Mutagenetix > Incidental Mutation

Incidental Mutation 'P0035:Brd4'

7658

Institutional Source

Beutler Lab

Gene Symbol

Brd4

Ensembl Gene

ENSMUSG00000024002

Gene Name

bromodomain containing 4

Synonyms

WI-11513, HUNK1, MCAP

MMRRC Submission

038285-MU

Accession Numbers

Essential gene?

Essential (E-score: 1.000) question?

Stock #

P0035 (G1)

Quality Score

Status

Validated

Chromosome

Chromosomal Location

32415248-32503696 bp(-) (GRCm39)

Type of Mutation

critical splice donor site (1 bp from exon)

DNA Base Change (assembly)

C to T at 32431812 bp (GRCm39)

Zygosity

Heterozygous

Amino Acid Change

Ref Sequence

ENSEMBL: ENSMUSP00000113070 (fasta)

Gene Model

predicted gene model for transcript(s): [ENSMUST00000003726] [ENSMUST00000114475] [ENSMUST00000119123] [ENSMUST00000120276] [ENSMUST00000121285] [ENSMUST00000125899] [ENSMUST00000127893]

AlphaFold

Q9ESU6

Predicted Effect

probably null
Transcript: ENSMUST00000003726

SMART Domains

Protein: ENSMUSP00000003726
Gene: ENSMUSG00000024002

Domain	Start	End	E-Value	Type
low complexity region	23	54	N/A	INTRINSIC
BROMO	56	166	1e-52	SMART
low complexity region	176	191	N/A	INTRINSIC
low complexity region	198	224	N/A	INTRINSIC
low complexity region	237	275	N/A	INTRINSIC
low complexity region	295	305	N/A	INTRINSIC
low complexity region	329	339	N/A	INTRINSIC
BROMO	352	461	1.2e-48	SMART
coiled coil region	504	570	N/A	INTRINSIC
Pfam:BET	611	675	6.4e-33	PFAM
low complexity region	701	722	N/A	INTRINSIC
low complexity region	746	796	N/A	INTRINSIC
low complexity region	828	854	N/A	INTRINSIC
low complexity region	890	926	N/A	INTRINSIC
low complexity region	929	939	N/A	INTRINSIC
low complexity region	953	1005	N/A	INTRINSIC
low complexity region	1013	1042	N/A	INTRINSIC
low complexity region	1086	1100	N/A	INTRINSIC
low complexity region	1105	1120	N/A	INTRINSIC
low complexity region	1135	1147	N/A	INTRINSIC
low complexity region	1201	1212	N/A	INTRINSIC
low complexity region	1248	1260	N/A	INTRINSIC
coiled coil region	1261	1345	N/A	INTRINSIC
Pfam:BRD4_CDT	1358	1400	3.8e-24	PFAM

Predicted Effect

probably benign
Transcript: ENSMUST00000114475

SMART Domains

Protein: ENSMUSP00000110119
Gene: ENSMUSG00000024002

Domain	Start	End	E-Value	Type
low complexity region	23	54	N/A	INTRINSIC
BROMO	56	166	1.67e-50	SMART
low complexity region	197	223	N/A	INTRINSIC
low complexity region	236	274	N/A	INTRINSIC
low complexity region	294	304	N/A	INTRINSIC
low complexity region	328	338	N/A	INTRINSIC
BROMO	351	460	1.81e-46	SMART
coiled coil region	503	569	N/A	INTRINSIC
PDB:2JNS\|A	606	683	3e-46	PDB
low complexity region	700	720	N/A	INTRINSIC

Predicted Effect

probably benign
Transcript: ENSMUST00000119123

SMART Domains

Protein: ENSMUSP00000113197
Gene: ENSMUSG00000024002

Domain	Start	End	E-Value	Type
low complexity region	23	54	N/A	INTRINSIC
BROMO	56	166	1.67e-50	SMART
low complexity region	197	223	N/A	INTRINSIC
low complexity region	236	274	N/A	INTRINSIC
low complexity region	294	304	N/A	INTRINSIC
low complexity region	328	338	N/A	INTRINSIC
BROMO	351	460	1.81e-46	SMART
coiled coil region	503	569	N/A	INTRINSIC
PDB:2JNS\|A	606	683	6e-46	PDB
low complexity region	700	721	N/A	INTRINSIC
low complexity region	745	795	N/A	INTRINSIC
low complexity region	827	853	N/A	INTRINSIC
low complexity region	889	925	N/A	INTRINSIC
low complexity region	928	938	N/A	INTRINSIC
low complexity region	952	1004	N/A	INTRINSIC
low complexity region	1012	1041	N/A	INTRINSIC
low complexity region	1085	1099	N/A	INTRINSIC
low complexity region	1104	1119	N/A	INTRINSIC
low complexity region	1134	1146	N/A	INTRINSIC
low complexity region	1200	1211	N/A	INTRINSIC
low complexity region	1247	1259	N/A	INTRINSIC
coiled coil region	1260	1344	N/A	INTRINSIC
low complexity region	1361	1381	N/A	INTRINSIC

