ID FIG4_HUMAN Reviewed; 907 AA. AC Q92562; Q53H49; Q5TCS6; DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot. DT 01-FEB-1997, sequence version 1. DT 24-JAN-2024, entry version 177. DE RecName: Full=Polyphosphoinositide phosphatase {ECO:0000305}; DE EC=3.1.3.- {ECO:0000269|PubMed:17556371, ECO:0000269|PubMed:33098764}; DE EC=3.1.3.36 {ECO:0000269|PubMed:17556371}; DE EC=3.1.3.86 {ECO:0000269|PubMed:17556371}; DE AltName: Full=Phosphatidylinositol 3,5-bisphosphate 5-phosphatase; DE AltName: Full=SAC domain-containing protein 3 {ECO:0000303|PubMed:17556371}; DE AltName: Full=Serine-protein phosphatase FIG4 {ECO:0000305}; DE EC=3.1.3.16 {ECO:0000269|PubMed:33098764}; GN Name=FIG4 {ECO:0000312|HGNC:HGNC:16873}; GN Synonyms=KIAA0274, SAC3 {ECO:0000303|PubMed:17556371}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain; RX PubMed=9039502; DOI=10.1093/dnares/3.5.321; RA Nagase T., Seki N., Ishikawa K., Ohira M., Kawarabayasi Y., Ohara O., RA Tanaka A., Kotani H., Miyajima N., Nomura N.; RT "Prediction of the coding sequences of unidentified human genes. VI. The RT coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of RT cDNA clones from cell line KG-1 and brain."; RL DNA Res. 3:321-329(1996). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT ALA-654. RC TISSUE=Colon; RA Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y., RA Tanaka A., Yokoyama S.; RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=14574404; DOI=10.1038/nature02055; RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., RA Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., RA Andrews T.D., Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., RA Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., RA Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., RA Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., RA Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., RA French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., RA Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., RA Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., RA Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., RA Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., RA Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., RA Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., RA Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., RA Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., RA Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., RA Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., RA Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., RA Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., RA Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., RA Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., RA West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., RA Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., RA Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., RA Rogers J., Beck S.; RT "The DNA sequence and analysis of human chromosome 6."; RL Nature 425:805-811(2003). