Incidental Mutation 'P0014:Acly'
| ID |
7593 |
| Institutional Source |
Beutler Lab
|
| Gene Symbol |
Acly
|
| Ensembl Gene |
ENSMUSG00000020917 |
| Gene Name |
ATP citrate lyase |
| Synonyms |
A730098H14Rik |
| MMRRC Submission |
038267-MU
|
| Accession Numbers |
|
| Essential gene? |
Essential
(E-score: 1.000)
|
| Stock # |
P0014 (G1)
|
| Quality Score |
|
|
Status
|
Validated
|
| Chromosome |
11 |
| Chromosomal Location |
100367179-100418826 bp(-) (GRCm39) |
| Type of Mutation |
missense |
| DNA Base Change (assembly) |
T to C
at 100375430 bp (GRCm39)
|
| Zygosity |
Heterozygous |
| Amino Acid Change |
Isoleucine to Valine
at position 787
(I787V)
|
| Ref Sequence |
ENSEMBL: ENSMUSP00000127632
(fasta)
|
| Gene Model |
predicted gene model for transcript(s):
[ENSMUST00000007131]
[ENSMUST00000107389]
[ENSMUST00000165111]
|
| AlphaFold |
Q91V92 |
| Predicted Effect |
probably benign
Transcript: ENSMUST00000007131
AA Change: I787V
PolyPhen 2
Score 0.031 (Sensitivity: 0.95; Specificity: 0.82)
|
| SMART Domains |
Protein: ENSMUSP00000007131
Gene: ENSMUSG00000020917
AA Change: I787V
| Domain | Start | End | E-Value | Type |
|---|
|
Pfam:ATP-grasp_2
|
6 |
207 |
2.4e-8 |
PFAM |
|
low complexity region
|
441 |
457 |
N/A |
INTRINSIC |
|
low complexity region
|
465 |
475 |
N/A |
INTRINSIC |
|
Pfam:CoA_binding
|
484 |
590 |
3.9e-14 |
PFAM |
|
Pfam:Ligase_CoA
|
650 |
775 |
1.2e-16 |
PFAM |
|
Pfam:Citrate_synt
|
868 |
1076 |
4.8e-22 |
PFAM |
|
| Predicted Effect |
probably benign
Transcript: ENSMUST00000107389
AA Change: I797V
PolyPhen 2
Score 0.028 (Sensitivity: 0.95; Specificity: 0.81)
|
| SMART Domains |
Protein: ENSMUSP00000103012
Gene: ENSMUSG00000020917
AA Change: I797V
| Domain | Start | End | E-Value | Type |
|---|
|
Pfam:Citrate_bind
|
244 |
421 |
1.7e-94 |
PFAM |
|
low complexity region
|
441 |
457 |
N/A |
INTRINSIC |
|
low complexity region
|
465 |
475 |
N/A |
INTRINSIC |
|
Pfam:CoA_binding
|
494 |
600 |
6.6e-15 |
PFAM |
|
Pfam:Ligase_CoA
|
660 |
785 |
2.1e-16 |
PFAM |
|
Pfam:Citrate_synt
|
879 |
1085 |
2e-21 |
PFAM |
|
| Predicted Effect |
noncoding transcript
Transcript: ENSMUST00000152969
|
| Predicted Effect |
probably benign
Transcript: ENSMUST00000165111
AA Change: I787V
PolyPhen 2
Score 0.031 (Sensitivity: 0.95; Specificity: 0.82)
|
| SMART Domains |
Protein: ENSMUSP00000127632
Gene: ENSMUSG00000020917
AA Change: I787V
| Domain | Start | End | E-Value | Type |
|---|
|
Pfam:ATP-grasp_2
|
6 |
207 |
2.4e-8 |
PFAM |
|
low complexity region
|
441 |
457 |
N/A |
INTRINSIC |
|
low complexity region
|
465 |
475 |
N/A |
INTRINSIC |
|
Pfam:CoA_binding
|
484 |
590 |
3.9e-14 |
PFAM |
|
Pfam:Ligase_CoA
|
650 |
775 |
1.2e-16 |
PFAM |
|
Pfam:Citrate_synt
|
868 |
1076 |
4.8e-22 |
PFAM |
|
| Meta Mutation Damage Score |
0.1618 |
| Coding Region Coverage |
- 1x: 85.4%
- 3x: 80.7%
- 10x: 66.7%
- 20x: 50.4%
|
| Validation Efficiency |
95% (100/105) |
| MGI Phenotype |
