{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,8]],"date-time":"2025-11-08T13:38:53Z","timestamp":1762609133947,"version":"3.41.2"},"reference-count":39,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2023,1,24]],"date-time":"2023-01-24T00:00:00Z","timestamp":1674518400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01GM24872"],"award-info":[{"award-number":["R01GM24872"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,8,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Loss-of-function mutations of FIG4 are responsible for neurological disorders in human and mouse that result from reduced abundance of the signaling lipid PI(3,5)P2. In contrast, loss-of-function mutations of the phosphoinositide kinase PIP4K2C result in elevated abundance of PI(3,5)P2. These opposing effects on PI(3,5)P2 suggested that we might be able to compensate for deficiency of FIG4 by reducing expression of PIP4K2C. To test this hypothesis in a whole animal model, we generated triallelic mice with genotype Fig 4\u2212\/\u2212, Pip4k2c+\/\u2212; these mice are null for Fig 4 and haploinsufficient for Pip4k2c. The neonatal lethality of Fig 4 null mice in the C57BL\/6J strain background was rescued by reduced expression of Pip4k2c. The lysosome enlargement characteristic of Fig 4 null cells was also reduced by heterozygous loss of Pip4k2c. The data demonstrate interaction between these two genes, and suggest that inhibition of the kinase PIPK4C2 could be a target for treatment of FIG4 deficiency disorders such as Charcot-Marie-Tooth Type 4J and Yunis-Var\u00f3n Syndrome.<\/jats:p>","DOI":"10.1093\/g3journal\/jkad007","type":"journal-article","created":{"date-parts":[[2023,1,24]],"date-time":"2023-01-24T06:10:53Z","timestamp":1674540653000},"source":"Crossref","is-referenced-by-count":5,"title":["Altered phenotypes due to genetic interaction between the mouse phosphoinositide biosynthesis genes <i>Fig4<\/i> and <i>Pip4k2c<\/i>"],"prefix":"10.1093","volume":"13","author":[{"given":"Xu","family":"Cao","sequence":"first","affiliation":[{"name":"Department of Human Genetics, University of Michigan , Ann Arbor, MI 48109-5618 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guy M","family":"Lenk","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, University of Michigan , Ann Arbor, MI 48109-5618 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9107-706X","authenticated-orcid":false,"given":"Miriam H","family":"Meisler","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, University of Michigan , Ann Arbor, MI 48109-5618 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2023,1,24]]},"reference":[{"key":"2024022108050420700_jkad007-B1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.29123","article-title":"Inhibition of pip4k\u03b3 ameliorates the pathological effects of mutant huntingtin protein","volume":"6","author":"Al-Ramahi","year":"2017","journal-title":"Elife"},{"issue":"12","key":"2024022108050420700_jkad007-B2","doi-asserted-by":"publisher","first-page":"1068","DOI":"10.1212\/WNL.0000000000000241","article-title":"Role of the phosphoinositide phosphatase FIG4 gene in familial epilepsy with polymicrogyria","volume":"82","author":"Baulac","year":"2014","journal-title":"Neurology"},{"key":"2024022108050420700_jkad007-B30","doi-asserted-by":"crossref","first-page":"4273","DOI":"10.1091\/mbc.e08-04-0405","article-title":"Assembly of a Fab1 phosphoinositide kinase signaling complex requires the Fig4 phosphoinositide phosphatase","volume":"19","author":"Botelho","year":"2008","journal-title":"Mol Biol Cell"},{"issue":"5","key":"2024022108050420700_jkad007-B3","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.229500","article-title":"The PIKfyve complex regulates the early melanosome homeostasis required for physiological amyloid formation","volume":"132","author":"Bissig","year":"2019","journal-title":"J Cell