Alternative titles; symbols
HGNC Approved Gene Symbol: ITPR3
Cytogenetic location: 6p21.31 Genomic coordinates (GRCh38): 6:33,621,322-33,696,562 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p21.31 | {Diabetes, type 1, susceptibility to} | 222100 | Autosomal recessive | 2 |
| Charcot-Marie-Tooth disease, demyelinating, type 1J | 620111 | Autosomal dominant | 3 |
The ITPR3 gene encodes IP3 receptor type 3, which releases intracellular Ca(2+) from the endoplasmic reticulum into the cytoplasm upon binding of the IP3 ligand (summary by Ronkko et al., 2020).
ITPR3 is a key molecule that couples phospholipase C beta-2 (PLCB2; 604114) with TRPM5 (604600) and plays an indispensable role in perception of sweet, bitter, and umami tastes (Hisatsune et al., 2007).
ITPR3 transduces many hormonal signals that regulate Ca(2+)-dependent processes in the intestinal epithelium. Maranto (1994) described complete sequence of the ITPR3 polypeptide (2,671 amino acids). Primary structure analysis indicated a pattern of conserved and variable regions, characteristic of the particular gene family. Immunocytochemical localization in the intestine was determined.
Yamamoto-Hino et al. (1994) showed that the type 3 receptor was present in all hematopoietic and lymphoma cell lines tested.
See also 147265.
Ozcelik et al. (1991) found that a cDNA probe for ITPR3 hybridized to DNA from hybrid cells containing human chromosome 6. In one hybrid that carried 6pter-p21, in the absence of an intact copy of this chromosome, hybridization was observed, thus mapping the gene to 6pter-p21.
Yamamoto-Hino et al. (1994) likewise mapped the ITPR3 gene to chromosome 6, specifically to 6p21, by isotopic in situ hybridization.
Stumpf (2022) mapped the ITPR3 gene to chromosome 6p21.31 based on an alignment of the ITPR3 sequence (GenBank BC146646) with the genomic sequence (GRCh38).
Wang et al. (2012) showed in mice that glucagon stimulates CRTC2 (608972) dephosphorylation in hepatocytes by mobilizing intracellular calcium stores and activating the calcium/calmodulin-dependent ser/thr-phosphatase calcineurin (PPP3CA; 114105). Glucagon increased cytosolic calcium concentration through the PKA-mediated phosphorylation of inositol-1,4,5-trisphosphate receptors (InsP3Rs) (ITPR1, 147265; ITPR2, 600144; ITPR3), which associated with CRTC2. After their activation, InsP3Rs enhanced gluconeogenic gene expression by promoting the calcineurin-mediated dephosphorylation of CRTC2. During feeding, increases in insulin signaling reduced CRTC2 activity via the AKT (164730)-mediated inactivation of InsP3Rs. InsP3R activity was increased in diabetes, leading to upregulation of the gluconeogenic program. As hepatic downregulation of InsP3Rs and calcineurin improved circulating glucose levels in insulin resistance, these results demonstrated how interactions between cAMP and calcium pathways at the level of the InsP3R modulate hepatic glucose production under fasting conditions and in diabetes.
Bononi et al. (2017) discovered that BAP1 (603089) localizes at the endoplasmic reticulum. There, it binds, deubiquitylates, and stabilizes IP3R3, modulating calcium release from the endoplasmic reticulum into the cytosol and mitochondria, promoting apoptosis. Reduced levels of BAP1 in BAP1 +/- carriers cause reduction both of IP3R3 levels and of Ca(2+) flux, preventing BAP1 +/- cells that accumulate DNA damage from executing apoptosis. A higher fraction of cells exposed to either ionizing or ultraviolet radiation, or to asbestos, survive genotoxic stress, resulting in a higher rate of cellular transformation. Bononi et al. (2017) proposed that the high incidence of cancers in BAP1 +/- carriers results from the combined reduced nuclear and cytoplasmic activities of BAP1. Bononi et al. (2017) concluded that their data provided a mechanistic rationale for the powerful ability of BAP1 to regulate gene-environment interaction in human carcinogenesis.