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] ATP citrate lyase is the primary enzyme responsible for the synthesis of cytosolic acetyl-CoA in many tissues. The enzyme is a tetramer (relative molecular weight approximately 440,000) of apparently identical subunits. It catalyzes the formation of acetyl-CoA and oxaloacetate from citrate and CoA with a concomitant hydrolysis of ATP to ADP and phosphate. The product, acetyl-CoA, serves several important biosynthetic pathways, including lipogenesis and cholesterogenesis. In nervous tissue, ATP citrate-lyase may be involved in the biosynthesis of acetylcholine. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Dec 2014]
PHENOTYPE: Homozygous null mutation of this gene results in embryonic lethality. Heterozygous mutants display no obvious abnormalities. Mice homozygous for a transgenic gene disruption exhibit embryonic lethality at E7. [provided by MGI curators]
|
| Allele List at MGI |
All alleles(37) : Targeted(1) Gene trapped(35) Transgenic(1)
|
| Other mutations in this stock |
Total: 19 list
| Gene | Ref | Var | Chr/Loc | Mutation | Predicted Effect | Zygosity |
|---|
| Abcb4 |
A |
G |
5: 9,000,083 (GRCm39) |
Y1017C |
probably benign |
Het |
| Aldob |
T |
C |
4: 49,538,153 (GRCm39) |
Q325R |
probably benign |
Het |
| Armh4 |
C |
T |
14: 49,989,116 (GRCm39) |
E618K |
probably damaging |
Het |
| Capns2 |
A |
G |
8: 93,628,842 (GRCm39) |
T244A |
probably damaging |
Het |
| Clec16a |
C |
T |
16: 10,378,020 (GRCm39) |
|
probably benign |
Het |
| Creb3 |
A |
G |
4: 43,563,265 (GRCm39) |
T121A |
possibly damaging |
Het |
| Ddah1 |
A |
G |
3: 145,558,913 (GRCm39) |
D160G |
probably benign |
Het |
| Dhx57 |
A |
T |
17: 80,582,620 (GRCm39) |
H328Q |
probably benign |
Het |
| Dmxl2 |
A |
C |
9: 54,309,048 (GRCm39) |
L1901R |
probably damaging |
Het |
| Dnah5 |
T |
A |
15: 28,403,619 (GRCm39) |
L3448Q |
probably damaging |
Het |
| Gcdh |
A |
G |
8: 85,615,154 (GRCm39) |
|
probably null |
Het |
| Lrrc8c |
T |
C |
5: 105,755,110 (GRCm39) |
V295A |
probably benign |
Het |
| Nek1 |
A |
T |
8: 61,524,781 (GRCm39) |
|
probably benign |
Het |
| Pkp2 |
C |
T |
16: 16,058,386 (GRCm39) |
P356L |
probably benign |
Het |
| Sipa1l3 |
T |
C |
7: 29,082,640 (GRCm39) |
T752A |
probably damaging |
Het |
| Slc38a2 |
C |
A |
15: 96,588,042 (GRCm39) |
W494L |
probably damaging |
Het |
| Ttn |
T |
C |
2: 76,628,814 (GRCm39) |
D12734G |
probably damaging |
Het |
| Uggt2 |
A |
G |
14: 119,281,950 (GRCm39) |
S742P |
probably damaging |
Het |
| Vwa3b |
C |
T |
1: 37,212,995 (GRCm39) |
|
probably benign |
Het |
|
| Other mutations in Acly |
| Allele | Source | Chr | Coord | Type | Predicted Effect | PPH Score |
|---|
|
IGL01336:Acly
|
APN |
11 |
100,386,736 (GRCm39) |
missense |
probably benign |
0.00 |
|
IGL01661:Acly
|
APN |
11 |
100,405,168 (GRCm39) |
splice site |
probably benign |
|
|
IGL02349:Acly
|
APN |
11 |
100,410,505 (GRCm39) |
missense |
probably benign |
0.01 |
|
IGL02792:Acly
|
APN |
11 |
100,369,236 (GRCm39) |
missense |
probably damaging |
0.97 |
|
IGL03026:Acly
|
APN |
11 |
100,410,516 (GRCm39) |
missense |
possibly damaging |
0.94 |
|
IGL03144:Acly
|
APN |
11 |
100,405,909 (GRCm39) |
missense |
