CoChat
Sign Up
Cited by 21Protein Kinase Regulation and GTPase SignalingGenomics and Rare DiseasesGenetics and Neurodevelopmental Disorders

Cryptic mutations of PLC family members in brain disorders: recent discoveries and a deep-learning-based approach

Open access
Lim, Key-Hwan, Yang, Sumin, Kim, Sung-Hyun, Ko, Euiseong, Kang, Mingon, Joo, Jae-Yeol·2023·Brain
DOI 10.1093/brain/awac451PMC PMC10115239
Open this paper in CoChat — free accountOpen PDF

Abstract

Phospholipase C (PLC) is an essential isozyme involved in the phosphoinositide signalling pathway, which maintains cellular homeostasis. Gain- and loss-of-function mutations in PLC affect enzymatic activity and are therefore associated with several disorders. Alternative splicing variants of PLC can interfere with complex signalling networks associated with oncogenic transformation and other diseases, including brain disorders. Cells and tissues with various mutations in PLC contribute different phosphoinositide signalling pathways and disease progression, however, identifying cryptic mutations in PLC remains challenging. Herein, we review both the mechanisms underlying PLC regulation of the phosphoinositide signalling pathway and the genetic variation of PLC in several brain disorders. In addition, we discuss the present challenges associated with the potential of deep-learning-based analysis for the identification of PLC mutations in brain disorders.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1093/brain/awac451

Cites

20 of 20 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 180

  1. [1]Rebecchi MJ, Pentyala SN. Structure, function, and control of phosphoinositide-specific phospholipase C. Physiol Rev. 2000; 80: 1291– 1335. 11015615
  2. [2]Suh PG, Park JI, Manzoli L, et al Multiple roles of phosphoinositide-specific phospholipase C isozymes. BMB Rep. 2008; 41: 415– 434. 18593525
  3. [4]Katan M, Cockcroft S. Phospholipase C families: Common themes and versatility in physiology and pathology. Prog Lipid Res. 2020; 80: 101065. 32966869
  4. [5]Nakamura Y, Fukami K. Regulation and physiological functions of mammalian phospholipase C. J Biochem. 2017; 161: mvw094. 28130414
  5. [6]Fukami K, Inanobe S, Kanemaru K, Nakamura Y. Phospholipase C is a key enzyme regulating intracellular calcium and modulating the phosphoinositide balance. Prog Lipid Res. 2010; 49: 429– 437. 20553968
  6. [7]Faenza I, Fiume R, Piazzi M, Colantoni A, Cocco L. Nuclear inositide specific phospholipase C signalling—Interactions and activity. FEBS J. 2013; 280: 6311– 6321. 23890371
  7. [8]Cocco L, Follo MY, Manzoli L, Suh PG. Phosphoinositide-specific phospholipase C in health and disease. J Lipid Res. 2015; 56: 1853– 1860. 25821234 PMC4583093
  8. [9]Yang YR, Follo MY, Cocco L, Suh PG. The physiological roles of primary phospholipase C. Adv Biol Regul. 2013; 53: 232– 241. 24041464
  9. [10]Yang YR, Kang DS, Lee C, et al Primary phospholipase C and brain disorders. Adv Biol Regul. 2016; 61: 80– 85. 26639088
  10. [12]Joo JY, Lim KH, Yang S, Kim SH, Cocco L, Suh PG. Prediction of genetic alteration of phospholipase C isozymes in brain disorders: Studies with deep learning. Adv Biol Regul. 2021; 82: 100833. 34773889
  11. [13]Whalen S, Schreiber J, Noble WS, Pollard KS. Navigating the pitfalls of applying machine learning in genomics. Nat Rev Genet. 2022; 23: 169– 181. 34837041
  12. [14]Paaby AB, Rockman MV. Cryptic genetic variation: Evolution’s hidden substrate. Nat Rev Genet. 2014; 15: 247– 258. 24614309 PMC4737706
  13. [16]Gardner EJ, Sifrim A, Lindsay SJ, et al Detecting cryptic clinically relevant structural variation in exome-sequencing data increases diagnostic yield for developmental disorders. Am J Hum Genet. 2021; 108: 2186– 2194. 34626536 PMC8595893
  14. [17]Rhee SG. Regulation of phosphoinositide-specific phospholipase C. Annu Rev Biochem. 2001; 70: 281– 312. 11395409 PMC4781088
  15. [18]Falasca M, Logan SK, Lehto VP, Baccante G, Lemmon MA, Schlessinger J. Activation of phospholipase cγ by PI 3-kinase-induced PH domain-mediated membrane targeting. EMBO J. 1998; 17: 414– 422. 9430633 PMC1170392
  16. [19]Garcia P, Gupta R, Shah S, et al The pleckstrin homology domain of phospholipase C-delta 1 binds with high affinity to phosphatidylinositol 4,5-bisphosphate in bilayer membranes. Biochemistry. 1995; 34: 16228– 16234. 8519781
  17. [20]Lyon AM, Tesmer JJ. Structural insights into phospholipase C-β function. Mol Pharmacol. 2013; 84: 488– 500. 23880553 PMC3781385
  18. [21]Kadamur G, Ross EM. Mammalian phospholipase C. Annu Rev Physiol. 2013; 75: 127– 154. 23140367