Kuchay et al. (2017) demonstrated that FBXL2 (605652), the receptor subunit of one of the 69 human SCF ubiquitin ligase complexes, binds IP3R3 and targets it for ubiquitin-, p97- (VCP; 601023), and proteasome-mediated degradation to limit Ca(2+) influx into mitochondria. FBXL2-knockdown cells and FBXL2-insensitive IP3R3 mutant knockin clones displayed increased cytosolic Ca(2+) release from the endoplasmic reticulum and sensitization to Ca(2+)-dependent apoptotic stimuli. Kuchay et al. (2017) found that PTEN (601728) competes with FBXL2 for IP3R3 binding, and the FBXL2-dependent degradation of IP3R3 is accelerated in Pten-null mouse embryonic fibroblasts and PTEN-null cancer cells. Reconstitution of PTEN-null cells with either wildtype PTEN or a catalytically dead mutant stabilized IP3R3 and induced persistent Ca(2+) mobilization and apoptosis. IP3R3 and PTEN protein levels directly correlated in human prostate cancer. Both in cell culture and xenograft models, a nondegradable IP3R3 mutant sensitized tumor cells with low or no PTEN expression to photodynamic therapy, which is based on the ability of photosensitizer drugs to cause Ca(2+)-dependent cytotoxicity after irradiation with visible light. Similarly, disruption of FBXL2 localization with GGTi-2418, a geranylgeranyl transferase inhibitor, sensitized xenotransplanted tumors to photodynamic therapy. Kuchay et al. (2017) concluded that they identified a novel molecular mechanism that limits mitochondrial Ca(2+) overload to prevent cell death. Notably, the authors provided proof of principle that inhibiting IP3R3 degradation in PTEN-deregulated cancers represents a valid therapeutic strategy.
Autosomal Dominant Demyelinating Charcot-Marie-Tooth Disease Type 1J
In a woman and her 2 daughters (family HMSN-D6) with autosomal dominant demyelinating Charcot-Marie-Tooth disease type 1J (CMT1J; 610111), Schabhuttl et al. (2014) identified a heterozygous missense mutation in the ITPR3 gene (T1424M; 147267.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but the authors noted that ITPR3 is expressed in Schwann cells and controls Ca(2+) signaling at the gap junction in peripheral nerves.
Lassuthova et al. (2016) identified a heterozygous missense variant (M1064V) in the ITPR3 gene in a patient with inherited peripheral neuropathy. The patient was part of a cohort of 198 individuals with peripheral neuropathy who were analyzed through a gene panel. Functional studies of the variant were not performed and clinical details were not provided.
In 4 affected members of a 3-generation Finnish family with CMT1J, Ronkko et al. (2020) identified a heterozygous missense mutation in the ITPR3 gene (V615M; 147267.0002). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression studies in patient fibroblasts showed altered Ca(2+) homeostasis and dynamics, with decreased IP3-mediated Ca(2+) release from intracellular stores. Similarly, siRNA-mediated knockdown of ITPR3 in control fibroblasts led to altered Ca(2+) flux dynamics in response to stimulation. The authors postulated a dominant-negative effect of the variant. The patients had onset of symptoms in their twenties, with slow progression. An unrelated boy, born of consanguineous Ashkenazi Jewish parents, with onset of CMT1J in early childhood was found to carry a de novo heterozygous missense variant in the ITPR3 gene (R2524C; 147267.0003). Functional studies of this variant and studies of patient cells were not performed.
Associations Pending Confirmation
For discussion of an association between variation in the ITPR3 gene and type 1 diabetes, see 222100.
For discussion of an association between variation in the ITPR3 gene and systemic lupus erythematosus, see 152700.
Futatsugi et al. (2005) generated mice lacking ITPR2 (600144) or ITPR3 or both by targeted disruption. The single-gene mutants were viable and showed no distinct abnormalities in appearance, at least for several months after birth. Mutant mice lacking both of these ITPRs were also viable during the embryonic period. At birth, double mutants were indistinguishable from nonhomozygous littermates, but double mutants gained less body weight after birth. After the weaning period, around postnatal day 20, double-knockout mice began losing weight and died by the fourth week of age. Double mutants did not eat dry food, but when fed wet mash beginning on postnatal day 20, they consumed this type of food and survived thereafter. Body weight increases of the double mutants were still smaller than those of their non-double-mutant littermates, despite consuming the same quantity of food. Futatsugi et al. (2005) found that these double mutants had exocrine dysfunction which caused difficulties with nutrient digestion. Severely impaired calcium signaling in acinar cells of the salivary glands and the pancreas in the double mutants ascribed the secretion deficits to a lack of intracellular calcium release. Despite a normal caloric intake, the double mutants were hypoglycemic and lean. Futatsugi et al. (2005) concluded that these results revealed ITPR2 and ITPR3 as key molecules in exocrine physiology underlying energy metabolism and animal growth.