possibly damaging |
0.84 |
|
IGL03230:Acly
|
APN |
11 |
100,384,885 (GRCm39) |
missense |
probably damaging |
0.99 |
|
IGL03266:Acly
|
APN |
11 |
100,374,578 (GRCm39) |
missense |
probably damaging |
1.00 |
|
Coyote
|
UTSW |
11 |
100,370,081 (GRCm39) |
missense |
probably damaging |
0.99 |
|
lupine
|
UTSW |
11 |
100,406,731 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R0195:Acly
|
UTSW |
11 |
100,403,800 (GRCm39) |
missense |
possibly damaging |
0.56 |
|
R0319:Acly
|
UTSW |
11 |
100,395,808 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R0598:Acly
|
UTSW |
11 |
100,369,216 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R1115:Acly
|
UTSW |
11 |
100,370,081 (GRCm39) |
missense |
probably damaging |
0.99 |
|
R1201:Acly
|
UTSW |
11 |
100,384,761 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R1498:Acly
|
UTSW |
11 |
100,374,627 (GRCm39) |
missense |
probably benign |
0.27 |
|
R1593:Acly
|
UTSW |
11 |
100,372,581 (GRCm39) |
missense |
possibly damaging |
0.74 |
|
R1804:Acly
|
UTSW |
11 |
100,406,731 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R1817:Acly
|
UTSW |
11 |
100,386,717 (GRCm39) |
missense |
probably benign |
0.00 |
|
R1980:Acly
|
UTSW |
11 |
100,386,702 (GRCm39) |
missense |
possibly damaging |
0.87 |
|
R1997:Acly
|
UTSW |
11 |
100,409,977 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R2125:Acly
|
UTSW |
11 |
100,414,322 (GRCm39) |
missense |
probably benign |
0.01 |
|
R3001:Acly
|
UTSW |
11 |
100,395,053 (GRCm39) |
missense |
possibly damaging |
0.91 |
|
R3002:Acly
|
UTSW |
11 |
100,395,053 (GRCm39) |
missense |
possibly damaging |
0.91 |
|
R3003:Acly
|
UTSW |
11 |
100,395,053 (GRCm39) |
missense |
possibly damaging |
0.91 |
|
R5194:Acly
|
UTSW |
11 |
100,414,372 (GRCm39) |
missense |
probably benign |
|
|
R5509:Acly
|
UTSW |
11 |
100,405,805 (GRCm39) |
missense |
probably damaging |
0.97 |
|
R5594:Acly
|
UTSW |
11 |
100,412,946 (GRCm39) |
splice site |
probably null |
|
|
R6077:Acly
|
UTSW |
11 |
100,410,583 (GRCm39) |
missense |
probably benign |
|
|
R6310:Acly
|
UTSW |
11 |
100,373,046 (GRCm39) |
missense |
possibly damaging |
0.92 |
|
R7099:Acly
|
UTSW |
11 |
100,383,117 (GRCm39) |
splice site |
probably null |
|
|
R7148:Acly
|
UTSW |
11 |
100,374,608 (GRCm39) |
missense |
possibly damaging |
0.49 |
|
R7149:Acly
|
UTSW |
11 |
100,375,451 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R7349:Acly
|
UTSW |
11 |
100,412,817 (GRCm39) |
missense |
probably benign |
|
|
R7450:Acly
|
UTSW |
11 |
100,370,101 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R7484:Acly
|
UTSW |
11 |
100,386,789 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R7687:Acly
|
UTSW |
11 |
100,395,680 (GRCm39) |
critical splice donor site |
probably null |
|
|
R7728:Acly
|
UTSW |
11 |
100,410,513 (GRCm39) |
missense |
probably benign |
0.06 |
|
R7728:Acly
|
UTSW |
11 |
100,407,623 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R7750:Acly
|
UTSW |
11 |
100,368,839 (GRCm39) |
critical splice donor site |
probably null |
|
|
R8042:Acly
|
UTSW |
11 |
