Defective Craniofacial Development and Brain Function in a Mouse Model for Depletion of Intracellular Inositol Synthesis

Ohnishi, Tetsuo; Murata, Takuya; Watanabe, Akïharu; Hida, Akiko; Ohba, Hideki; Iwayama, Yoshimi; Mishima, Kazuo; Gondo, Yoichi; Yoshikawa, Takeo

doi:10.1074/jbc.m113.536706

Cited by 26 publications

(22 citation statements)

References 57 publications

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“…Berry et al 18 demonstrated in mice that homozygous deletion of the sodium myo-inositol cotransporter-1 (SMIT), whose product is responsible for importing inositol into cells, caused lethality of mice shortly after birth. Ohnishi et al 19 screened an ethyl-nitrosourea mutant library for Impa1 −/− mutations and found a Thr95Lys missense mutation, which caused perinatal death of the mice and was also rescued by inositol supplementation. Homozygotes exhibited hyperlocomotive behavior and prolonged circadian periods.…”

Section: Discussionmentioning

confidence: 98%

A homozygous loss-of-function mutation in inositol monophosphatase 1 (IMPA1) causes severe intellectual disability

et al. 2015

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The genetic basis of intellectual disability (ID) is extremely heterogeneous and relatively little is known about the role of autosomal recessive traits. In a field study performed in a highly inbred area of Northeastern Brazil, we identified and investigated a large consanguineous family with nine adult members affected by severe ID associated with disruptive behavior. The Genome-Wide Human SNP Array 6.0 microarray was used to determine regions of homozygosity by descent from three affected and one normal family member. Whole-exome sequencing (WES) was performed in one affected patient using the Nextera Rapid-Capture Exome kit and Illumina HiSeq2500 system to identify the causative mutation. Potentially deleterious variants detected in regions of homozygosity by descent and not present in either 59 723 unrelated individuals from the Exome Aggregation Consortium (Browser) or 1484 Brazilians were subject to further scrutiny and segregation analysis by Sanger sequencing. Homozygosity-by-descent analysis disclosed a 20.7-Mb candidate region at 8q12.3-q21.2 (lod score: 3.11). WES identified a homozygous deleterious variant in inositol monophosphatase 1 (IMPA1) (NM_005536), consisting of a 5-bp duplication (c.489_493dupGGGCT; chr8: 82,583,247; GRCh37/hg19) leading to a frameshift and a premature stop codon (p.Ser165Trpfs*10) that cosegregated with the disease in 26 genotyped family members. The IMPA1 gene product is responsible for the final step of biotransformation of inositol triphosphate and diacylglycerol, two second messengers. Despite its many physiological functions, no clinical phenotype has been assigned to this gene dysfunction to date. Additionally, IMPA1 is the main target of lithium, a drug that is at the forefront of treatment for bipolar disorder.

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Section: Discussionmentioning

confidence: 98%

A homozygous loss-of-function mutation in inositol monophosphatase 1 (IMPA1) causes severe intellectual disability

et al. 2015

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“…In addition, p53 induced INPP1 and INPP5 (28) that are involved in myo-inositol salvage pathway. Myo-inositol is one of the chemical compounds which is essential for living organisms (29), and myo-inositol depletion affects cell survival and growth (30). Myo-inositol was also reported to suppress tumor growth in vitro and in vivo (31)(32)(33)(34)(35)(36)(37)(38).…”

Section: Discussionmentioning

confidence: 99%

Regulation of myo-inositol biosynthesis by p53-ISYNA1 pathway

Koguchi

Tanikawa

Mori

et al. 2016

International Journal of Oncology

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In response to various cellular stresses, p53 exerts its tumor suppressive effects such as apoptosis, cell cycle arrest, and senescence through the induction of its target genes. Recently, p53 was shown to control cellular homeostasis by regulating energy metabolism, glycolysis, antioxidant effect, and autophagy. However, its function in inositol synthesis was not reported. Through a microarray screening, we found that five genes related with myo-inositol metabolism were induced by p53. DNA damage enhanced intracellular myo-inositol content in HCT116 p53+/+ cells, but not in HCT116 p53-/- cells. We also indicated that inositol 3-phosphate synthase (ISYNA1) which encodes an enzyme essential for myo-inositol biosynthesis as a direct target of p53. Activated p53 regulated ISYNA1 expression through p53 response element in the seventh exon. Ectopic ISYNA1 expression increased myo-inositol levels in the cells and suppressed tumor cell growth. Knockdown of ISYNA1 caused resistance to adriamycin treatment, demonstrating the role of ISYNA1 in p53-mediated growth suppression. Furthermore, ISYNA1 expression was significantly associated with p53 mutation in bladder, breast cancer, head and neck squamous cell carcinoma, lung squamous cell carcinoma, and pancreatic adenocarcinoma. Our findings revealed a novel role of p53 in myo-inositol biosynthesis which could be a potential therapeutic target.

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“…For instance, higher levels of brain inositol are reported in bipolar disorder patients, and lithium reduces brain inositol levels in both patients and animals (Allison and Stewart, ; Davanzo et al, ). Also, IMPase knockout mice (specifically mice lacking IMPA1 that encodes the IMPase gene that regulates inositol metabolism in brain) show lithium‐like effects in behavioural models (Cryns et al, ; Ohnishi et al, ).…”

Section: Introductionmentioning

confidence: 99%

Ebselen has lithium‐like effects on central 5‐HT_2A receptor function

Antoniadou

Kouskou

Arsiwala

et al. 2018

British J Pharmacology

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Defective Craniofacial Development and Brain Function in a Mouse Model for Depletion of Intracellular Inositol Synthesis

Cited by 26 publications

References 57 publications

A homozygous loss-of-function mutation in inositol monophosphatase 1 (IMPA1) causes severe intellectual disability

A homozygous loss-of-function mutation in inositol monophosphatase 1 (IMPA1) causes severe intellectual disability

Regulation of myo-inositol biosynthesis by p53-ISYNA1 pathway

Ebselen has lithium‐like effects on central 5‐HT_2A receptor function

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Defective Craniofacial Development and Brain Function in a Mouse Model for Depletion of Intracellular Inositol Synthesis

Cited by 26 publications

References 57 publications

A homozygous loss-of-function mutation in inositol monophosphatase 1 (IMPA1) causes severe intellectual disability

A homozygous loss-of-function mutation in inositol monophosphatase 1 (IMPA1) causes severe intellectual disability

Regulation of myo-inositol biosynthesis by p53-ISYNA1 pathway

Ebselen has lithium‐like effects on central 5‐HT2A receptor function

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Ebselen has lithium‐like effects on central 5‐HT_2A receptor function