  19. [22]Fukaya M, Uchigashima M, Nomura S, Hasegawa Y, Kikuchi H, Watanabe M. Predominant expression of phospholipase Cβ1 in telencephalic principal neurons and cerebellar interneurons, and its close association with related signaling molecules in somatodendritic neuronal elements. Eur J Neurosci. 2008; 28: 1744– 1759. 18973591
  20. [23]Watanabe M, Nakamura M, Sato K, Kano M, Simon MI, Inoue Y. Patterns of expression for the mRNA corresponding to the four isoforms of phospholipase cβ in mouse brain. Eur J Neurosci. 1998; 10: 2016– 2025. 9753089
  21. [24]Hannan AJ, Kind PC, Blakemore C. Phospholipase C-β1 expression correlates with neuronal differentiation and synaptic plasticity in rat somatosensory cortex. Neuropharmacology. 1998; 37(4–5): 593– 605. 9705000
  22. [25]Spires TL, Molnar Z, Kind PC, et al Activity-dependent regulation of synapse and dendritic spine morphology in developing barrel cortex requires phospholipase C-β1 signalling. Cereb Cortex. 2005; 15: 385– 393. 15749982
  23. [26]Dalfo E, Albasanz JL, Martin M, Ferrer I. Abnormal metabotropic glutamate receptor expression and signaling in the cerebral cortex in diffuse Lewy body disease is associated with irregular α-synuclein/phospholipase C (PLCβ1) interactions. Brain Pathol. 2004; 14: 388– 398. 15605986 PMC8095885
  24. [27]Lu G, Chang JT, Liu Z, Chen Y, Li M, Zhu JJ. Phospholipase C β 1: A candidate signature gene for proneural subtype high-grade glioma. Mol Neurobiol. 2016; 53: 6511– 6525. 26614510 PMC5085994
  25. [28]Ratti S, Marvi MV, Mongiorgi S, et al Impact of phospholipase C β1 in glioblastoma: A study on the main mechanisms of tumor aggressiveness. Cell Mol Life Sci. 2022; 79: 195. 35303162 PMC8933313
  26. [29]Sun L, Mao G, Kunapuli SP, Dhanasekaran DN, Rao AK. Alternative splice variants of phospholipase C-β2 are expressed in platelets: Effect on gαq-dependent activation and localization. Platelets. 2007; 18: 217– 223. 17497434
  27. [30]Adamiak M, Suszynska M, Abdel-Latif A, Abdelbaset-Ismail A, Ratajczak J, Ratajczak MZ. The involvement of hematopoietic-specific PLC-β2 in homing and engraftment of hematopoietic stem/progenitor cells. Stem Cell Rev Rep. 2016; 12: 613– 620. 27704316 PMC5106505
  28. [31]Tang W, Zhang Y, Xu W, et al A PLCβ/PI3Kγ-GSK3 signaling pathway regulates cofilin phosphatase slingshot2 and neutrophil polarization and chemotaxis. Dev Cell. 2011; 21: 1038– 1050. 22172670 PMC3241930
  29. [32]Bertagnolo V, Benedusi M, Querzoli P, et al PLC-β2 is highly expressed in breast cancer and is associated with a poor outcome: A study on tissue microarrays. Int J Oncol. 2006; 28: 863– 872. 16525635
  30. [33]Bertagnolo V, Benedusi M, Brugnoli F, et al Phospholipase C-β 2 promotes mitosis and migration of human breast cancer-derived cells. Carcinogenesis. 2007; 28: 1638– 1645. 17429106
  31. [34]Zhang H, Xie T, Shui Y, Qi Y. Knockdown of PLCB2 expression reduces melanoma cell viability and promotes melanoma cell apoptosis by altering ras/raf/MAPK signals. Mol Med Rep. 2020; 21: 420– 428. 31746389
  32. [35]Kawakami T, Xiao W. Phospholipase C-β in immune cells. Adv Biol Regul. 2013; 53: 249– 257. 23981313 PMC4324595
  33. [36]Li Z, Jiang H, Xie W, Zhang Z, Smrcka AV, Wu D. Roles of PLC-β2 and -β3 and PI3Kγ in chemoattractant-mediated signal transduction. Science. 2000; 287: 1046– 1049. 10669417
  34. [37]Wang Z, Liu B, Wang P, et al Phospholipase C β3 deficiency leads to macrophage hypersensitivity to apoptotic induction and reduction of atherosclerosis in mice. J Clin Invest. 2008; 118: 195– 204. 18079968 PMC2129238
  35. [38]Chang WS, Wang YH, Zhu XT, Wu CJ. Genome-wide profiling of miRNA and mRNA expression in Alzheimer’s disease. Med Sci Monit. 2017; 23: 2721– 2731. 28578378 PMC5467707
  36. [39]Mamoor S. Phospholipase C β2 (PLCB2) is differentially expressed in the dorsolateral prefrontal cortex of patients with psychotic disorders. PsyArXiv. [Preprint] 10.31234/osf.io/h452e · DOI
  37. [40]Han SK, Mancino V, Simon MI. Phospholipase cβ 3 mediates the scratching response activated by the histamine H1 receptor on C-fiber nociceptive neurons. Neuron. 2006; 52: 691– 703. 17114052
  38. [41]Cai Y, Stafford LJ, Bryan BA, Mitchell D, Liu M. G-protein-activated phospholipase C-β, new partners for cell polarity proteins Par3 and Par6. Oncogene. 2005; 24: 4293– 4300. 15782111
  39. [42]Mathews JL, Smrcka AV, Bidlack JM. A novel gβγ-subunit inhibitor selectively modulates mu-opioid-dependent antinociception and attenuates acute morphine-induced antinociceptive tolerance and dependence. J Neurosci. 2008; 28: 12183– 9. 19020012 PMC2646892