Hisatsune et al. (2007) found that Itpr3-knockout mice had normal taste bud morphology, normal expression of taste-related proteins, and largely normal responses to salty and acid tastes. However, taste perception of sweet, bitter, and umami was abnormal in Itpr3-knockout mice. The authors concluded that Itpr3 is a crucial mediator of sweet, bitter, and umami tastes in mice.
In a woman and her 2 daughters (family HMSN-D6) with autosomal dominant demyelinating Charcot-Marie-Tooth disease type 1J (CMT1J; 620111), Schabhuttl et al. (2014) identified a heterozygous c.4271C-T transition in the ITPR3 gene, resulting in a thr1424-to-met (T1424M) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Linkage analysis was consistent with the findings. Functional studies of the variant and studies of patient cells were not performed, but the authors noted that ITPR3 is expressed in Schwann cells and controls Ca(2+) signaling at the gap junction in peripheral nerves. Exome sequencing also identified a heterozygous missense variant (V234I) in the TEC gene (600583) that segregated with the disorder, but was not considered to be a candidate for the phenotype. Clinical details were limited, but the proband (one of the daughters) was noted to have onset of peripheral neuropathy affecting the lower limbs at 40 years of age. She had mild sensory impairment and areflexia of the lower limbs. Motor nerve conduction studies detected a value of 34.7 m/s.
In 4 affected members of a 3-generation Finnish family with demyelinating Charcot-Marie-Tooth disease type 1J (CMT1J; 620111), Ronkko et al. (2020) identified a heterozygous c.1843G-A transition (c.1843G-A, NM_002224.4) in exon 16 of the ITPR3 gene, resulting in a val615-to-met (V615M) substitution at a highly conserved residue in the ARM1 domain adjacent to the IP3-binding domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Skin fibroblasts derived from 2 of the patients showed decreased ITPR3 protein levels in 1 patient and normal protein levels in the other that was associated with increased mRNA, suggesting a compensatory upregulation response. In vitro functional expression studies in patient fibroblasts showed altered Ca(2+) homeostasis and dynamics, with decreased IP3-mediated Ca(2+) release from intracellular stores. Similarly, siRNA-mediated knockdown of ITPR3 in control fibroblasts led to altered Ca(2+) flux dynamics in response to stimulation. The authors postulated a dominant-negative effect of the variant. The patients had onset of symptoms in their twenties, with slow progression. Nerve conduction velocities ranged from 33 to 45 m/s, which could be interpreted as an 'intermediate' value. Sural nerve biopsy showed hypertrophic neuropathy with prominent onion bulb formation.
In a 16-year-old boy (patient 5), born of consanguineous Ashkenazi Jewish parents, with demyelinating Charcot-Marie-Tooth disease type 1J (CMT1J; 620111), Ronkko et al. (2020) identified a de novo heterozygous c.7570C-T transition (c.7570C-T, NM_002224.4) in exon 55 of the ITPR3 gene, resulting in an arg2524-to-cys (R2524C) substitution at a highly conserved residue in the channel pore in the transmembrane domain. The mutation, which was found by trio-based sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed. The patient had onset of symptoms at age 4 years with distal muscle weakness and atrophy affecting the lower and upper limbs, as well as sensory loss with areflexia. Nerve conduction velocity was 32 m/s, well within the demyelinating range.