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [5] RP FUNCTION, SUBCELLULAR LOCATION, IDENTIFICATION IN THE PI(3,5)P2 REGULATORY RP COMPLEX, AND MUTAGENESIS OF ASP-488. RX PubMed=17556371; DOI=10.1074/jbc.m611678200; RA Sbrissa D., Ikonomov O.C., Fu Z., Ijuin T., Gruenberg J., Takenawa T., RA Shisheva A.; RT "Core protein machinery for mammalian phosphatidylinositol 3,5-bisphosphate RT synthesis and turnover that regulates the progression of endosomal RT transport. Novel Sac phosphatase joins the ArPIKfyve-PIKfyve complex."; RL J. Biol. Chem. 282:23878-23891(2007). RN [6] RP IDENTIFICATION IN THE PI(3,5)P2 REGULATORY COMPLEX. RX PubMed=18950639; DOI=10.1016/j.jmb.2008.10.009; RA Sbrissa D., Ikonomov O.C., Fenner H., Shisheva A.; RT "ArPIKfyve homomeric and heteromeric interactions scaffold PIKfyve and Sac3 RT in a complex to promote PIKfyve activity and functionality."; RL J. Mol. Biol. 384:766-779(2008). RN [7] {ECO:0007744|PDB:7K1W} RP STRUCTURE BY ELECTRON MICROSCOPY (5.10 ANGSTROMS), IDENTIFICATION IN THE RP PI(3,5)P2 REGULATORY COMPLEX, FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS RP OF CYS-486. RX PubMed=33098764; DOI=10.1016/j.molcel.2020.10.003; RA Lees J.A., Li P., Kumar N., Weisman L.S., Reinisch K.M.; RT "Insights into Lysosomal PI(3,5)P2 Homeostasis from a Structural- RT Biochemical Analysis of the PIKfyve Lipid Kinase Complex."; RL Mol. Cell 80:736-743.e4(2020). RN [8] RP VARIANT CMT4J THR-41. RX PubMed=17572665; DOI=10.1038/nature05876; RA Chow C.Y., Zhang Y., Dowling J.J., Jin N., Adamska M., Shiga K., RA Szigeti K., Shy M.E., Li J., Zhang X., Lupski J.R., Weisman L.S., RA Meisler M.H.; RT "Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and RT patients with CMT4J."; RL Nature 448:68-72(2007). RN [9] RP VARIANT ALS11 TYR-53, AND VARIANTS GLY-48; GLY-388; VAL-411; CYS-647 AND RP THR-902. RX PubMed=19118816; DOI=10.1016/j.ajhg.2008.12.010; RA Chow C.Y., Landers J.E., Bergren S.K., Sapp P.C., Grant A.E., Jones J.M., RA Everett L., Lenk G.M., McKenna-Yasek D.M., Weisman L.S., Figlewicz D., RA Brown R.H., Meisler M.H.; RT "Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients RT with ALS."; RL Am. J. Hum. Genet. 84:85-88(2009). RN [10] RP VARIANTS CMT4J PRO-17; THR-41 AND LYS-302, AND CHARACTERIZATION OF VARIANT RP CMT4J LYS-302. RX PubMed=21705420; DOI=10.1093/brain/awr148; RA Nicholson G., Lenk G.M., Reddel S.W., Grant A.E., Towne C.F., RA Ferguson C.J., Simpson E., Scheuerle A., Yasick M., Hoffman S., Blouin R., RA Brandt C., Coppola G., Biesecker L.G., Batish S.D., Meisler M.H.; RT "Distinctive genetic and clinical features of CMT4J: a severe neuropathy RT caused by mutations in the PI(3,5)P(2) phosphatase FIG4."; RL Brain 134:1959-1971(2011). RN [11] RP CHARACTERIZATION OF VARIANT CMT4J THR-41. RX PubMed=21655088; DOI=10.1371/journal.pgen.1002104; RA Lenk G.M., Ferguson C.J., Chow C.Y., Jin N., Jones J.M., Grant A.E., RA Zolov S.N., Winters J.J., Giger R.J., Dowling J.J., Weisman L.S., RA Meisler M.H.; RT "Pathogenic mechanism of the FIG4 mutation responsible for Charcot-Marie- RT Tooth disease CMT4J."; RL PLoS Genet. 