo, E. J., Neve, R. L., Reichardt, L. F., and Huang, E. J. (2004) Interaction of Brn3a and HIPK2 Mediates Transcriptional Repression of Sensory Neuron Survival. J Cell Biol. 167, 257-267.

8. Trapasso, F., Aqeilan, R. I., Iuliano, R., Visone, R., Gaudio, E., Ciuffini, L., Alder, H., Paduano, F., Pierantoni, G. M., Soddu, S., Croce, C. M., and Fusco, A. (2009) Targeted Disruption of the Murine Homeodomain-Interacting Protein Kinase-2 Causes Growth Deficiency in Vivo and Cell Cycle Arrest in Vitro. DNA Cell Biol. 28, 161-167.

Posted On

2013-01-20

Science Writer

Anne Murray