  40. [43]Bianchi E, Norcini M, Smrcka A, Ghelardini C. Supraspinal gβγ-dependent stimulation of PLCβ3 originating from G inhibitory protein-mu opioid receptor-coupling is necessary for morphine induced acute hyperalgesia. J Neurochem. 2009; 111: 171– 180. 19656263 PMC2778018
  41. [44]Xiao W, Hong H, Kawakami Y, et al Tumor suppression by phospholipase C-β3 via SHP-1-mediated dephosphorylation of Stat5. Cancer Cell. 2009; 16: 161– 171. 19647226 PMC2744338
  42. [45]Adamski FM, Timms KM, Shieh BH. A unique isoform of phospholipase Cβ4 highly expressed in the cerebellum and eye. Biochim Biophys Acta. 1999; 1444: 55– 60. 9931434
  43. [46]Tanaka O, Kondo H. Localization of mRNAs for three novel members (β3, β4 and γ2) of phospholipase C family in mature rat brain. Neurosci Lett. 1994; 182: 17– 20. 7891878
  44. [47]Kim D, Jun KS, Lee SB, et al Phospholipase C isozymes selectively couple to specific neurotransmitter receptors. Nature. 1997; 389: 290– 293. 9305844
  45. [48]Cheong E, Zheng Y, Lee K, et al Deletion of phospholipase C β4 in thalamocortical relay nucleus leads to absence seizures. Proc Natl Acad Sci U S A. 2009; 106: 21912– 7. 19955421 PMC2799818
  46. [49]Jiang H, Lyubarsky A, Dodd R, et al Phospholipase C β 4 is involved in modulating the visual response in mice. Proc Natl Acad Sci U S A. 1996; 93: 14598– 14601. 8962098 PMC26179
  47. [50]Marchina E, Misasi S, Bozzato A, et al Gene expression profile in fibroblasts of Huntington’s disease patients and controls. J Neurol Sci. 2014; 337(1–2): 42– 46. 24296361
  48. [51]Smith MR, Liu YL, Kim SR, et al PLC Γ 1 src homology domain induces mitogenesis in quiescent NIH 3T3 fibroblasts. Biochem Biophys Res Commun. 1996; 222: 186– 193. 8630067
  49. [52]Owusu Obeng E, Rusciano I, Marvi MV, et al Phosphoinositide-dependent signaling in cancer: A focus on phospholipase C isozymes. Int J Mol Sci. 2020; 21: 2581. 32276377 PMC7177890
  50. [53]Nakamura Y, Fukami K. Roles of phospholipase C isozymes in organogenesis and embryonic development. Physiology (Bethesda). 2009; 24: 332– 341. 19996364
  51. [54]Minichiello L. Trkb signalling pathways in LTP and learning. Nat Rev Neurosci. 2009; 10: 850– 860. 19927149
  52. [55]Park H, Poo MM. Neurotrophin regulation of neural circuit development and function. Nat Rev Neurosci. 2013; 14: 7– 23. 23254191
  53. [56]Jang HJ, Yang YR, Kim JK, et al Phospholipase C-γ1 involved in brain disorders. Adv Biol Regul. 2013; 53: 51– 62. 23063587
  54. [57]Matsumoto T, Numakawa T, Yokomaku D, et al Brain-derived neurotrophic factor-induced potentiation of glutamate and GABA release: Different dependency on signaling pathways and neuronal activity. Mol Cell Neurosci. 2006; 31: 70– 84. 16214365
  55. [58]He XP, Wen R, McNamara JO. Impairment of kindling development in phospholipase Cγ1 heterozygous mice. Epilepsia. 2014; 55: 456– 463. 24502564 PMC4046707
  56. [59]Gudasheva TA, Logvinov IO, Nikolaev SV, Antipova TA, Povarnina PY, Seredenin SB. Dipeptide mimetics of different NGF and BDNF loops activate PLC-γ1. Dokl Biochem Biophys. 2020; 494: 244– 247. 33119826
  57. [60]Kang DS, Yang YR, Lee C, Kim S, Ryu SH, Suh PG. Roles of phosphoinositide-specific phospholipase Cγ1 in brain development. Adv Biol Regul. 2016; 60: 167– 173. 26588873
  58. [61]Yang YR, Jung JH, Kim SJ, et al Forebrain-specific ablation of phospholipase Cγ1 causes manic-like behavior. Mol Psychiatry. 2017; 22: 1473– 1482. 28138157
  59. [62]Kim SH, Yang S, Lim KH, et al Prediction of Alzheimer’s disease-specific phospholipase c γ-1 SNV by deep learning-based approach for high-throughput screening. Proc Natl Acad Sci U S A. 2021; 118: e2011250118. 33397809 PMC7826347
  60. [63]Wells A, Grandis JR. Phospholipase C-γ1 in tumor progression. Clin Exp Metastasis. 2003; 20: 285– 290. 12856715
  61. [64]Khoshyomn S, Penar PL, Rossi J, Wells A, Abramson DL, Bhushan A. Inhibition of phospholipase C-γ1 activation blocks glioma cell motility and invasion of fetal rat brain aggregates. Neurosurgery. 1999; 44: 568– 77; discussion 577-8. 10069594
  62. [65]Engebraaten O, Bjerkvig R, Pedersen PH, Laerum OD. Effects of EGF, bFGF, NGF and PDGF(bb) on cell proliferative, migratory and invasive capacities of human brain-tumour biopsies in vitro. Int J Cancer. 1993; 53: 209– 214. 8381111
  63. [66]Kurosaki T, Maeda A, Ishiai M, Hashimoto A, Inabe K, Takata M. Regulation of the phospholipase C-γ2 pathway in B cells. Immunol Rev. 2000; 176: 19– 29. 11043765