7:E1002104-E1002104(2011). RN [12] RP VARIANTS YVS ASP-104 AND PRO-175, AND CHARACTERIZATION OF VARIANTS YVS RP ASP-104 AND PRO-175. RX PubMed=23623387; DOI=10.1016/j.ajhg.2013.03.020; RA Campeau P.M., Lenk G.M., Lu J.T., Bae Y., Burrage L., Turnpenny P., RA Roman Corona-Rivera J., Morandi L., Mora M., Reutter H., RA Vulto-van Silfhout A.T., Faivre L., Haan E., Gibbs R.A., Meisler M.H., RA Lee B.H.; RT "Yunis-Varon syndrome is caused by mutations in FIG4, encoding a RT phosphoinositide phosphatase."; RL Am. J. Hum. Genet. 92:781-791(2013). RN [13] RP INVOLVEMENT IN BTOP, VARIANT BTOP VAL-783, AND CHARACTERIZATION OF VARIANT RP BTOP VAL-783. RX PubMed=24598713; DOI=10.1212/wnl.0000000000000241; RA Baulac S., Lenk G.M., Dufresnois B., Ouled Amar Bencheikh B., Couarch P., RA Renard J., Larson P.A., Ferguson C.J., Noe E., Poirier K., Hubans C., RA Ferreira S., Guerrini R., Ouazzani R., El Hachimi K.H., Meisler M.H., RA Leguern E.; RT "Role of the phosphoinositide phosphatase FIG4 gene in familial epilepsy RT with polymicrogyria."; RL Neurology 82:1068-1075(2014). CC -!- FUNCTION: Dual specificity phosphatase component of the PI(3,5)P2 CC regulatory complex which regulates both the synthesis and turnover of CC phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) (PubMed:17556371, CC PubMed:33098764). Catalyzes the dephosphorylation of CC phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) to form CC phosphatidylinositol 3-phosphate (PubMed:33098764). Has serine-protein CC phosphatase activity acting on PIKfyve to stimulate its lipid kinase CC activity, its catalytically activity being required for maximal CC PI(3,5)P2 production (PubMed:33098764). In vitro, hydrolyzes all three CC D5-phosphorylated polyphosphoinositide and although displaying CC preferences for PtdIns(3,5)P2, it is capable of hydrolyzing CC PtdIns(3,4,5)P3 and PtdIns(4,5)P2, at least in vitro (PubMed:17556371). CC {ECO:0000269|PubMed:17556371, ECO:0000269|PubMed:33098764}. CC -!- CATALYTIC ACTIVITY: CC Reaction=a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,5- CC bisphosphate) + H2O = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo- CC inositol-3-phosphate) + phosphate; Xref=Rhea:RHEA:32955, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:43474, ChEBI:CHEBI:57923, CC ChEBI:CHEBI:58088; Evidence={ECO:0000269|PubMed:17556371, CC ECO:0000269|PubMed:33098764}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:32956; CC Evidence={ECO:0000269|PubMed:17556371, ECO:0000269|PubMed:33098764}; CC -!- CATALYTIC ACTIVITY: CC Reaction=a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-4,5- CC bisphosphate) + H2O = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo- CC inositol 4-phosphate) + phosphate; Xref=Rhea:RHEA:22764, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:43474, ChEBI:CHEBI:58178, CC ChEBI:CHEBI:58456; EC=3.1.3.36; CC Evidence={ECO:0000269|PubMed:17556371}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:22765; CC Evidence={ECO:0000269|PubMed:17556371}; CC -!