Predicted Effect

probably null
Transcript: ENSMUST00000120276

SMART Domains

Protein: ENSMUSP00000112474
Gene: ENSMUSG00000024002

Domain	Start	End	E-Value	Type
low complexity region	23	54	N/A	INTRINSIC
BROMO	56	166	1.67e-50	SMART
low complexity region	197	223	N/A	INTRINSIC
low complexity region	236	274	N/A	INTRINSIC
low complexity region	294	304	N/A	INTRINSIC
low complexity region	328	338	N/A	INTRINSIC
BROMO	351	460	1.81e-46	SMART
coiled coil region	503	569	N/A	INTRINSIC
PDB:2JNS\|A	606	683	3e-46	PDB
low complexity region	700	721	N/A	INTRINSIC

Predicted Effect

probably null
Transcript: ENSMUST00000121285

SMART Domains

Protein: ENSMUSP00000113070
Gene: ENSMUSG00000024002

Domain	Start	End	E-Value	Type
low complexity region	23	54	N/A	INTRINSIC
BROMO	56	166	1.67e-50	SMART
low complexity region	197	223	N/A	INTRINSIC
low complexity region	236	274	N/A	INTRINSIC
low complexity region	294	304	N/A	INTRINSIC
low complexity region	328	338	N/A	INTRINSIC
BROMO	351	460	1.81e-46	SMART
coiled coil region	503	569	N/A	INTRINSIC
PDB:2JNS\|A	606	683	6e-46	PDB
low complexity region	700	721	N/A	INTRINSIC
low complexity region	745	795	N/A	INTRINSIC
low complexity region	827	853	N/A	INTRINSIC
low complexity region	889	925	N/A	INTRINSIC
low complexity region	928	938	N/A	INTRINSIC
low complexity region	952	1004	N/A	INTRINSIC
low complexity region	1012	1041	N/A	INTRINSIC
low complexity region	1085	1099	N/A	INTRINSIC
low complexity region	1104	1119	N/A	INTRINSIC
low complexity region	1134	1146	N/A	INTRINSIC
low complexity region	1200	1211	N/A	INTRINSIC
low complexity region	1247	1259	N/A	INTRINSIC
coiled coil region	1260	1344	N/A	INTRINSIC
low complexity region	1361	1381	N/A	INTRINSIC

Predicted Effect

probably benign
Transcript: ENSMUST00000125899

SMART Domains

Protein: ENSMUSP00000115277
Gene: ENSMUSG00000024002

Domain	Start	End	E-Value	Type
low complexity region	23	54	N/A	INTRINSIC
BROMO	56	144	5.02e-31	SMART

Predicted Effect

probably benign
Transcript: ENSMUST00000127893

SMART Domains

Protein: ENSMUSP00000115163
Gene: ENSMUSG00000024002

Domain	Start	End	E-Value	Type
low complexity region	23	54	N/A	INTRINSIC
BROMO	56	166	1.67e-50	SMART
low complexity region	197	223	N/A	INTRINSIC
low complexity region	236	274	N/A	INTRINSIC
low complexity region	294	304	N/A	INTRINSIC
low complexity region	328	338	N/A	INTRINSIC
BROMO	351	460	1.81e-46	SMART
coiled coil region	503	531	N/A	INTRINSIC
low complexity region	536	557	N/A	INTRINSIC

Meta Mutation Damage Score

0.9597

Coding Region Coverage

1x: 79.0%
3x: 68.4%
10x: 37.5%
20x: 15.8%

Validation Efficiency

82% (103/125)

MGI Phenotype

FUNCTION: This gene was temporarily named bromodomain-containing 5 (Brd5) and was renamed bromodomain-containing 4 (Brd4). [provided by RefSeq, Jul 2008]
PHENOTYPE: Homozygotes for a gene-trap null mutation die soon after implantation. Heterozygotes exhibit impaired pre- and postnatal growth, head malformations, lack of subcutaneous fat, cataracts, and abnormal liver cells. [provided by MGI curators]

Allele List at MGI

All alleles(161) : Targeted(1) Gene trapped(160)