  64. [67]Kurosaki T, Okada T. Regulation of phospholipase C-γ2 and phosphoinositide 3-kinase pathways by adaptor proteins in B lymphocytes. Int Rev Immunol. 2001; 20: 697– 711. 11913946
  65. [74]Allen V, Swigart P, Cheung R, Cockcroft S, Katan M. Regulation of inositol lipid-specific phospholipase cdelta by changes in Ca2+ ion concentrations. Biochem J. 1997; 327(Pt 2): 545– 552. 9359428 PMC1218828
  66. [75]Stallings JD, Zeng YX, Narvaez F, Rebecchi MJ. Phospholipase C-delta1 expression is linked to proliferation, DNA synthesis, and cyclin E levels. J Biol Chem. 2008; 283: 13992– 14001. 18359940
  67. [76]Nakamura Y, Kanemarum K, Fukami K. Physiological functions of phospholipase Cdelta1 and phospholipase Cdelta3. Adv Biol Regul. 2013; 53: 356– 362. 23948486
  68. [77]Shimohama S, Perry G, Richey P, et al Abnormal accumulation of phospholipase C-delta in filamentous inclusions of human neurodegenerative diseases. Neurosci Lett. 1993; 162(1–2): 183– 186. 8121625
  69. [78]Shimohama S, Perry G, Richey P, et al Characterization of the association of phospholipase C-delta with Alzheimer neurofibrillary tangles. Brain Res. 1995; 669: 217– 224. 7712177
  70. [79]Shimohama S, Sasaki Y, Fujimoto S, et al Phospholipase C isozymes in the human brain and their changes in Alzheimer’s disease. Neuroscience. 1997; 82: 999– 1007. 9466424
  71. [80]Xiang T, Li L, Fan Y, et al PLCD1 Is a functional tumor suppressor inducing G2/M arrest and frequently methylated in breast cancer. Cancer Biol Ther. 2010; 10: 520– 527. 20657189
  72. [81]Hu XT, Zhang FB, Fan YC, et al Phospholipase C delta 1 is a novel 3p22.3 tumor suppressor involved in cytoskeleton organization, with its epigenetic silencing correlated with high-stage gastric cancer. Oncogene. 2009; 28: 2466– 2475. 19448674
  73. [82]Xiang Q, He X, Mu J, et al The phosphoinositide hydrolase phospholipase C delta1 inhibits epithelial-mesenchymal transition and is silenced in colorectal cancer. J Cell Physiol. 2019; 234: 13906– 13916. 30618183 PMC13483015
  74. [83]Liu W, Liu X, Wang L, et al PLCD3, A flotillin2-interacting protein, is involved in proliferation, migration and invasion of nasopharyngeal carcinoma cells. Oncol Rep. 2017; 39: 45– 52. 29115528 PMC5783603
  75. [84]Fukami K, Nakao K, Inoue T, et al Requirement of phospholipase Cdelta4 for the zona pellucida-induced acrosome reaction. Science. 2001; 292: 920– 923. 11340203
  76. [85]Fukami K, Yoshida M, Inoue T, et al Phospholipase Cdelta4 is required for Ca2+ mobilization essential for acrosome reaction in sperm. J Cell Biol. 2003; 161: 79– 88. 12695499 PMC2172882
  77. [86]Leung DW, Tompkins C, Brewer J, et al Phospholipase C delta-4 overexpression upregulates ErbB1/2 expression, ERK signaling pathway, and proliferation in MCF-7 cells. Mol Cancer. 2004; 3: 15. 15140260 PMC420486
  78. [87]Irino Y, Cho H, Nakamura Y, et al Phospholipase C delta-type consists of three isozymes: Bovine PLCdelta2 is a homologue of human/mouse PLCdelta4. Biochem Biophys Res Commun. 2004; 320: 537– 543. 15219862
  79. [88]Shibatohge M, Kariya K, Liao Y, et al Identification of PLC210, a Caenorhabditis elegans phospholipase C, as a putative effector of ras. J Biol Chem. 1998; 273: 6218– 6222. 9497345
  80. [89]Bunney TD, Katan M. Phospholipase C epsilon: Linking second messengers and small GTPases. Trends Cell Biol. 2006; 16: 640– 648. 17085049
  81. [90]Madukwe JC, Garland-Kuntz EE, Lyon AM, Smrcka AV. G protein βγ subunits directly interact with and activate phospholipase C. J Biol Chem. 2018; 293: 6387– 6397. 29535186 PMC5925795
  82. [91]Bunney TD, Harris R, Gandarillas NL, et al Structural and mechanistic insights into ras association domains of phospholipase C epsilon. Mol Cell. 2006; 21: 495– 507. 16483931
  83. [92]Jin TG, Satoh T, Liao Y, et al Role of the CDC25 homology domain of phospholipase cepsilon in amplification of Rap1-dependent signaling. J Biol Chem. 2001; 276: 30301– 7. 11395506
  84. [93]Smrcka AV, Brown JH, Holz GG. Role of phospholipase cepsilon in physiological phosphoinositide signaling networks. Cell Signal. 2012; 24: 1333– 1343. 22286105 PMC3325758
  85. [94]Kelley GG, Reks SE, Ondrako JM, Smrcka AV. Phospholipase C(epsilon): A novel ras effector. EMBO J. 2001; 20: 743– 754. 11179219 PMC145421
  86. [95]Song C, Hu CD, Masago M, et al Regulation of a novel human phospholipase C, PLCepsilon, through membrane targeting by ras. J Biol Chem. 2001; 276: 2752– 2757. 11022048
  87. [96]Margolis B, Rhee SG, Felder S, et al EGF induces tyrosine phosphorylation of phospholipase C-II: A potential mechanism for EGF receptor signaling. Cell. 1989; 57: 1101– 1107. 2472218