- CATALYTIC ACTIVITY: CC Reaction=a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4,5- CC trisphosphate) + H2O = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo- CC inositol-3,4-bisphosphate) + phosphate; Xref=Rhea:RHEA:25528, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:43474, ChEBI:CHEBI:57658, CC ChEBI:CHEBI:57836; EC=3.1.3.86; CC Evidence={ECO:0000269|PubMed:17556371}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:25529; CC Evidence={ECO:0000269|PubMed:17556371}; CC -!- CATALYTIC ACTIVITY: CC Reaction=H2O + O-phospho-L-seryl-[protein] = L-seryl-[protein] + CC phosphate; Xref=Rhea:RHEA:20629, Rhea:RHEA-COMP:9863, Rhea:RHEA- CC COMP:11604, ChEBI:CHEBI:15377, ChEBI:CHEBI:29999, ChEBI:CHEBI:43474, CC ChEBI:CHEBI:83421; EC=3.1.3.16; CC Evidence={ECO:0000269|PubMed:33098764}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:20630; CC Evidence={ECO:0000269|PubMed:33098764}; CC -!- SUBUNIT: Component of the PI(3,5)P2 regulatory complex/PAS complex, at CC least composed of PIKFYVE, FIG4 and VAC14. VAC14 nucleates the assembly CC of the complex and serves as a scaffold by pentamerizing into a star- CC shaped structure, which can bind a single copy each of PIKFYVE and FIG4 CC and coordinates their activities. {ECO:0000269|PubMed:17556371, CC ECO:0000269|PubMed:18950639, ECO:0000269|PubMed:33098764}. CC -!- INTERACTION: CC Q92562; Q9H8Y8: GORASP2; NbExp=3; IntAct=EBI-4290773, EBI-739467; CC Q92562; Q08AM6: VAC14; NbExp=5; IntAct=EBI-4290773, EBI-2107455; CC -!- SUBCELLULAR LOCATION: Endosome membrane {ECO:0000269|PubMed:17556371}. CC Note=Localization requires VAC14 and PIKFYVE. CC {ECO:0000269|PubMed:17556371}. CC -!- DISEASE: Charcot-Marie-Tooth disease 4J (CMT4J) [MIM:611228]: A CC recessive demyelinating form of Charcot-Marie-Tooth disease, a disorder CC of the peripheral nervous system, characterized by progressive weakness CC and atrophy, initially of the peroneal muscles and later of the distal CC muscles of the arms. Charcot-Marie-Tooth disease is classified in two CC main groups on the basis of electrophysiologic properties and CC histopathology: primary peripheral demyelinating neuropathies CC (designated CMT1 when they are dominantly inherited) and primary CC peripheral axonal neuropathies (CMT2). Demyelinating neuropathies are CC characterized by severely reduced nerve conduction velocities (less CC than 38 m/sec), segmental demyelination and remyelination with onion CC bulb formations on nerve biopsy, slowly progressive distal muscle CC atrophy and weakness, absent deep tendon reflexes, and hollow feet. By CC convention autosomal recessive forms of demyelinating Charcot-Marie- CC Tooth disease are designated CMT4. {ECO:0000269|PubMed:17572665, CC ECO:0000269|PubMed:21655088, ECO:0000269|PubMed:21705420}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Amyotrophic lateral sclerosis 11 (ALS11) [MIM:612577]: A CC neurodegenerative disorder affecting upper motor neurons in the brain CC and lower motor neurons in the brain stem and spinal cord, resulting in CC fatal paralysis. Sensory abnormalities are absent. The pathologic CC hallmarks of the disease include pallor of the corticospinal tract due CC to loss of motor neurons, presence of ubiquitin-positive inclusions CC within surviving motor neurons, and deposition of pathologic CC aggregates. The