Incidental Mutation 'P0021:Fig4'
ID |
7716 |
Institutional Source |
Beutler Lab
|
Gene Symbol |
Fig4
|
Ensembl Gene |
ENSMUSG00000038417 |
Gene Name |
FIG4 phosphoinositide 5-phosphatase |
Synonyms |
A530089I17Rik |
MMRRC Submission |
038274-MU
|
Accession Numbers |
|
Essential gene? |
Possibly essential
(E-score: 0.530)
|
Stock # |
P0021 (G1)
|
Quality Score |
|
Status
|
Validated
|
Chromosome |
10 |
Chromosomal Location |
41064168-41179237 bp(-) (GRCm39) |
Type of Mutation |
missense |
DNA Base Change (assembly) |
A to G
at 41127821 bp (GRCm39)
|
Zygosity |
Heterozygous |
Amino Acid Change |
Serine to Proline
at position 548
(S548P)
|
Ref Sequence |
ENSEMBL: ENSMUSP00000039598
(fasta)
|
Gene Model |
predicted gene model for transcript(s):
[ENSMUST00000043814]
|
AlphaFold |
Q91WF7 |
Predicted Effect |
probably damaging
Transcript: ENSMUST00000043814
AA Change: S548P
PolyPhen 2
Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)
|
SMART Domains |
Protein: ENSMUSP00000039598 Gene: ENSMUSG00000038417 AA Change: S548P
Domain | Start | End | E-Value | Type |
Pfam:Syja_N
|
93 |
424 |
1.7e-79 |
PFAM |
Blast:Lactamase_B
|
533 |
610 |
6e-21 |
BLAST |
low complexity region
|
742 |
771 |
N/A |
INTRINSIC |
low complexity region
|
805 |
813 |
N/A |
INTRINSIC |
|
Meta Mutation Damage Score |
0.9537 |
Coding Region Coverage |
- 1x: 73.1%
- 3x: 63.5%
- 10x: 31.6%
- 20x: 17.3%
|
Validation Efficiency |
79% (146/184) |
MGI Phenotype |
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] The protein encoded by this gene belongs to the SAC domain-containing protein gene family. The SAC domain, approximately 400 amino acids in length and consisting of seven conserved motifs, has been shown to possess phosphoinositide phosphatase activity. The yeast homolog, Sac1p, is involved in the regulation of various phosphoinositides, and affects diverse cellular functions such as actin cytoskeleton organization, Golgi function, and maintenance of vacuole morphology. Membrane-bound phosphoinositides function as signaling molecules and play a key role in vesicle trafficking in eukaryotic cells. Mutations in this gene have been associated with Charcot-Marie-Tooth disease, type 4J. [provided by RefSeq, Jul 2008] PHENOTYPE: Mice homozygous for a spontaneous allele exhibit premature death, severe tremors, diluted coat color, neurodegeneration, impaired coordination, muscle weakness, small size and reduced spleen. [provided by MGI curators]
|
Allele List at MGI |
All alleles(16) : Targeted(3) Gene trapped(12) Spontaneous(1)
|
Other mutations in this stock |
Total: 7 list
Gene | Ref | Var | Chr/Loc | Mutation | Predicted Effect | Zygosity |
Fas |
A |
G |
19: 34,284,610 (GRCm39) |
E39G |
probably damaging |
Het |
Msh4 |
T |
A |
3: 153,594,455 (GRCm39) |
E115D |
probably damaging |
Het |
Ptpn13 |
A |
G |
5: 103,676,686 (GRCm39) |
E683G |
probably benign |
Het |
Rasgrp3 |
G |
T |
17: 75,807,708 (GRCm39) |
R255L |
probably damaging |
Het |
Rnf168 |
C |
T |
16: 32,117,705 (GRCm39) |