Other mutations in this stock

Total: 18 list
Gene	Ref	Var	Chr/Loc	Mutation	Predicted Effect	Zygosity
Bub1b	G	A	2: 118,452,666 (GRCm39)	E440K	probably damaging	Het
Cfap70	A	G	14: 20,474,539 (GRCm39)		probably benign	Het
Cryba2	A	G	1: 74,929,171 (GRCm39)	S191P	probably damaging	Het
Dsg3	A	C	18: 20,673,026 (GRCm39)	N899T	probably benign	Het
Htr2b	A	T	1: 86,038,452 (GRCm39)	H51Q	probably benign	Het
Lmod2	T	C	6: 24,597,885 (GRCm39)	S2P	probably damaging	Het
Lrrc37a	T	A	11: 103,393,958 (GRCm39)	E489V	possibly damaging	Het
Mdn1	A	T	4: 32,749,934 (GRCm39)	Q4372H	probably benign	Het
Med13l	C	T	5: 118,880,685 (GRCm39)	T1259I	probably benign	Het
Muc4	T	C	16: 32,580,622 (GRCm39)		probably benign	Het
Pcsk2	C	T	2: 143,637,871 (GRCm39)	T369I	probably damaging	Het
Pggt1b	G	C	18: 46,392,787 (GRCm39)	H121Q	probably damaging	Het
Pkhd1	T	C	1: 20,187,571 (GRCm39)	D3579G	probably benign	Het
Psd	T	C	19: 46,309,400 (GRCm39)	E520G	possibly damaging	Het
Scfd2	A	T	5: 74,385,980 (GRCm39)	M613K	possibly damaging	Het
Tbc1d32	A	C	10: 56,074,535 (GRCm39)	F226C	probably damaging	Het
Ttc8	T	C	12: 98,942,675 (GRCm39)		probably benign	Het
Zfp462	T	C	4: 55,009,086 (GRCm39)	S351P	probably benign	Het

Other mutations in Brd4

Allele	Source	Chr	Coord	Type	Predicted Effect	PPH Score
IGL01736:Brd4	APN	17	32,417,649 (GRCm39)	splice site	probably benign
IGL01758:Brd4	APN	17	32,431,803 (GRCm39)	unclassified	probably benign
IGL02750:Brd4	APN	17	32,417,353 (GRCm39)	unclassified	probably benign
IGL03066:Brd4	APN	17	32,418,062 (GRCm39)	intron	probably benign
IGL03338:Brd4	APN	17	32,432,046 (GRCm39)	missense	probably damaging	1.00
Admirable	UTSW	17	32,444,557 (GRCm39)	missense	unknown
H8562:Brd4	UTSW	17	32,448,377 (GRCm39)	splice site	probably benign
R0243:Brd4	UTSW	17	32,443,097 (GRCm39)	missense	probably benign	0.15
R0281:Brd4	UTSW	17	32,432,514 (GRCm39)	unclassified	probably benign
R0331:Brd4	UTSW	17	32,421,489 (GRCm39)	missense	probably benign	0.01
R0722:Brd4	UTSW	17	32,431,956 (GRCm39)	missense	possibly damaging	0.76
R0750:Brd4	UTSW	17	32,439,226 (GRCm39)	missense	probably benign	0.09
R1544:Brd4	UTSW	17	32,417,646 (GRCm39)	splice site	probably benign
R1920:Brd4	UTSW	17	32,417,060 (GRCm39)	unclassified	probably benign
R1922:Brd4	UTSW	17	32,417,060 (GRCm39)	unclassified	probably benign
R1957:Brd4	UTSW	17	32,440,340 (GRCm39)	missense	possibly damaging	0.50
R2240:Brd4	UTSW	17	32,432,613 (GRCm39)	unclassified	probably benign
R2316:Brd4	UTSW	17	32,431,884 (GRCm39)	missense	probably benign	0.03
R2333:Brd4	UTSW	17	32,440,431 (GRCm39)	missense	probably damaging	0.97
R3809:Brd4	UTSW	17	32,430,244 (GRCm39)	missense	possibly damaging	0.72
R4273:Brd4	UTSW	17	32,433,756 (GRCm39)	missense	probably benign
R4595:Brd4	UTSW	17	32,417,896 (GRCm39)	missense	probably damaging	0.97
R4854:Brd4	UTSW	17	32,439,211 (GRCm39)	missense	probably damaging	0.96
R4923:Brd4	UTSW	17	32,418,214 (GRCm39)	missense	probably benign	0.38
R5014:Brd4	UTSW	17	32,417,372 (GRCm39)	unclassified	probably benign
R5757:Brd4	UTSW	17	32,420,272 (GRCm39)	unclassified	probably benign
R5979:Brd4	UTSW	17	32,417,700 (GRCm39)	missense	probably benign	0.32
R6212:Brd4	UTSW	17	32,421,423 (GRCm39)	missense	probably damaging	0.98
R6394:Brd4	UTSW	17	32,443,121 (GRCm39)	nonsense	probably null
R6643:Brd4	UTSW	17	32,417,470 (GRCm39)	missense	unknown
R7024:Brd4	UTSW	17	32,440,884 (GRCm39)	utr 3 prime	probably benign
R7033:Brd4	UTSW	17	32,417,989 (GRCm39)	missense	probably benign	0.13
R7220:Brd4	UTSW	17	32,444,557 (GRCm39)	missense	unknown
R7682:Brd4	UTSW	17	32,420,134 (GRCm39)	missense	unknown
R7731:Brd4	UTSW	17	32,430,198 (GRCm39)	missense	possibly damaging	0.73
R7732:Brd4	UTSW	17	32,440,386 (GRCm39)	missense	unknown
R7750:Brd4	UTSW	17	32,432,521 (GRCm39)	missense	unknown
R7756:Brd4	UTSW	17	32,417,956 (GRCm39)	missense	unknown
R7758:Brd4	UTSW	17	32,417,956 (GRCm39)	missense	unknown
R7779:Brd4	UTSW	17	32,431,910 (GRCm39)	missense	probably benign	0.03
R8214:Brd4	UTSW	17	32,431,921 (GRCm39)	missense	probably benign	0.19
R8405:Brd4	UTSW	17	32,448,505 (GRCm39)	missense	unknown
R9675:Brd4	UTSW	17	32,433,786 (GRCm39)	missense	unknown
X0064:Brd4	UTSW	17	32,420,101 (GRCm39)	unclassified	probably benign