etiology of amyotrophic lateral sclerosis is likely to CC be multifactorial, involving both genetic and environmental factors. CC The disease is inherited in 5-10% of the cases. CC {ECO:0000269|PubMed:19118816}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Yunis-Varon syndrome (YVS) [MIM:216340]: A severe autosomal CC recessive disorder characterized by skeletal defects, including CC cleidocranial dysplasia and digital anomalies, and severe neurologic CC involvement with neuronal loss. Enlarged cytoplasmic vacuoles are found CC in neurons, muscle, and cartilage. The disorder is usually lethal in CC infancy. {ECO:0000269|PubMed:23623387}. Note=The disease is caused by CC variants affecting the gene represented in this entry. CC -!- DISEASE: Polymicrogyria, bilateral temporooccipital (BTOP) CC [MIM:612691]: A disease characterized by temporo-occipital CC polymicrogyria, psychiatric manifestations, and epilepsy. CC {ECO:0000269|PubMed:24598713}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SEQUENCE CAUTION: CC Sequence=BAA13403.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; D87464; BAA13403.2; ALT_INIT; mRNA. DR EMBL; AK222732; BAD96452.1; -; mRNA. DR EMBL; AL133472; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL512303; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC041338; AAH41338.1; -; mRNA. DR CCDS; CCDS5078.1; -. DR RefSeq; NP_055660.1; NM_014845.5. DR PDB; 7K1W; EM; 5.10 A; F=1-907. DR PDBsum; 7K1W; -. DR AlphaFoldDB; Q92562; -. DR SMR; Q92562; -. DR BioGRID; 115225; 27. DR CORUM; Q92562; -. DR IntAct; Q92562; 5. DR MINT; Q92562; -. DR STRING; 9606.ENSP00000230124; -. DR DEPOD; FIG4; -. DR GlyGen; Q92562; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q92562; -. DR PhosphoSitePlus; Q92562; -. DR SwissPalm; Q92562; -. DR BioMuta; FIG4; -. DR DMDM; 2497367; -. DR EPD; Q92562; -. DR jPOST; Q92562; -. DR MassIVE; Q92562; -. DR MaxQB; Q92562; -. DR PaxDb; 9606-ENSP00000230124; -. DR PeptideAtlas; Q92562; -. DR ProteomicsDB; 75318; -. DR Pumba; Q92562; -. DR TopDownProteomics; Q92562; -. DR ABCD; Q92562; 1 sequenced antibody. DR Antibodypedia; 56156; 286 antibodies from 29 providers. DR DNASU; 9896; -. DR Ensembl; ENST00000230124.8; ENSP00000230124.4; ENSG00000112367.12. DR GeneID; 9896; -. DR KEGG; hsa:9896; -. DR MANE-Select; ENST00000230124.8; ENSP00000230124.4; NM_014845.6; NP_055660.1. DR UCSC; uc003ptt.3; human. DR AGR; HGNC:16873; -. DR CTD; 9896; -. DR DisGeNET; 9896; -. DR GeneCards; FIG4; -. DR HGNC; HGNC:16873; FIG4. DR HPA; ENSG00000112367; Low tissue specificity. DR MalaCards; FIG4; -. DR MIM; 216340; phenotype. DR MIM; 609390; gene. DR MIM; 611228; phenotype. DR MIM; 612577; phenotype. DR MIM; 612691; phenotype. DR neXtProt; NX_Q92562; -. DR OpenTargets; ENSG00000112367; -. DR Orphanet; 803; Amyotrophic lateral sclerosis. DR Orphanet; 208441; Bilateral parasagittal parieto-occipital polymicrogyria. DR Orphanet; 139515; Charcot-Marie-Tooth disease type 4J. DR Orphanet; 3472; Yunis-Varon syndrome. DR PharmGKB; PA162388528; -. DR VEuPathDB; HostDB:ENSG00000112367; -. DR eggNOG; KOG1888; Eukaryota. DR GeneTree; ENSGT00550000074943; -. DR