Sci"},{"issue":"5","key":"2024022108050420700_jkad007-B31","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1016\/j.ajhg.2013.03.020","article-title":"Yunis-Var\u00f3n syndrome is caused by mutations in FIG4, encoding a phosphoinositide phosphatase","volume":"92","author":"Campeau","year":"2013","journal-title":"Am J Hum Genet"},{"issue":"7149","key":"2024022108050420700_jkad007-B4","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1038\/nature05876","article-title":"Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J","volume":"448","author":"Chow","year":"2007","journal-title":"Nature"},{"issue":"3","key":"2024022108050420700_jkad007-B5","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1002\/cne.22161","article-title":"Distribution and neuronal expression of phosphatidylinositol phosphate kinase IIgamma in the mouse brain","volume":"517","author":"Clarke","year":"2009","journal-title":"J Comp Neurol"},{"issue":"6","key":"2024022108050420700_jkad007-B32","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1002\/mdc3.12797","article-title":"VAC14 Gene-Related Parkinsonism-Dystonia With Response to Deep Brain Stimulation","volume":"6","author":"de Gusmao","journal-title":"Mov Disord Clin Pract"},{"issue":"1","key":"2024022108050420700_jkad007-B6","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1038\/ncomms1037","article-title":"PI(3,5)P(2) controls membrane trafficking by direct activation of mucolipin ca(2+) release channels in the endolysosome","volume":"1","author":"Dong","year":"2010","journal-title":"Nat Commun"},{"issue":"16","key":"2024022108050420700_jkad007-B7","doi-asserted-by":"publisher","first-page":"3525","DOI":"10.1093\/hmg\/dds179","article-title":"Neuronal expression of Fig 4 is both necessary and sufficient to prevent spongiform neurodegeneration","volume":"21","author":"Ferguson","year":"2012","journal-title":"Hum Mol Genet"},{"issue":"24","key":"2024022108050420700_jkad007-B8","doi-asserted-by":"publisher","first-page":"4868","DOI":"10.1093\/hmg\/ddp460","article-title":"Defective autophagy in neurons and astrocytes from mice deficient in PI(3,5)P2","volume":"18","author":"Ferguson","year":"2009","journal-title":"Hum Mol Genet"},{"key":"2024022108050420700_jkad007-B33","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1247\/csf.17003","article-title":"PI5P and PI(3,5)P2: Minor, but Essential Phosphoinositides","volume":"42","author":"Hasegawa","year":"2017","journal-title":"Cell Struct Funct"},{"issue":"6","key":"2024022108050420700_jkad007-B9","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1016\/j.molmed.2012.04.004","article-title":"Myotubularin phosphoinositide phosphatases: cellular functions and disease pathophysiology","volume":"18","author":"Hnia","year":"2012","journal-title":"Trends Mol Med"},{"issue":"24","key":"2024022108050420700_jkad007-B10","doi-asserted-by":"publisher","first-page":"3221","DOI":"10.1038\/emboj.2008.248","article-title":"VAC14 Nucleates a protein complex essential for the acute interconversion of PI3P and PI(3,5)P(2) in yeast and mouse","volume":"27","author":"Jin","year":"2008","journal-title":"EMBO J"},{"issue":"7","key":"2024022108050420700_jkad007-B11","doi-asserted-by":"publisher","first-page":"2075","DOI":"10.1083\/jcb.201611144","article-title":"Early protection to stress mediated by CDK-dependent PI3,5P2 signaling from the vacuole\/lysosome","volume":"216","author":"Jin","year":"2017","journal-title":"J Cell Biol"},{"key":"2024022108050420700_jkad007-B34","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1002\/acn3.51175","article-title":"Clinical features of homozygous FIG4-p.Ile41Thr Charcot-Marie-Tooth 4J patients","volume":"8","author":"Lafontaine","year":"2021","journal-title":"Ann Clin Transl Neurol"},{"issue":"4","key":"2024022108050420700_jkad007-B35","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1016\/j.molcel.2020.10.003","article-title":"Insights into Lysosomal PI(3,5)P2 Homeostasis from a Structural-Biochemical Analysis of the PIKfyve Lipid