  88. [97]Lo Vasco VR. Phosphoinositide pathway and the signal transduction network in neural development. Neurosci Bull. 2012; 28: 789– 800. 23152330 PMC5561820
  89. [98]Nomikos M, Swann K, Lai FA. Starting a new life: Sperm PLC-ζ mobilizes the Ca2+ signal that induces egg activation and embryo development: An essential phospholipase C with implications for male infertility. Bioessays. 2012; 34: 126– 134. 22086556
  90. [99]Nomikos M, Blayney LM, Larman MG, et al Role of phospholipase C-ζ domains in Ca2+-dependent phosphatidylinositol 4,5-bisphosphate hydrolysis and cytoplasmic Ca2+ oscillations. J Biol Chem. 2005; 280: 31011– 8. 16000311
  91. [100]Yoon SY, Jellerette T, Salicioni AM, et al Human sperm devoid of PLC, ζ 1 fail to induce Ca(2+) release and are unable to initiate the first step of embryo development. J Clin Invest. 2008; 118: 3671– 3681. 18924610 PMC2567839
  92. [101]Heytens E, Parrington J, Coward K, et al Reduced amounts and abnormal forms of phospholipase C ζ (PLCζ) in spermatozoa from infertile men. Hum Reprod. 2009; 24: 2417– 2428. 19584136
  93. [102]Katan M. New insights into the families of PLC enzymes: Looking back and going forward. Biochem J. 2005; 391(Pt 3): e7–9. 16238548 PMC1276975
  94. [103]Zhou Y, Wing MR, Sondek J, Harden TK. Molecular cloning and characterization of PLC-eta2. Biochem J. 2005; 391(Pt 3): 667– 676. 16107206 PMC1276968
  95. [104]Kim JK, Choi JW, Lim S, et al Phospholipase C-eta1 is activated by intracellular Ca(2+) mobilization and enhances GPCRs/PLC/Ca(2+) signaling. Cell Signal. 2011; 23: 1022– 1029. 21262355
  96. [105]Popovics P, Beswick W, Guild SB, et al Phospholipase C-eta2 is activated by elevated intracellular Ca(2+) levels. Cell Signal. 2011; 23: 1777– 1784. 21740965
  97. [106]Hwang JI, Oh YS, Shin KJ, Kim H, Ryu SH, Suh PG. Molecular cloning and characterization of a novel phospholipase C, PLC-eta. Biochem J. 2005; 389(Pt 1): 181– 186. 15702972 PMC1184550
  98. [107]Stewart AJ, Mukherjee J, Roberts SJ, Lester D, Farquharson C. Identification of a novel class of mammalian phosphoinositol-specific phospholipase C enzymes. Int J Mol Med. 2005; 15: 117– 121. 15583837
  99. [108]Nakahara M, Shimozawa M, Nakamura Y, et al A novel phospholipase C, PLC(eta)2, is a neuron-specific isozyme. J Biol Chem. 2005; 280: 29128– 29134. 15899900
  100. [109]Popovics P, Stewart AJ. Phospholipase C-eta activity may contribute to Alzheimer’s disease-associated calciumopathy. J Alzheimers Dis. 2012; 30: 737– 744. 22475800
  101. [110]Cockcroft S. The latest phospholipase C, PLCeta, is implicated in neuronal function. Trends Biochem Sci. 2006; 31: 4– 7. 16310357
  102. [111]Zhou Y, Sondek J, Harden TK. Activation of human phospholipase C-eta2 by gβγ. Biochemistry. 2008; 47: 4410– 4417. 18361507 PMC2649797
  103. [112]Stewart AJ, Morgan K, Farquharson C, Millar RP. Phospholipase C-eta enzymes as putative protein kinase C and Ca2+ signalling components in neuronal and neuroendocrine tissues. Neuroendocrinology. 2007; 86: 243– 248. 17895620
  104. [113]Gellatly SA, Kalujnaia S, Cramb G. Cloning, tissue distribution and sub-cellular localisation of phospholipase C X-domain containing protein (PLCXD) isoforms. Biochem Biophys Res Commun. 2012; 424: 651– 656. 22732399
  105. [114]Bunney TD, Katan M. PLC regulation: Emerging pictures for molecular mechanisms. Trends Biochem Sci. 2011; 36: 88– 96. 20870410
  106. [115]Ratti S, Follo MY, Ramazzotti G, et al Nuclear phospholipase C isoenzyme imbalance leads to pathologies in brain, hematologic, neuromuscular, and fertility disorders. J Lipid Res. 2019; 60: 312– 317. 30287524 PMC6358293
  107. [116]Rusciano I, Marvi MV, Owusu Obeng E, et al Location-dependent role of phospholipase C signaling in the brain: Physiology and pathology. Adv Biol Regul. 2021; 79: 100771. 33303387
  108. [117]Woods NK, Padmanabhan J. Neuronal calcium signaling and Alzheimer’s disease. Adv Exp Med Biol. 2012; 740: 1193– 1217. 22453989
  109. [118]Lo Vasco VR. The phosphoinositide signal transduction pathway in the pathogenesis of Alzheimer’s disease. Curr Alzheimer Res. 2018; 15: 355– 362. 28847278
  110. [119]Fani G, Mannini B, Vecchi G, et al Aβ oligomers dysregulate calcium homeostasis by mechanosensitive activation of AMPA and NMDA receptors. ACS Chem Neurosci. 2021; 12: 766– 781. 33538575 PMC7898266
  111. [120]Pchitskaya E, Popugaeva E, Bezprozvanny I. Calcium signaling and molecular mechanisms underlying neurodegenerative diseases. Cell Calcium. 2018; 70: 87– 94. 28728834 PMC5748019