HOGENOM; CLU_003016_0_3_1; -. DR InParanoid; Q92562; -. DR OrthoDB; 996872at2759; -. DR PhylomeDB; Q92562; -. DR TreeFam; TF105702; -. DR BioCyc; MetaCyc:HS12771-MONOMER; -. DR PathwayCommons; Q92562; -. DR Reactome; R-HSA-1660514; Synthesis of PIPs at the Golgi membrane. DR Reactome; R-HSA-1660516; Synthesis of PIPs at the early endosome membrane. DR Reactome; R-HSA-1660517; Synthesis of PIPs at the late endosome membrane. DR SignaLink; Q92562; -. DR SIGNOR; Q92562; -. DR BioGRID-ORCS; 9896; 35 hits in 1174 CRISPR screens. DR ChiTaRS; FIG4; human. DR GeneWiki; Fig4; -. DR GenomeRNAi; 9896; -. DR Pharos; Q92562; Tbio. DR PRO; PR:Q92562; -. DR Proteomes; UP000005640; Chromosome 6. DR RNAct; Q92562; Protein. DR Bgee; ENSG00000112367; Expressed in middle temporal gyrus and 205 other cell types or tissues. DR ExpressionAtlas; Q92562; baseline and differential. DR GO; GO:0031901; C:early endosome membrane; TAS:Reactome. DR GO; GO:0010008; C:endosome membrane; IDA:UniProtKB. DR GO; GO:0000139; C:Golgi membrane; TAS:Reactome. DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:HPA. DR GO; GO:0031902; C:late endosome membrane; TAS:Reactome. DR GO; GO:0005811; C:lipid droplet; IDA:HPA. DR GO; GO:0034485; F:phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase activity; IEA:RHEA. DR GO; GO:0043813; F:phosphatidylinositol-3,5-bisphosphate 5-phosphatase activity; IBA:GO_Central. DR GO; GO:0004439; F:phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity; IEA:RHEA. DR GO; GO:0004722; F:protein serine/threonine phosphatase activity; IEA:RHEA. DR GO; GO:0007626; P:locomotory behavior; IEA:Ensembl. DR GO; GO:0032288; P:myelin assembly; IEA:Ensembl. DR GO; GO:0031642; P:negative regulation of myelination; IEA:Ensembl. DR GO; GO:0048666; P:neuron development; IEA:Ensembl. DR GO; GO:0006661; P:phosphatidylinositol biosynthetic process; TAS:Reactome. DR GO; GO:0046856; P:phosphatidylinositol dephosphorylation; IBA:GO_Central. DR GO; GO:0043473; P:pigmentation; IEA:Ensembl. DR GO; GO:0007033; P:vacuole organization; IEA:Ensembl. DR InterPro; IPR043573; Fig4-like. DR InterPro; IPR002013; SAC_dom. DR PANTHER; PTHR45738; POLYPHOSPHOINOSITIDE PHOSPHATASE; 1. DR PANTHER; PTHR45738:SF5; POLYPHOSPHOINOSITIDE PHOSPHATASE; 1. DR Pfam; PF02383; Syja_N; 1. DR PROSITE; PS50275; SAC; 1. DR Genevisible; Q92562; HS. PE 1: Evidence at protein level; KW 3D-structure; Amyotrophic lateral sclerosis; Charcot-Marie-Tooth disease; KW Disease variant; Endosome; Hydrolase; Membrane; Neurodegeneration; KW Neuropathy; Reference proteome. FT CHAIN 1..907 FT /note="Polyphosphoinositide phosphatase" FT /id="PRO_0000209743" FT DOMAIN 154..547 FT /note="SAC" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00183" FT REGION 707..788 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT VARIANT 17 FT /note="L -> P (in CMT4J; dbSNP:rs587777713)" FT /evidence="ECO:0000269|PubMed:21705420" FT /id="VAR_071957" FT VARIANT 41 FT /note="I -> T (in CMT4J; the mutant protein is unstable; FT low levels of the protein results from impaired interaction FT with VAC14; dbSNP:rs121908287)" FT /evidence="ECO:0000269|PubMed:17572665, FT