Kinase Complex","volume":"80","author":"Lees","year":"2020","journal-title":"Mol Cell"},{"issue":"5","key":"2024022108050420700_jkad007-B12","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1002\/humu.23720","article-title":"Cerebral hypomyelination associated with biallelic variants of FIG4","volume":"40","author":"Lenk","year":"2019","journal-title":"Hum Mutat"},{"issue":"6","key":"2024022108050420700_jkad007-B13","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1002104","article-title":"Pathogenic mechanism of the FIG4 mutation responsible for Charcot-Marie-Tooth disease CMT4J","volume":"7","author":"Lenk","year":"2011","journal-title":"PLoS Genet"},{"key":"2024022108050420700_jkad007-B14","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/B978-0-12-397926-1.00014-7","article-title":"Mouse models of PI(3,5)P2 deficiency with impaired lysosome function","volume":"534","author":"Lenk","year":"2014","journal-title":"Methods Enzymol"},{"issue":"1","key":"2024022108050420700_jkad007-B15","doi-asserted-by":"publisher","first-page":"9609","DOI":"10.1038\/s41598-019-45939-w","article-title":"CRISPR Knockout screen implicates three genes in lysosome function","volume":"9","author":"Lenk","year":"2019","journal-title":"Sci Rep"},{"issue":"1","key":"2024022108050420700_jkad007-B16","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1016\/j.ajhg.2016.05.008","article-title":"Biallelic mutations of VAC14 in pediatric-onset neurological disease","volume":"99","author":"Lenk","year":"2016","journal-title":"Am J Hum Genet"},{"key":"2024022108050420700_jkad007-B17","doi-asserted-by":"publisher","first-page":"e74136","DOI":"10.7554\/eLife.74136","article-title":"Tonic inhibition of the chloride\/proton antiporter ClC-7 by PI(3,5)P2 is crucial for lysosomal pH maintenance","volume":"11","author":"Leray","year":"2022","journal-title":"Elife"},{"key":"2024022108050420700_jkad007-B36","first-page":"e13023","article-title":"PI(3,5)P2 biosynthesis regulates oligodendrocyte differentiation by intrinsic and extrinsic mechanisms","volume":"5","author":"Mironova","year":"2016"},{"key":"2024022108050420700_jkad007-B37","doi-asserted-by":"crossref","first-page":"1959","DOI":"10.1093\/brain\/awr148","article-title":"Distinctive genetic and clinical features of CMT4J: a severe neuropathy caused by mutations in the PI(3,5)P2 phosphatase FIG4","volume":"134","author":"Nicholson","year":"2011","journal-title":"Brain"},{"key":"2024022108050420700_jkad007-B38","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1111\/febs.15127","article-title":"Phosphoinositides in autophagy: current roles and future insights","volume":"287","author":"Palamiuc","year":"2019","journal-title":"FEBS J"},{"key":"2024022108050420700_jkad007-B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2022.102543","article-title":"Activation of endo-lysosomal two-pore channels by NAADP and PI(3,5)P2","volume":"103","author":"Patel","year":"2022","journal-title":"Cell Calcium"},{"issue":"11","key":"2024022108050420700_jkad007-B19","doi-asserted-by":"publisher","DOI":"10.1172\/JCI137159","article-title":"AAV9-mediated FIG4 delivery prolongs life span in charcot-marie-tooth disease type 4J mouse model","volume":"131","author":"Presa","year":"2021","journal-title":"J Clin Invest"},{"key":"2024022108050420700_jkad007-B20","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.664608","article-title":"Novel mechanism for an old drug: phenazopyridine is a kinase inhibitor affecting autophagy and cellular differentiation","volume":"12","author":"Preynat-Seauve","year":"2021","journal-title":"Front Pharmacol"},{"key":"2024022108050420700_jkad007-B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2022.102086","article-title":"Roles of PIKfyve in multiple cellular pathways","volume":"76","author":"Rivero-R\u00edos","year":"2022","journal-title":"Curr Opin Cell