  112. [121]Berridge MJ. Dysregulation of neural calcium signaling in Alzheimer disease, bipolar disorder and schizophrenia. Prion. 2013; 7: 2– 13. 22895098 PMC3609045
  113. [122]Tong BC, Wu AJ, Li M, Cheung KH. Calcium signaling in Alzheimer’s disease & therapies. Biochim Biophys Acta Mol Cell Res. 2018; 1865(11 Pt B): 1745– 1760. 30059692
  114. [123]Berridge MJ. Calcium signalling and Alzheimer’s disease. Neurochem Res. 2011; 36: 1149– 1156. 21184278
  115. [124]Green KN. Calcium in the initiation, progression and as an effector of Alzheimer’s disease pathology. J Cell Mol Med. 2009; 13(9A): 2787– 2799. 19650832 PMC4498936
  116. [125]Stutzmann GE, Smith I, Caccamo A, Oddo S, Laferla FM, Parker I. Enhanced ryanodine receptor recruitment contributes to Ca2+ disruptions in young, adult, and aged Alzheimer’s disease mice. J Neurosci. 2006; 26: 5180– 5189. 16687509 PMC6674246
  117. [126]Cheung KH, Mei L, Mak DO, et al Gain-of-function enhancement of IP3 receptor modal gating by familial Alzheimer’s disease-linked presenilin mutants in human cells and mouse neurons. Sci Signal. 2010; 3: ra22. 20332427 PMC2898196
  118. [127]Mondal AC. Role of GPCR signaling and calcium dysregulation in Alzheimer’s disease. Mol Cell Neurosci. 2019; 101: 103414. 31655116
  119. [128]Popugaeva E, Pchitskaya E, Bezprozvanny I. Dysregulation of intracellular calcium signaling in Alzheimer’s disease. Antioxid Redox Signal. 2018; 29: 1176– 1188. 29890840 PMC6157344
  120. [129]Chiocchetti AG, Bour HS, Freitag CM. Glutamatergic candidate genes in autism spectrum disorder: An overview. J Neural Transm (Vienna). 2014; 121: 1081– 1106. 24493018
  121. [130]Nisar S, Bhat AA, Masoodi T, et al Genetics of glutamate and its receptors in autism spectrum disorder. Mol Psychiatry. 2022; 27: 2380– 2392. 35296811 PMC9135628
  122. [132]Huang EJ, Reichardt LF. Neurotrophins: Roles in neuronal development and function. Annu Rev Neurosci. 2001; 24: 677– 736. 11520916 PMC2758233
  123. [133]Zhang F, Kang Z, Li W, Xiao Z, Zhou X. Roles of brain-derived neurotrophic factor/tropomyosin-related kinase B (BDNF/TrkB) signalling in Alzheimer’s disease. J Clin Neurosci. 2012; 19: 946– 949. 22613489
  124. [134]Giralt A, Rodrigo T, Martin ED, et al Brain-derived neurotrophic factor modulates the severity of cognitive alterations induced by mutant huntingtin: Involvement of phospholipaseCγ activity and glutamate receptor expression. Neuroscience. 2009; 158: 1234– 1250. 19121372
  125. [135]Jin W. Regulation of BDNF-TrkB signaling and potential therapeutic strategies for Parkinson’s disease. J Clin Med. 2020; 9: 257. 31963575 PMC7019526
  126. [136]Pandya CD, Kutiyanawalla A, Pillai A. BDNF-TrkB signaling and neuroprotection in schizophrenia. Asian J Psychiatr. 2013; 6: 22– 28. 23380313 PMC3565158
  127. [137]Reynolds CH, Garwood CJ, Wray S, et al Phosphorylation regulates tau interactions with SRC homology 3 domains of phosphatidylinositol 3-kinase, phospholipase Cγ1, Grb2, and SRC family kinases. J Biol Chem. 2008; 283: 18177– 18186. 18467332
  128. [138]Perrone F, Cacace R, van der Zee J, Van Broeckhoven C. Emerging genetic complexity and rare genetic variants in neurodegenerative brain diseases. Genome Med. 2021; 13: 59. 33853652 PMC8048219
  129. [139]Blauwendraat C, Nalls MA, Singleton AB. The genetic architecture of Parkinson’s disease. Lancet Neurol. 2020; 19: 170– 178. 31521533 PMC8972299
  130. [140]Rudakou U, Yu E, Krohn L, et al Targeted sequencing of Parkinson’s disease loci genes highlights SYT11, FGF20 and other associations. Brain. 2021; 144: 462– 472. 33349842 PMC7940168
  131. [141]Lipstein N, Verhoeven-Duif NM, Michelassi FE, et al Synaptic UNC13A protein variant causes increased neurotransmission and dyskinetic movement disorder. J Clin Invest. 2017; 127: 1005– 1018. 28192369 PMC5330740
  132. [142]Parihar R, Ganesh S. The SCN1A gene variants and epileptic encephalopathies. J Hum Genet. 2013; 58: 573– 580. 23884151
  133. [143]Jonckheere AI, Renkema GH, Bras M, et al A complex V ATP5A1 defect causes fatal neonatal mitochondrial encephalopathy. Brain. 2013; 136(Pt 5): 1544– 1554. 23599390
  134. [145]Singh T, Kurki MI, Curtis D, et al Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders. Nat Neurosci. 2016; 19: 571– 577. 26974950 PMC6689268
  135. [146]Gordovez FJA, McMahon FJ. The genetics of bipolar disorder. Mol Psychiatry. 2020; 25: 544– 559. 31907381
  136. [147]Uher R. The role of genetic variation in the causation of mental illness: An evolution-informed framework. Mol Psychiatry. 2009; 14: 1072– 1082. 19704409