Bononi, A., Giorgi, C., Patergnani, S., Larson, D., Verbruggen, K., Tanji, M., Pellegrini, L., Signorato, V., Olivetto, F., Pastorino, S., Nasu, M., Napolitano, A., and 13 others. BAP1 regulates IP3R3-mediated Ca(2+) flux to mitochondria suppressing cell transformation. Nature 546: 549-553, 2017. [PubMed: 28614305] [Full Text: https://doi.org/10.1038/nature22798]
Futatsugi, A., Nakamura, T., Yamada, M. K., Ebisui, E., Nakamura, K., Uchida, K., Kitaguchi, T., Takahashi-Iwanaga, H., Noda, T., Aruga, J., Mikoshiba, K. IP(3) receptor types 2 and 3 mediate exocrine secretion underlying energy metabolism. Science 309: 2232-2234, 2005. [PubMed: 16195467] [Full Text: https://doi.org/10.1126/science.1114110]
Hisatsune, C., Yasumatsu, K., Takahashi-Iwanaga, H., Ogawa, N., Kuroda, Y., Yoshida, R., Ninomiya, Y., Mikoshiba, K. Abnormal taste perception in mice lacking the type 3 inositol 1,4,5-trisphosphate receptor. J. Biol. Chem. 282: 37225-37231, 2007. [PubMed: 17925404] [Full Text: https://doi.org/10.1074/jbc.M705641200]
Kuchay, S., Giorgi, C., Simoneschi, D., Pagan, J., Missiroli, S., Saraf, A., Florens, L., Washburn, M. P., Collazo-Lorduy, A., Castillo-Martin, M., Cordon-Cardo, C., Sebti, S. M., Pinton, P., Pagano, M. PTEN counteracts FBXL2 to promote IP3R3- and Ca(2+)-mediated apoptosis limiting tumour growth. Nature 546: 554-558, 2017. [PubMed: 28614300] [Full Text: https://doi.org/10.1038/nature22965]
Lassuthova, P., Safka Brozkova, D., Krutova, M., Neupauerova, J., Haberlova, J., Mazanec, R., Drimal, P., Seeman, P. Improving diagnosis of inherited peripheral neuropathies through gene panel analysis. Orphanet J. Rare Dis. 11: 118, 2016. [PubMed: 27549087] [Full Text: https://doi.org/10.1186/s13023-016-0500-5]
Maranto, A. R. Primary structure, ligand binding, and localization of the human type 3 inositol 1,4,5-trisphosphate receptor expressed in intestinal epithelium. J. Biol. Chem. 269: 1222-1230, 1994. [PubMed: 8288584]
Ozcelik, T., Suedhof, T. C., Francke, U. The genes for inositol 1,4,5-triphosphate receptors 1 (ITPR1) and 3 (ITPR3) are localized on human chromosomes 3p and 6pter-p21, respectively. (Abstract) Cytogenet. Cell Genet. 58: 1880 only, 1991.
Ronkko, J., Molchanova, S., Revah-Politi, A., Pereira, E. M., Auranen, M., Toppila, J., Kvist, J., Ludwig, A., Neumann, J., Bultynck, G., Humblet-Baron, S., Liston, A., Paetau, A., Rivera, C., Harms, M. B., Tyynismaa, H., Ylikallio, E. Dominant mutations in ITPR3 cause Charcot-Marie-Tooth disease. Ann. Clin. Transl. Neurol. 7: 1962-1972, 2020. [PubMed: 32949214] [Full Text: https://doi.org/10.1002/acn3.51190]
Schabhuttl, M., Wieland, T., Senderek, J., Baets, J., Timmerman, V., De Jonghe, P., Reilly, M. M., Stieglbauer, K., Laich, E., Windhager, R., Erwa, W., Trajanoski, S., Strom, T. M., Auer-Grumbach, M. Whole-exome sequencing in patients with inherited neuropathies: outcome and challenges. J. Neurol. 261: 970-982, 2014. [PubMed: 24627108] [Full Text: https://doi.org/10.1007/s00415-014-7289-8]
Stumpf, A. M. Personal Communication. Baltimore, Md. 11/03/2022.
Wang, Y., Li, G., Goode, J., Paz, J. C., Ouyang, K., Screaton, R., Fischer, W. H., Chen, J., Tabas, I., Montminy, M. Inositol-1,4,5-trisphosphate receptor regulates hepatic gluconeogenesis in fasting and diabetes. Nature 485: 128-132, 2012. [PubMed: 22495310] [Full Text: https://doi.org/10.1038/nature10988]
Yamamoto-Hino, M., Sugiyama, T., Hikichi, K., Mattei, M. G., Hasegawa, K., Sekine, S., Sakurada, K., Miyawaki, A., Furuichi, T., Hasegawa, M., Mikoshiba, K. Cloning and characterization of human type 2 and type 3 inositol 1,4,5-trisphosphate receptors. Receptors Channels 2: 9-22, 1994. [PubMed: 8081734]