Alternative titles; symbols
HGNC Approved Gene Symbol: INPP4A
Cytogenetic location: 2q11.2 Genomic coordinates (GRCh38): 2:98,444,587-98,594,392 (from NCBI)
Inositol polyphosphate 4-phosphatase catalyzes the hydrolysis of the 4-position phosphate of inositol 3,4-bisphosphate and inositol 1,3,4-trisphosphate. It also catalyzes, at a much higher rate, the hydrolysis of the 4-position phosphate of phosphatidylinositol 3,4-bisphosphate. Norris et al. (1995) noted that the latter activity has been implicated in mitogenesis mediated by PDGF receptor, the oxidative burst of neutrophils, and translocation of the glucose transporter to the plasma membrane.
Norris et al. (1995) purified Inpp4a from rat brain and obtained partial amino acid sequence from which degenerate primers were designed. A PCR product was obtained and used to isolate a 5,607-bp composite cDNA which encodes a 939-amino acid reading frame from the rat. The authors screened a human brain cDNA library and identified a sequence that predicts a 938-amino acid protein which is 97% identical to the rat protein. Recombinant protein was shown to have the appropriate enzymatic activity. Northern blots indicated that, in the rat, the gene is widely expressed with highest levels in the brain, heart, and skeletal muscle.
By Western blot analysis of mouse tissues, Shearn et al. (2001) identified an Inpp4a splice variant with an apparent molecular mass of 110 kD in spleen, skeletal muscle, lung, and uterus. This splice variant, which the authors called IP4P1-alpha-3, was expressed in human platelets and in MEG-01 megakaryocytes and Jurkat T cells, but not in brain. Shearn et al. (2001) determined that this variant contains an additional internal domain of 40 amino acids that is proline rich and contains a PEST sequence characteristic of proteins that are rapidly degraded by the calpain (see 114240) family of proteases. The variant results from the use of a 5-prime GU donor splice site during the excision of intron 15. Two other splice variants, which the authors called IP4P1-alpha-1 and IP4P1-alpha-2, result from alternative splicing of exons 15 and 16.
Shearn et al. (2001) determined that the INPP4A gene contains 25 exons and spans more than 67 kb.
By fluorescence in situ hybridization, Joseph et al. (1999) mapped the INPP4A gene to chromosome 2q11.2. The mouse Inpp4a gene maps to chromosome 1 (Nystuen et al., 2001).
Mice homozygous for the weeble (wbl) mutation show severe locomotor instability. Nystuen et al. (2001) observed ataxia in wbl mice at postnatal day 14 (P14), and affected mice usually died by P24. Heterozygotes showed no overt locomotor defects. Histologically, the wbl cerebellum appeared normal at P4, but by P8 it was smaller and immature compared with controls. At P21, the cerebellum degenerated further, predominantly in pyramidal cells in the CA1 field. Neurons with pycnotic nuclei, suggestive of apoptotic cell death, were observed in cerebellum and occasionally in deep layers of the cerebral cortex. Loss of wbl Purkinje cells, detected by P6, was widespread by P8. Nystuen et al. (2001) determined that wbl resulted from a 1-bp deletion in exon 10 of the Inpp4a gene, causing a frameshift that created a stop codon at amino acid 263. RT-PCR detected no Inpp4a expression in wbl mouse brain RNA.
Sasaki et al. (2010) generated mice deficient in Inpp4a by targeted disruption. Inpp4a-null mice developed neurodegeneration in the striatum with severe involuntary movement disorders. In vitro, Inpp4a gene silencing via short hairpin RNA rendered cultured primary striatum neurons vulnerable to cell death mediated by NMDA receptors (NMDARs). Mechanistically, INPP4A is found at the postsynaptic density and regulates synaptic NMDAR localization and NMDAR-mediated excitatory postsynaptic current. Thus, INPP4A protects neurons from excitotoxic cell death and thereby maintains the functional integrity of the brain. Sasaki et al. (2010) concluded that their study demonstrated that phosphatidylinositol-3,4-bisphosphate (PtdIns(3,4)P2) and phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4, 5)P3) and the phosphatases acting on them can have distinct regulatory roles, and provided insight into the unique aspects and physiologic significance of PtdIns(3,4)P2 metabolism. Sasaki et al. (2010) stated that INPP4A represents the first signaling protein identified with a function in neurons to suppress excitotoxic cell death and thus may prove a drug target for the treatment of neurodegenerative disorders.
Joseph, R. E., Walker, J., Norris, F. A. Assignment of the inositol polyphosphate 4-phosphatase type I gene (INPP4A) to human chromosome band 2q11.2 by in situ hybridization. Cytogenet. Cell Genet. 87: 276-277, 1999. [PubMed: 10702694] [Full Text: https://doi.org/10.1159/000015448]
Norris, F. A., Auethavekiat, V., Majerus, P. W. The isolation and characterization of cDNA encoding human and rat brain inositol polyphosphate 4-phosphatase. J. Biol. Chem. 270: 16128-16133, 1995. [PubMed: 7608176] [Full Text: https://doi.org/10.1074/jbc.270.27.16128]
Nystuen, A., Legare, M. E., Shultz, L. D., Frankel, W. N. A null mutation in inositol polyphosphate 4-phosphatase type I causes selective neuronal loss in weeble mutant mice. Neuron 32: 203-212, 2001. [PubMed: 11683991] [Full Text: https://doi.org/10.1016/s0896-6273(01)00468-8]
Sasaki, J., Kofuji, S., Itoh, R., Momiyama, T., Takayama, K., Murakami, H., Chida, S., Tsuya, Y., Takasuga, S., Eguchi, S., Asanuma, K., Horie, Y., Mirua, K., Davies, E. M., Mitchell, C., Yamazaki, M., Hirai, H., Takenawa, T., Suzuki, A., Sasaki, T. The PtdIns(3,4)P(2) phosphatase INPP4A is a suppressor of excitotoxic neuronal death. Nature 465: 497-501, 2010. [PubMed: 20463662] [Full Text: https://doi.org/10.1038/nature09023]
Shearn, C. T., Walker, J., Norris, F. A. Identification of a novel spliceoform of inositol polyphosphate 4-phosphatase type I-alpha expressed in human platelets: structure of human inositol polyphosphate 4-phosphatase type I gene. Biochem. Biophys. Res. Commun. 286: 119-125, 2001. [PubMed: 11485317] [Full Text: https://doi.org/10.1006/bbrc.2001.5331]