Biol"},{"issue":"7699","key":"2024022108050420700_jkad007-B22","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1038\/nature26139","article-title":"Structural insights into the voltage and phospholipid activation of the mammalian TPC1 channel","volume":"556","author":"She","year":"2018","journal-title":"Nature"},{"issue":"27","key":"2024022108050420700_jkad007-B23","doi-asserted-by":"publisher","first-page":"7596","DOI":"10.1073\/pnas.1600934113","article-title":"Deletion of the gene Pip4k2c, a novel phosphatidylinositol kinase, results in hyperactivation of the immune system","volume":"113","author":"Shim","year":"2016","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"4","key":"2024022108050420700_jkad007-B24","doi-asserted-by":"publisher","first-page":"905","DOI":"10.1534\/genetics.120.303596","article-title":"Content and performance of the MiniMUGA genotyping array: a new tool to improve rigor and reproducibility in mouse research","volume":"216","author":"Sigmon","year":"2020","journal-title":"Genetics"},{"issue":"5","key":"2024022108050420700_jkad007-B25","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1016\/j.chembiol.2020.02.003","article-title":"Targeting the PI5P4K lipid kinase family in cancer using covalent inhibitors","volume":"27","author":"Sivakumaren","year":"2020","journal-title":"Cell Chem Biol"},{"issue":"17","key":"2024022108050420700_jkad007-B26","doi-asserted-by":"publisher","first-page":"1835","DOI":"10.1091\/mbc.E18-09-0556","article-title":"Roles for a lipid phosphatase in the activation of its opposing lipid kinase","volume":"31","author":"Strunk","year":"2020","journal-title":"Mol Biol Cell"},{"issue":"2","key":"2024022108050420700_jkad007-B39","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1093\/hmg\/ddu451","article-title":"Loss of Fig4 in both Schwann cells and motor neurons contributes to CMT4J neuropathy","volume":"24","author":"Vaccari","year":"2015","journal-title":"Hum Mol Genet"},{"issue":"7","key":"2024022108050420700_jkad007-B27","doi-asserted-by":"publisher","first-page":"1991","DOI":"10.1016\/j.celrep.2019.04.070","article-title":"PIP4Ks Suppress insulin signaling through a catalytic-independent mechanism","volume":"27","author":"Wang","year":"2019","journal-title":"Cell Rep"},{"issue":"13","key":"2024022108050420700_jkad007-B28","doi-asserted-by":"publisher","first-page":"1718","DOI":"10.1091\/mbc.E18-01-0015","article-title":"PI(3,5)P2 controls vacuole potassium transport to support cellular osmoregulation","volume":"29","author":"Wilson","year":"2018","journal-title":"Mol Biol Cell"},{"issue":"12","key":"2024022108050420700_jkad007-B29","doi-asserted-by":"publisher","first-page":"2847","DOI":"10.1111\/epi.16741","article-title":"Gabra2 is a genetic modifier of Scn8a encephalopathy in the mouse","volume":"61","author":"Yu","year":"2020","journal-title":"Epilepsia"}],"container-title":["G3: Genes, Genomes, Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/g3journal\/advance-article-pdf\/doi\/10.1093\/g3journal\/jkad007\/48836627\/jkad007.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/g3journal\/article-pdf\/13\/8\/jkad007\/56717649\/jkad007.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/g3journal\/article-pdf\/13\/8\/jkad007\/56717649\/jkad007.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,21]],"date-time":"2024-02-21T08:05:15Z","timestamp":1708502715000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/g3journal\/article\/doi\/10.1093\/g3journal\/jkad007\/6999064"}},"subtitle":[],"editor":[{"given":"H","family":"Bellen","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2023,1,24]]},"references-count":39,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,1,24]]},"published-print":{"date-parts":[[2023,8,9]]}},"URL":"https:\/\/doi.org\/10.1093\/g3journal\/jkad007","relation":{},"ISSN":["2160-1836"],"issn-type":[{"type":"electronic","value":"2160-1836"}],"subject":[],"published-other":{"date-parts":[[2023,8]]},"published":{"date-parts":[[2023,1,24]]},"article-number":"jkad007"}}