T422I |
probably damaging |
Het |
Smarcd1 |
T |
C |
15: 99,610,242 (GRCm39) |
|
probably benign |
Het |
Stxbp1 |
T |
C |
2: 32,713,550 (GRCm39) |
K29E |
probably damaging |
Het |
|
Other mutations in Fig4 |
Allele | Source | Chr | Coord | Type | Predicted Effect | PPH Score |
IGL00972:Fig4
|
APN |
10 |
41,127,784 (GRCm39) |
missense |
probably damaging |
0.99 |
IGL01013:Fig4
|
APN |
10 |
41,143,782 (GRCm39) |
missense |
probably benign |
0.00 |
IGL01066:Fig4
|
APN |
10 |
41,161,413 (GRCm39) |
splice site |
probably benign |
|
IGL01501:Fig4
|
APN |
10 |
41,146,370 (GRCm39) |
missense |
probably benign |
|
IGL01503:Fig4
|
APN |
10 |
41,132,514 (GRCm39) |
missense |
probably benign |
0.00 |
IGL01535:Fig4
|
APN |
10 |
41,132,490 (GRCm39) |
missense |
probably benign |
0.00 |
IGL01733:Fig4
|
APN |
10 |
41,153,389 (GRCm39) |
missense |
possibly damaging |
0.49 |
IGL01782:Fig4
|
APN |
10 |
41,146,396 (GRCm39) |
missense |
probably benign |
0.18 |
IGL01866:Fig4
|
APN |
10 |
41,108,160 (GRCm39) |
missense |
possibly damaging |
0.77 |
IGL01934:Fig4
|
APN |
10 |
41,104,108 (GRCm39) |
missense |
probably benign |
0.03 |
IGL01966:Fig4
|
APN |
10 |
41,108,098 (GRCm39) |
splice site |
probably null |
|
IGL02032:Fig4
|
APN |
10 |
41,179,002 (GRCm39) |
missense |
probably benign |
0.00 |
IGL02225:Fig4
|
APN |
10 |
41,132,448 (GRCm39) |
missense |
probably benign |
|
IGL02345:Fig4
|
APN |
10 |
41,143,770 (GRCm39) |
missense |
probably null |
1.00 |
IGL02532:Fig4
|
APN |
10 |
41,161,277 (GRCm39) |
splice site |
probably benign |
|
IGL02686:Fig4
|
APN |
10 |
41,140,000 (GRCm39) |
missense |
probably damaging |
0.99 |
IGL02965:Fig4
|
APN |
10 |
41,161,661 (GRCm39) |
missense |
probably damaging |
0.98 |
R0017:Fig4
|
UTSW |
10 |
41,149,003 (GRCm39) |
missense |
possibly damaging |
0.94 |
R0017:Fig4
|
UTSW |
10 |
41,149,003 (GRCm39) |
missense |
possibly damaging |
0.94 |
R0117:Fig4
|
UTSW |
10 |
41,106,037 (GRCm39) |
nonsense |
probably null |
|
R0144:Fig4
|
UTSW |
10 |
41,134,045 (GRCm39) |
missense |
probably damaging |
0.99 |
R0655:Fig4
|
UTSW |
10 |
41,161,673 (GRCm39) |
missense |
probably damaging |
1.00 |
R0701:Fig4
|
UTSW |
10 |
41,116,508 (GRCm39) |
nonsense |
probably null |
|
R0751:Fig4
|
UTSW |
10 |
41,148,978 (GRCm39) |
missense |
probably damaging |
1.00 |
R1540:Fig4
|
UTSW |
10 |
41,064,582 (GRCm39) |
missense |
possibly damaging |
0.60 |
R1586:Fig4
|
UTSW |
10 |
41,141,423 (GRCm39) |
missense |
probably damaging |
0.99 |
R2916:Fig4
|
UTSW |
10 |
41,134,071 (GRCm39) |
missense |
probably damaging |
0.98 |
R3927:Fig4
|
UTSW |
10 |
41,139,135 (GRCm39) |
missense |
probably benign |
|
R4304:Fig4
|
UTSW |
10 |
41,132,423 (GRCm39) |
missense |
probably benign |
0.01 |
R4586:Fig4
|
UTSW |
10 |
41,064,628 (GRCm39) |
missense |
probably damaging |
1.00 |
R4678:Fig4
|
UTSW |
10 |
41,148,994 (GRCm39) |
missense |
probably benign |
0.27 |
R4858:Fig4
|
UTSW |
10 |
41,109,586 (GRCm39) |
missense |
probably benign |
0.00 |
R5614:Fig4
|
UTSW |
10 |
41,148,981 (GRCm39) |