Nature of Mutation

Multiple transcripts of the Brd4 gene are displayed on Ensembl.

Protein Function and Prediction

The Brd4 gene encodes multiple isoforms of a nuclear protein that plays a role in a process governing chromosomal dynamics during mitosis. The standard isoform contains 1400 amino acids and has two bromo domains at residues 75-147 and 369-441 that associate with chromatin (Uniprot Q9ESU6). Brd4 is a member of the BET family of nuclear proteins and is proposed to have a role in chromosomal dynamics during mitosis (1) by binding preferentially to acetylated chromatin. Further studies identified Brd4 as a component of the E2 chromosomal attachment complex (2). Brd4 can function in both gene activation and repression [reviewed in (3)]. Inhibition of Brd4 function by exposure to anti-Brd4 antibodies can lead to G2/M arrest (1); overexpression leads to G1/S arrest (4).

Expression/Localization

Northern blot of mouse and human tissues found that Brd4 is ubiquitously expressed (1;5). Immunofluoresence detected the Brd4 protein in the nucleus and in mitotic cells Brd4 is almost exclusively at condensed chromosomes (1).

Background

Brd4^{Gt(pGT1.8TM)ST132Nimr/ Gt(pGT1.8TM)ST132Nimr}; MGI:2674141

involves: 129P2/Ola * C57BL/6J

Homozygotes for a gene-trap null mutation die soon after implantation (6). Heterozygotes exhibit impaired pre- and postnatal growth, head malformations, lack of subcutaneous fat, cataracts, and abnormal liver cells (6).

References

1. Dey, A., Ellenberg, J., Farina, A., Coleman, A. E., Maruyama, T., Sciortino, S., Lippincott-Schwartz, J., and Ozato, K. (2000) A Bromodomain Protein, MCAP, Associates with Mitotic Chromosomes and Affects G(2)-to-M Transition. Mol Cell Biol. 20, 6537-6549.

2. You, J., Croyle, J. L., Nishimura, A., Ozato, K., and Howley, P. M. (2004) Interaction of the Bovine Papillomavirus E2 Protein with Brd4 Tethers the Viral DNA to Host Mitotic Chromosomes. Cell. 117, 349-360.

3. Wu, S. Y., and Chiang, C. M. (2007) The Double Bromodomain-Containing Chromatin Adaptor Brd4 and Transcriptional Regulation. J Biol Chem. 282, 13141-13145.

4. Maruyama, T., Farina, A., Dey, A., Cheong, J., Bermudez, V. P., Tamura, T., Sciortino, S., Shuman, J., Hurwitz, J., and Ozato, K. (2002) A Mammalian Bromodomain Protein, brd4, Interacts with Replication Factor C and Inhibits Progression to S Phase. Mol Cell Biol. 22, 6509-6520.

5. French, C. A., Miyoshi, I., Kubonishi, I., Grier, H. E., Perez-Atayde, A. R., and Fletcher, J. A. (2003) BRD4-NUT Fusion Oncogene: A Novel Mechanism in Aggressive Carcinoma. Cancer Res. 63, 304-307.

6. Houzelstein, D., Bullock, S. L., Lynch, D. E., Grigorieva, E. F., Wilson, V. A., and Beddington, R. S. (2002) Growth and Early Postimplantation Defects in Mice Deficient for the Bromodomain-Containing Protein Brd4. Mol Cell Biol. 22, 3794-3802.

Posted On

2012-10-29

Science Writer

Anne Murray