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) question?
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

DomainStartEndE-ValueType
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 question?
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
GeneRefVarChr/LocMutationPredicted EffectZygosity
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
AlleleSourceChrCoordTypePredicted EffectPPH 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
Posted On 2012-10-29
Science Writer Anne Murray