missense |
probably damaging |
0.98 |
R5896:Fig4
|
UTSW |
10 |
41,130,881 (GRCm39) |
missense |
possibly damaging |
0.67 |
R6126:Fig4
|
UTSW |
10 |
41,141,443 (GRCm39) |
missense |
probably damaging |
0.99 |
R7056:Fig4
|
UTSW |
10 |
41,096,928 (GRCm39) |
missense |
probably benign |
0.09 |
R7350:Fig4
|
UTSW |
10 |
41,127,752 (GRCm39) |
missense |
probably benign |
0.03 |
R7452:Fig4
|
UTSW |
10 |
41,116,633 (GRCm39) |
missense |
possibly damaging |
0.88 |
R7481:Fig4
|
UTSW |
10 |
41,106,001 (GRCm39) |
critical splice donor site |
probably null |
|
R7610:Fig4
|
UTSW |
10 |
41,129,709 (GRCm39) |
missense |
probably damaging |
1.00 |
R7818:Fig4
|
UTSW |
10 |
41,139,162 (GRCm39) |
missense |
probably damaging |
0.98 |
R7830:Fig4
|
UTSW |
10 |
41,132,462 (GRCm39) |
missense |
probably benign |
0.00 |
R8263:Fig4
|
UTSW |
10 |
41,143,711 (GRCm39) |
nonsense |
probably null |
|
R8319:Fig4
|
UTSW |
10 |
41,139,097 (GRCm39) |
missense |
probably damaging |
1.00 |
R8409:Fig4
|
UTSW |
10 |
41,141,427 (GRCm39) |
missense |
probably benign |
0.01 |
R8435:Fig4
|
UTSW |
10 |
41,161,670 (GRCm39) |
missense |
probably benign |
|
R8474:Fig4
|
UTSW |
10 |
41,108,170 (GRCm39) |
missense |
probably benign |
0.30 |
R9086:Fig4
|
UTSW |
10 |
41,161,399 (GRCm39) |
missense |
possibly damaging |
0.50 |
R9131:Fig4
|
UTSW |
10 |
41,141,407 (GRCm39) |
missense |
possibly damaging |
0.95 |
R9248:Fig4
|
UTSW |
10 |
41,153,478 (GRCm39) |
missense |
probably benign |
|
R9401:Fig4
|
UTSW |
10 |
41,143,733 (GRCm39) |
missense |
probably benign |
|
R9564:Fig4
|
UTSW |
10 |
41,161,387 (GRCm39) |
missense |
probably benign |
0.20 |
R9627:Fig4
|
UTSW |
10 |
41,108,178 (GRCm39) |
missense |
probably benign |
0.01 |
R9649:Fig4
|
UTSW |
10 |
41,143,763 (GRCm39) |
missense |
probably benign |
0.00 |
Z1088:Fig4
|
UTSW |
10 |
41,129,727 (GRCm39) |
missense |
probably damaging |
1.00 |
|
Protein Function and Prediction |
FIG4 is a PtdIns(3,5)P2 5-phosphatase that functions in a trimolecular complex that tightly regulates the level of PtdIns(3,5)P2 (1;2). FIG4 hydrolyzes the D5 phosphate from PtdIns(4,5)P2, PtdIns(3,5)P2, and PtdIns(3,4,5)P3, but it does not use PtdIns(5)P or other PtdIns substrates (3). Fig4 maintains peripheral nervous system myelin and is required for normal neural development (4). It is proposed that Fig4 may prevent the accumulation of lysosomes after neuronal/glial injury and in neurodegeneration (4).
|
Expression/Localization |
Fig4 declines from the embryonic stage to adulthood, Fig4 levels remain high in myelinating cells and dorsal root ganglion (DRG) sensory neurons (4). Fig4 predominantly resides in early endosomes (4).
|
Background |
Mutations in FIG4 are linked to amyotrophic lateral sclerosis 11 [OMIM: #612577; (5)] and Charcot-Marie-Tooth disease, type 4J [OMIM: #611228; (6;7)]. Charcot-Marie-Tooth disease is a peripheral neuropathy characterized by distal motor and sensory impairment resulting in gait difficulties and associated with foot deformities.