ECO:0000269|PubMed:21655088, ECO:0000269|PubMed:21705420" FT /id="VAR_036974" FT VARIANT 48 FT /note="D -> G (in dbSNP:rs1296748657)" FT /evidence="ECO:0000269|PubMed:19118816" FT /id="VAR_054831" FT VARIANT 53 FT /note="D -> Y (in ALS11; dbSNP:rs121908290)" FT /evidence="ECO:0000269|PubMed:19118816" FT /id="VAR_054832" FT VARIANT 104 FT /note="G -> D (in YVS; complete loss of function mutation; FT dbSNP:rs397509395)" FT /evidence="ECO:0000269|PubMed:23623387" FT /id="VAR_070051" FT VARIANT 175 FT /note="L -> P (in YVS; complete loss of function mutation; FT dbSNP:rs397514707)" FT /evidence="ECO:0000269|PubMed:23623387" FT /id="VAR_070052" FT VARIANT 302 FT /note="E -> K (in CMT4J; loss of function; FT dbSNP:rs587777714)" FT /evidence="ECO:0000269|PubMed:21705420" FT /id="VAR_071958" FT VARIANT 364 FT /note="M -> L (in dbSNP:rs2295837)" FT /id="VAR_020378" FT VARIANT 388 FT /note="R -> G (in dbSNP:rs1562667776)" FT /evidence="ECO:0000269|PubMed:19118816" FT /id="VAR_054833" FT VARIANT 411 FT /note="I -> V (in dbSNP:rs959747660)" FT /evidence="ECO:0000269|PubMed:19118816" FT /id="VAR_054834" FT VARIANT 647 FT /note="Y -> C (in dbSNP:rs150301327)" FT /evidence="ECO:0000269|PubMed:19118816" FT /id="VAR_054835" FT VARIANT 654 FT /note="V -> A (in dbSNP:rs9885672)" FT /evidence="ECO:0000269|Ref.2" FT /id="VAR_022826" FT VARIANT 783 FT /note="D -> V (in BTOP; partial loss of function; FT dbSNP:rs587777716)" FT /evidence="ECO:0000269|PubMed:24598713" FT /id="VAR_071959" FT VARIANT 902 FT /note="I -> T (in dbSNP:rs1162967341)" FT /evidence="ECO:0000269|PubMed:19118816" FT /id="VAR_054836" FT MUTAGEN 486 FT /note="C->S: Loss of phosphatase activity on PIKFYVE." FT /evidence="ECO:0000269|PubMed:33098764" FT MUTAGEN 488 FT /note="D->A: Loss of activity." FT /evidence="ECO:0000269|PubMed:17556371" FT CONFLICT 310 FT /note="V -> A (in Ref. 2; BAD96452)" FT /evidence="ECO:0000305" FT CONFLICT 453 FT /note="S -> P (in Ref. 2; BAD96452)" FT /evidence="ECO:0000305" FT CONFLICT 598 FT /note="F -> S (in Ref. 2; BAD96452)" FT /evidence="ECO:0000305" SQ SEQUENCE 907 AA; 103635 MW; 7B6F115C095EC332 CRC64; MPTAAAPIIS SVQKLVLYET RARYFLVGSN NAETKYRVLK IDRTEPKDLV IIDDRHVYTQ QEVRELLGRL DLGNRTKMGQ KGSSGLFRAV SAFGVVGFVR FLEGYYIVLI TKRRKMADIG GHAIYKVEDT NMIYIPNDSV RVTHPDEARY LRIFQNVDLS SNFYFSYSYD LSHSLQYNLT VLRMPLEMLK SEMTQNRQES FDIFEDEGLI TQGGSGVFGI CSEPYMKYVW NGELLDIIKS TVHRDWLLYI IHGFCGQSKL LIYGRPVYVT LIARRSSKFA GTRFLKRGAN CEGDVANEVE TEQILCDASV MSFTAGSYSS YVQVRGSVPL YWSQDISTMM PKPPITLDQA DPFAHVAALH FDQMFQRFGS PIIILNLVKE REKRKHERIL SEELVAAVTY LNQFLPPEHT IVYIPWDMAK YTKSKLCNVL DRLNVIAESV VKKTGFFVNR PDSYCSILRP DEKWNELGGC VIPTGRLQTG ILRTNCVDCL DRTNTAQFMV GKCALAYQLY SLGLIDKPNL QFDTDAVRLF EELYEDHGDT LSLQYGGSQL VHRVKTYRKI APWTQHSKDI MQTLSRYYSN AFSDADRQDS INLFLGVFHP TEGKPHLWEL PTDFYLHHKN TMRLLPTRRS YTYWWTPEVI KHLPLPYDEV ICAVNLKKLI VKKFHKYEEE IDIHNEFFRP YELSSFDDTF CLAMTSSARD FMPKTVGIDP SPFTVRKPDE TGKSVLGNKS NREEAVLQRK TAASAPPPPS EEAVSSSSED DSGTDREEEG SVSQRSTPVK MTDAGDSAKV TENVVQPMKE LYGINLSDGL SEEDFSIYSR FVQLGQSQHK QDKNSQQPCS RCSDGVIKLT PISAFSQDNI YEVQPPRVDR KSTEIFQAHI QASQGIMQPL GKEDSSMYRE YIRNRYL //