100,405,151 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R8221:Acly
|
UTSW |
11 |
100,410,576 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R8407:Acly
|
UTSW |
11 |
100,384,897 (GRCm39) |
missense |
possibly damaging |
0.67 |
|
R8677:Acly
|
UTSW |
11 |
100,410,569 (GRCm39) |
missense |
probably damaging |
0.96 |
|
R8721:Acly
|
UTSW |
11 |
100,412,806 (GRCm39) |
critical splice donor site |
probably null |
|
|
R8861:Acly
|
UTSW |
11 |
100,375,424 (GRCm39) |
critical splice donor site |
probably null |
|
|
R8894:Acly
|
UTSW |
11 |
100,407,639 (GRCm39) |
missense |
probably benign |
0.21 |
|
R9171:Acly
|
UTSW |
11 |
100,407,657 (GRCm39) |
missense |
probably benign |
|
|
R9622:Acly
|
UTSW |
11 |
100,395,785 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R9632:Acly
|
UTSW |
11 |
100,389,072 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R9729:Acly
|
UTSW |
11 |
100,407,711 (GRCm39) |
missense |
probably benign |
0.00 |
|
R9784:Acly
|
UTSW |
11 |
100,389,112 (GRCm39) |
missense |
probably benign |
0.03 |
|
X0028:Acly
|
UTSW |
11 |
100,386,759 (GRCm39) |
missense |
probably damaging |
1.00 |
|
| Protein Function and Prediction |
ATP citrase lyase (Acly; OMIM: *108728) is an enzyme required for the synthesis of cytosolic acetyl-CoA, which subsequently functions in biosynthetic pathways such as lipogenesis and cholesterogenesis (1;2).
|
| Expression/Localization |
Acly levels increase in the rat brain during the first week of suckling (3). Acly is expressed at high levels in the kidney (4;5); lower levels are observed in the adrenals, intestine, and lung (3).
|
| Background |
AclyTgTn(sb-cHS4,Tyr)2517BOve/ TgTn(sb-cHS4,Tyr)2517BOve; MGI:5287022
FVB/N-AclyTgTn(sb-cHS4,Tyr)2517BOve
Homozygous animals are embryonic lethal at approximately E7: between implantation and somite formation (MGI:5287022).
AclyGt(NPX098)Byg/ Gt(NPX098)Byg; MGI:3036686
involves: 129P2/OlaHsd * C57BL/6
This model is also embryonic lethal; the lethality occurs around E8.5 between somite formation and embryo turning (2).
|
| References |
1. Wellen, K. E., Hatzivassiliou, G., Sachdeva, U. M., Bui, T. V., Cross, J. R., and Thompson, C. B. (2009) ATP-Citrate Lyase Links Cellular Metabolism to Histone Acetylation. Science. 324, 1076-1080.
2. Beigneux, A. P., Kosinski, C., Gavino, B., Horton, J. D., Skarnes, W. C., and Young, S. G. (2004) ATP-Citrate Lyase Deficiency in the Mouse. J Biol Chem. 279, 9557-9564.
3. Elshourbagy, N. A., Near, J. C., Kmetz, P. J., Sathe, G. M., Southan, C., Strickler, J. E., Gross, M., Young, J. F., Wells, T. N., and Groot, P. H. (1990) Rat ATP Citrate-Lyase. Molecular Cloning and Sequence Analysis of a Full-Length cDNA and mRNA Abundance as a Function of Diet, Organ, and Age. J Biol Chem. 265, 1430-1435.
5. Melnick, J. Z., Srere, P. A., Elshourbagy, N. A., Moe, O. W., Preisig, P. A., and Alpern, R. J. (1996) Adenosine Triphosphate Citrate Lyase Mediates Hypocitraturia in Rats. J Clin Invest. 98, 2381-2387. |
| Posted On |
2012-10-05 |
| Science Writer |
Anne Murray |
Incidental Mutation