Fig4plt1/plt1; MGI:3716838
involves: 129 * C3H * C57BL/6J * CAST/Ei * SJL
Mice homozygous for a spontaneous allele exhibit premature death, diluted coat color, neurodegeneration, and spongiform encephalopathy (8).
Fig4plt1/plt1; MGI:3716838
involves: 129P2/OlaHsd * C3H * C57BL/6 * CAST/Ei * SJL
Mice homozygous for a spontaneous allele exhibit premature death, severe tremors, diluted coat color, neurodegeneration, impaired coordination, muscle weakness, small size and reduced spleen (6;9).
|
References |
1. Gary, J. D., Sato, T. K., Stefan, C. J., Bonangelino, C. J., Weisman, L. S., and Emr, S. D. (2002) Regulation of Fab1 Phosphatidylinositol 3-Phosphate 5-Kinase Pathway by Vac7 Protein and Fig4, a Polyphosphoinositide Phosphatase Family Member. Mol Biol Cell. 13, 1238-1251.
3. Sbrissa, D., Ikonomov, O. C., Fu, Z., Ijuin, T., Gruenberg, J., Takenawa, T., and Shisheva, A. (2007) Core Protein Machinery for Mammalian Phosphatidylinositol 3,5-Bisphosphate Synthesis and Turnover that Regulates the Progression of Endosomal Transport. Novel Sac Phosphatase Joins the ArPIKfyve-PIKfyve Complex. J Biol Chem. 282, 23878-23891.
4. Guo, J., Ma, Y. H., Yan, Q., Wang, L., Zeng, Y. S., Wu, J. L., and Li, J. (2012) Fig4 Expression in the Rodent Nervous System and its Potential Role in Preventing Abnormal Lysosomal Accumulation. J Neuropathol Exp Neurol. 71, 28-39.
5. Chow, C. Y., Landers, J. E., Bergren, S. K., Sapp, P. C., Grant, A. E., Jones, J. M., Everett, L., Lenk, G. M., McKenna-Yasek, D. M., Weisman, L. S., Figlewicz, D., Brown, R. H., and Meisler, M. H. (2009) Deleterious Variants of FIG4, a Phosphoinositide Phosphatase, in Patients with ALS. Am J Hum Genet. 84, 85-88.
6. Chow, C. Y., Zhang, Y., Dowling, J. J., Jin, N., Adamska, M., Shiga, K., Szigeti, K., Shy, M. E., Li, J., Zhang, X., Lupski, J. R., Weisman, L. S., and Meisler, M. H. (2007) Mutation of FIG4 Causes Neurodegeneration in the Pale Tremor Mouse and Patients with CMT4J. Nature. 448, 68-72.
7. Nicholson, G., Lenk, G. M., Reddel, S. W., Grant, A. E., Towne, C. F., Ferguson, C. J., Simpson, E., Scheuerle, A., Yasick, M., Hoffman, S., Blouin, R., Brandt, C., Coppola, G., Biesecker, L. G., Batish, S. D., and Meisler, M. H. (2011) Distinctive Genetic and Clinical Features of CMT4J: A Severe Neuropathy Caused by Mutations in the PI(3,5)P(2) Phosphatase FIG4. Brain. 134, 1959-1971.
8. Lenk, G. M., Ferguson, C. J., Chow, C. Y., Jin, N., Jones, J. M., Grant, A. E., Zolov, S. N., Winters, J. J., Giger, R. J., Dowling, J. J., Weisman, L. S., and Meisler, M. H. (2011) Pathogenic Mechanism of the FIG4 Mutation Responsible for Charcot-Marie-Tooth Disease CMT4J. PLoS Genet. 7, e1002104.
9. Ferguson, C. J., Lenk, G. M., Jones, J. M., Grant, A. E., Winters, J. J., Dowling, J. J., Giger, R. J., and Meisler, M. H. (2012) Neuronal Expression of Fig4 is both Necessary and Sufficient to Prevent Spongiform Neurodegeneration. Hum Mol Genet. 21, 3525-3534.
|
Posted On |
2012-10-29 |
Science Writer |
Anne Murray |