  137. [148]Komlodi-Pasztor E, Blakeley JO. Brain cancers in genetic syndromes. Curr Neurol Neurosci Rep. 2021; 21: 64. 34806136
  138. [149]Eichler EE. Genetic variation, comparative genomics, and the diagnosis of disease. N Engl J Med. 2019; 381: 64– 74. 31269367 PMC6681822
  139. [151]Brookes AJ, Robinson PN. Human genotype-phenotype databases: Aims, challenges and opportunities. Nat Rev Genet. 2015; 16: 702– 715. 26553330
  140. [152]Scharfe CPI, Tremmel R, Schwab M, Kohlbacher O, Marks DS. Genetic variation in human drug-related genes. Genome Med. 2017; 9: 117. 29273096 PMC5740940
  141. [153]Hajicek N, Keith NC, Siraliev-Perez E, et al Structural basis for the activation of PLC-γ isozymes by phosphorylation and cancer-associated mutations. Elife. 2019; 8: e51700. 31889510 PMC7004563
  142. [155]Schnoeder TM, Schwarzer A, Jayavelu AK, et al PLCG1 is required for AML1-ETO leukemia stem cell self-renewal. Blood. 2022; 139: 1080– 1097. 34695195 PMC8854675
  143. [156]Azam M. Placating AML1-ETO. Blood. 2022; 139: 959– 961. 35175324
  144. [157]Campbell CD, Eichler EE. Properties and rates of germline mutations in humans. Trends Genet. 2013; 29: 575– 584. 23684843 PMC3785239
  145. [158]Genomes Project Consortium, Auton A, Brooks LD, et al A global reference for human genetic variation. Nature. 2015; 526: 68– 74. 26432245 PMC4750478
  146. [159]Stenson PD, Ball EV, Mort M, Phillips AD, Shaw K, Cooper DN. The human gene mutation database (HGMD) and its exploitation in the fields of personalized genomics and molecular evolution. Curr Protoc Bioinformatics. 2012; 39: 1– 13. 22948725
  147. [160]Zhang Y, Shen F, Mojarad MR, et al Systematic identification of latent disease-gene associations from PubMed articles. PLoS ONE. 2018; 13: e0191568. 29373609 PMC5786305
  148. [162]Devinsky O, Vezzani A, O’Brien TJ, et al Epilepsy. Nature Reviews Disease Primers. 2018; 4: 18024. 29722352
  149. [163]Kim HY, Suh PG, Kim JI. The role of phospholipase C in GABAergic inhibition and its relevance to epilepsy. Int J Mol Sci. 2021; 22: 3149. 33808762 PMC8003358
  150. [164]Lal D, Ruppert AK, Trucks H, et al Burden analysis of rare microdeletions suggests a strong impact of neurodevelopmental genes in genetic generalised epilepsies. PLoS Genet. 2015; 11: e1005226. 25950944 PMC4423931
  151. [165]Turecki G, Grof P, Cavazzoni P, et al Evidence for a role of phospholipase C-γ1 in the pathogenesis of bipolar disorder. Mol Psychiatry. 1998; 3: 534– 538. 9857980
  152. [166]Nurnberger JI Jr, Koller DL, Jung J, et al Identification of pathways for bipolar disorder: A meta-analysis. JAMA Psychiatry. 2014; 71: 657– 664. 24718920 PMC4523227
  153. [167]Masi A, DeMayo MM, Glozier N, Guastella AJ. An overview of autism spectrum disorder, heterogeneity and treatment options. Neurosci Bull. 2017; 33: 183– 193. 28213805 PMC5360849
  154. [168]Iossifov I, O’Roak BJ, Sanders SJ, et al The contribution of de novo coding mutations to autism spectrum disorder. Nature. 2014; 515: 216– 221. 25363768 PMC4313871
  155. [170]Lim ET, Uddin M, De Rubeis S, et al Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder. Nat Neurosci. 2017; 20: 1217– 1224. 28714951 PMC5672813
  156. [171]Shimohama S, Kamiya S, Fujii M, et al Mutation in the pleckstrin homology domain of the human phospholipase C-delta 1 gene is associated with loss of function. Biochem Biophys Res Commun. 1998; 245: 722– 728. 9588182
  157. [172]Van Cauwenberghe C, Van Broeckhoven C, Sleegers K. The genetic landscape of Alzheimer disease: Clinical implications and perspectives. Genet Med. 2016; 18: 421– 430. 26312828 PMC4857183
  158. [173]Shimohama S, Homma Y, Suenaga T, et al Aberrant accumulation of phospholipase C-delta in Alzheimer brains. Am J Pathol. 1991; 139: 737– 742. 1928298 PMC1886302
  159. [174]Kleineidam L, Chouraki V, Prochnicki T, et al PLCG2 Protective variant p.P522R modulates tau pathology and disease progression in patients with mild cognitive impairment. Acta Neuropathol. 2020; 139: 1025– 1044. 32166339 PMC7244617
  160. [176]Kurian MA, Meyer E, Vassallo G, et al Phospholipase C β 1 deficiency is associated with early-onset epileptic encephalopathy. Brain. 2010; 133: 2964– 2970. 20833646
  161. [177]Ngoh A, McTague A, Wentzensen IM, et al Severe infantile epileptic encephalopathy due to mutations in PLCB1: Expansion of the genotypic and phenotypic disease spectrum. Dev Med Child Neurol. 2014; 56: 1124– 1128. 24684524 PMC4230412
  162. [178]Myers KA. PLCB1 biallelic point mutations cause West syndrome. Pediatr Neurol. 2019; 91: 62– 64. 30554916
