{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n IMPA1 encodes myo‐inositol monophosphatase 1, a pivotal enzyme that dephosphorylates myo‐inositol‐1‐phosphate to generate free myo‐inositol—a key precursor in the phosphatidylinositol signaling cascade. Its function is fundamental in diverse biological contexts. For example, in the nervous system, local translation of IMPA1 mRNA in axons is regulated by factors such as nerve growth factor, thereby supporting nuclear CREB activation and axonal integrity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In reproductive tissues, IMPA1 is highly active in Sertoli cells and round spermatids, suggesting a role in maintaining high myo‐inositol levels that may contribute to osmotic regulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Animal model studies have underscored its indispensability; complete genetic inactivation of IMPA1 leads to early embryonic lethality—a phenotype reversible by maternal myo‐inositol supplementation—and its deficiency in mice recapitulates behavioral and neurophysiological features reminiscent of lithium’s mode of action."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In humans, loss‐of‐function mutations in IMPA1 have been associated with severe intellectual disability and disruptive behavior. Cellular studies using patient‐derived induced pluripotent stem cells revealed impaired proliferation and neuronal differentiation, while associated alterations in electroencephalographic rhythms further implicate IMPA1 in normal neurophysiology."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, regulatory mechanisms—such as modulation by calbindin, S100B, and specific microRNAs—impact IMPA1 expression and activity. In muscle cells, for instance, increased levels of miR‐1933-3p reduce IMPA1 transcript and protein accumulation, implicating such regulatory pathways in neuromuscular disorders like myasthenia gravis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to its roles in mammals, adaptive expression of IMPA1 has been documented in osmoregulatory responses in fish under salinity stress, highlighting its evolutionary conservation in managing cellular ion balance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, dysregulated IMPA1 expression has also been implicated in oncogenic pathways. Elevated levels of IMPA1 correlate with aberrant phosphoinositide signaling and poorer prognosis in diffuse large B-cell lymphoma, emphasizing its potential role in cancer progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these studies delineate IMPA1 as a multifunctional enzyme central to inositol homeostasis and downstream signaling processes across a broad spectrum of tissues. Its precise regulation is essential for normal embryonic development, neural function, osmotic adaptation, and even influences pathological states such as neurodevelopmental disorders, psychiatric conditions, and certain cancers."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}, {"type": "fg_fs", "start_ref": "6", "end_ref": "8"}, {"type": "fg_f", "ref": "10"}, {"type": "fg_f", "ref": "5"}, {"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Catia Andreassi, Carola Zimmermann, Richard Mitter, et al. "}, {"type": "b", "children": [{"type": "t", "text": "An NGF-responsive element targets myo-inositol monophosphatase-1 mRNA to sympathetic neuron axons."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Neurosci (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nn.2486"}], "href": "https://doi.org/10.1038/nn.2486"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20118926"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20118926"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Theodore R Chauvin, Michael D Griswold "}, {"type": "b", "children": [{"type": "t", "text": "Characterization of the expression and regulation of genes necessary for myo-inositol biosynthesis and transport in the seminiferous epithelium."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biol Reprod (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1095/biolreprod.103.022731"}], "href": "https://doi.org/10.1095/biolreprod.103.022731"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14613899"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14613899"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Kim Cryns, Alon Shamir, Nathalie Van Acker, et al. "}, {"type": "b", "children": [{"type": "t", "text": "IMPA1 is essential for embryonic development and lithium-like pilocarpine sensitivity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neuropsychopharmacology (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.npp.1301431"}], "href": "https://doi.org/10.1038/sj.npp.1301431"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17460611"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17460611"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Tetsuo Ohnishi, Takuya Murata, Akiko Watanabe, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Defective craniofacial development and brain function in a mouse model for depletion of intracellular inositol synthesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M113.536706"}], "href": "https://doi.org/10.1074/jbc.M113.536706"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24554717"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24554717"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Élise Morlet, Franz Hozer, Jean-François Costemale-Lacoste "}, {"type": "b", "children": [{"type": "t", "text": "Neuroprotective effects of lithium: what are the implications in humans with neurodegenerative disorders?"}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Geriatr Psychol Neuropsychiatr Vieil (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1684/pnv.2017.0718"}], "href": "https://doi.org/10.1684/pnv.2017.0718"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29400298"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29400298"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "T Figueiredo, U S Melo, A L S Pessoa, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A homozygous loss-of-function mutation in inositol monophosphatase 1 (IMPA1) causes severe intellectual disability."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Psychiatry (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/mp.2015.150"}], "href": "https://doi.org/10.1038/mp.2015.150"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26416544"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26416544"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Christopher P Walker, Andre L S Pessoa, Thalita Figueiredo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Loss-of-function mutation in inositol monophosphatase 1 (IMPA1) results in abnormal synchrony in resting-state EEG."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Orphanet J Rare Dis (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s13023-018-0977-1"}], "href": "https://doi.org/10.1186/s13023-018-0977-1"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30616629"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30616629"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Galila Agam, Orna Almog "}, {"type": "b", "children": [{"type": "t", "text": "Calbindin D28k and S100B have a similar interaction site with the lithium-inhibitable enzyme inositol monophosphatase-1: a new drug target site."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Med Chem (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/jm5019324"}], "href": "https://doi.org/10.1021/jm5019324"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25665147"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25665147"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Evgenii Bogatikov, Ida Lindblad, Tanel Punga, et al. "}, {"type": "b", "children": [{"type": "t", "text": "miR-1933-3p is upregulated in skeletal muscles of MuSK+ EAMG mice and affects Impa1 and Mrpl27."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurosci Res (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.neures.2019.02.003"}], "href": "https://doi.org/10.1016/j.neures.2019.02.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30763589"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30763589"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Aijun Ma, Wenxiao Cui, Xinan Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Osmoregulation by the myo-inositol biosynthesis pathway in turbot Scophthalmus maximus and its regulation by anabolite and c-Myc."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Comp Biochem Physiol A Mol Integr Physiol (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cbpa.2019.110636"}], "href": "https://doi.org/10.1016/j.cbpa.2019.110636"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31846703"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31846703"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Suvi-Katri Leivonen, Katherine Icay, Kirsi Jäntti, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MicroRNAs regulate key cell survival pathways and mediate chemosensitivity during progression of diffuse large B-cell lymphoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood Cancer J (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41408-017-0033-8"}], "href": "https://doi.org/10.1038/s41408-017-0033-8"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29242506"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29242506"}]}]}]}