  163. [179]Nashabat M, Al Qahtani XS, Almakdob S, et al The landscape of early infantile epileptic encephalopathy in a consanguineous population. Seizure. 2019; 69: 154– 172. 31054490
  164. [180]Desprairies C, Valence S, Maurey H, et al Three novel patients with epileptic encephalopathy due to biallelic mutations in the PLCB1 gene. Clin Genet. 2020; 97: 477– 482. 31883110
  165. [182]Fabbri C. The role of genetics in bipolar disorder. Curr Top Behav Neurosci. 2021; 48: 41– 60. 32767004
  166. [183]Kataoka M, Matoba N, Sawada T, et al Exome sequencing for bipolar disorder points to roles of de novo loss-of-function and protein-altering mutations. Mol Psychiatry. 2016; 21: 885– 893. 27217147 PMC5414074
  167. [184]Jamain S, Cichon S, Etain B, et al Common and rare variant analysis in early-onset bipolar disorder vulnerability. PLoS ONE. 2014; 9: e104326. 25111785 PMC4128749
  168. [185]Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014; 511: 421– 427. 25056061 PMC4112379
  169. [186]Pardinas AF, Holmans P, Pocklington AJ, et al Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection. Nat Genet. 2018; 50: 381– 389. 29483656 PMC5918692
  170. [187]Lo Vasco VR, Cardinale G, Polonia P. Deletion of PLCB1 gene in schizophrenia-affected patients. J Cell Mol Med. 2012; 16: 844– 851. 22507702 PMC3822853
  171. [189]Devlin B, Scherer SW. Genetic architecture in autism spectrum disorder. Curr Opin Genet Dev. 2012; 22: 229– 237. 22463983
  172. [190]Wu J, Yu P, Jin X, et al Genomic landscapes of Chinese sporadic autism spectrum disorders revealed by whole-genome sequencing. J Genet Genomics. 2018; 45: 527– 538. 30392784
  173. [192]Bannach-Brown A, Przybyla P, Thomas J, et al Machine learning algorithms for systematic review: Reducing workload in a preclinical review of animal studies and reducing human screening error. Syst Rev. 2019; 8: 23. 30646959 PMC6334440
  174. [193]van Hilten A, Kushner SA, Kayser M, et al Gennet framework: Interpretable deep learning for predicting phenotypes from genetic data. Commun Biol. 2021; 4: 1094. 34535759 PMC8448759
  175. [194]Bilal M, Raza SEA, Azam A, et al Development and validation of a weakly supervised deep learning framework to predict the status of molecular pathways and key mutations in colorectal cancer from routine histology images: A retrospective study. Lancet Digit Health. 2021; 3: e763. 34686474 PMC8609154
  176. [195]Bellot P, de Los Campos G, Perez-Enciso M. Can deep learning improve genomic prediction of complex human traits? Genetics. 2018; 210: 809– 819. 30171033 PMC6218236
  177. [196]Kleppe A, Skrede OJ, De Raedt S, Liestol K, Kerr DJ, Danielsen HE. Designing deep learning studies in cancer diagnostics. Nat Rev Cancer. 2021; 21: 199– 211. 33514930
  178. [197]Eraslan G, Avsec Z, Gagneur J, Theis FJ. Deep learning: New computational modelling techniques for genomics. Nat Rev Genet. 2019; 20: 389– 403. 30971806
  179. [198]Huang K, Xiao C, Glass LM, Critchlow CW, Gibson G, Sun J. Machine learning applications for therapeutic tasks with genomics data. Patterns (N Y). 2021; 2: 100328. 34693370 PMC8515011
  180. [199]Lei Y, Li S, Liu Z, et al A deep-learning framework for multi-level peptide-protein interaction prediction. Nat Commun. 2021; 12: 5465. 34526500 PMC8443569

Cited by

Sorted by citations

Authors
Lim, K.-H., Yang, S., Kim, S.-H., Ko, E., Kang, M., & Joo, J.-Y.
Affiliations
  • Chungbuk National University (KR)
  • Hanyang University (KR)
  • University of Nevada, Las Vegas (US)
Corresponding author
Joo, Jae-Yeol
ORCID
Venue
Brain
Publisher
Oxford University Press (OUP)
Published
2022-11-30
Volume
146
Issue
4
Pages
1267-1280
ISSN
  • 0006-8950 (ISSN-L)
  • 1460-2156
DOI
10.1093/brain/awac451
PMC
PMC10115239
OpenAlex
W4310398084
Cited by
21
References
20
Citations by year
2026: 5 · 2025: 12 · 2024: 2 · 2023: 2
FWCI
0.42
Type
journal article
Language
en
Open access
Licence
Locations
  • Brain (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
  • National Research Foundation of Korea
  • Ministry of Science and ICT (2022R1A2C1002984, 2022R1C1C1002933, 22-BR-02-08)
  • Korea Brain Research Institute
  • Hanyang University (202200000000904)
  • Chungbuk National University
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
phospholipase C, PLC isozymes, alternative splicing isoforms, brain disorders, gain-of-function mutations, loss-of-function mutations, deep learning, mutation detection, genetic variation
MeSH terms
Deep Learning, Brain Diseases, Humans, Mutation, Phosphatidylinositols, Type C Phospholipases, Phosphoinositide Phospholipase C

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review