Alternative titles; symbols
HGNC Approved Gene Symbol: PI4KB
Cytogenetic location: 1q21.3 Genomic coordinates (GRCh38): 1:151,291,797-151,327,715 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q21.3 | Deafness, autosomal dominant 87 | 620281 | Autosomal dominant | 3 |
For general information on phosphatidylinositol (PI) 4-kinases, see PIK4CA (600286).
By degenerate PCR, library screening, and 5-prime-RACE, Meyers and Cantley (1997) cloned human placenta and heart cDNAs encoding a novel PI 4-kinase, which they called PI4K-beta. The predicted 801-amino acid PI4K-beta protein contains an N-terminal lipid kinase unique domain, which is shared by members of both the PI 3-kinase (e.g., 171834) and PI 4-kinase families, and a C-terminal catalytic domain, which defines this protein as a member of a much larger protein/lipid kinase family. PI4K-beta shares significant amino acid sequence similarity with yeast PIK1. Western blot analysis of mammalian cell lysates using an antibody against PI4K-beta detected a 110-kD protein. Northern blot analysis showed that PI4K-beta is ubiquitously expressed as an approximately 4-kb transcript, with highest expression in heart, pancreas, and skeletal muscle.
Saito et al. (1997) isolated a PI 4-kinase cDNA from a human adult brain cDNA library. The sequence of the cDNA was highly identical to that of the PI4K-beta cDNA (Meyers and Cantley, 1997), and Saito et al. (1997) suggested that they represented alternative products of the same gene.
Suzuki et al. (1997) cloned 3 forms of cDNAs encoding human PIK4CB, which they named NPIK for 'novel putative phosphatidylinositol kinase;' 2 of the cDNAs had different 5-prime open reading frame sequences, and the third contained a 45-bp insertion within the coding sequence. The authors suggested that these cDNAs resulted from alternative transcription initiation sites and alternative splicing. By Northern blot analysis, they detected 4.8- and 3.6-kb transcripts whose relative levels varied in different tissues. Using the green fluorescent protein system, they demonstrated that PIK4CB is localized in the cytoplasm.
By immunofluorescence analysis, Su et al. (2020) detected expression of PI4KB in 11-week human fetal ear sections, primarily in the epithelium of the spinal organ of Corti. Whole-mount in situ hybridization of pi4kb in zebrafish larvae demonstrated expression as early as 26 hours postfertilization, mainly in the otic vesicles. Immunofluorescent staining confirmed the expression pattern of Pi4kb in the cristae of zebrafish inner ear at the protein level.
Biochemical analyses by Meyers and Cantley (1997) indicated that PI4K-beta is a type III enzyme that is sensitive to wortmannin. They stated that PI4K-beta is likely the wortmannin-sensitive PI 4-kinase described by Nakanishi et al. (1995) that is responsible for regulating the synthesis of agonist-sensitive pools of polyphosphoinositides.
Mora et al. (2002) showed that Pi4k-beta inhibited insulin-stimulated translocation of glucose transporter-4 (GLUT4, or SLC2A4; 138190) in mouse adipocytes through its interaction with neuronal calcium sensor-1 (NCS1, or FREQ; 603315).
Gromada et al. (2005) found that NCS1 increased exocytosis in rodent pancreatic beta cells by promoting priming of secretory granules for release and increasing the number of granules residing in the readily releasable pool. The effect of Ncs1 on exocytosis was mediated through increased Pi4k-beta activity and generation of phosphoinositides, specifically phosphatidylinositol 4-phosphate (PtdIns(4)P) and PtdIns(4,5)P2. In turn, PtdIns(4,5)P2 controlled exocytosis through Ca(2+)-dependent activator protein for secretion (CADPS; 604667). Gromada et al. (2005) concluded that NCS1 and its downstream target, PI4K-beta, are critical for glucose-induced insulin secretion due to their capacity to regulate the release competence of secretory granules.
Jovic et al. (2012) found that the PtdIns4P-synthesizing enzymes PI4KII-alpha (PI4K2A; 609763) and PI4KIII-beta had distinct and sequential roles in the lysosomal delivery of beta-glucosidase (GBA; 606463) and its receptor, LIMP2 (602257). Activity of PI4KIII-beta at the Golgi was required to drive exit of LIMP2 from the Golgi, whereas PI4KII-alpha at the trans-Golgi network regulated sorting of LIMP2 toward the late endosome/lysosome compartment. Knockdown or inhibition of PI3KIII-beta led to accumulation of LIMP2 at the Golgi compartment, and knockdown of either LIMP2 or PI4KII-alpha increased beta-GC secretion. Mutations in PI4KII-alpha that disrupted its association with AP3 (see AP3B1; 603401) disrupted lysosomal LIMP2 targeting.
Nagashima et al. (2020) found that microdomains of phosphatidylinositol 4-phosphate on trans-Golgi network vesicles were recruited to mitochondria-endoplasmic reticulum (ER) contact sites and can drive mitochondrial division downstream of DRP1 (603850). The loss of the small guanosine triphosphatase ADP-ribosylation factor-1 (ARF1; 103180) or its effector PIK4KIII-beta in different mammalian cell lines prevented phosphatidylinositol 4-phosphate generation and led to a hyperfused and branched mitochondrial network marked with extended mitochondrial constriction sites. Nagashima et al. (2020) concluded that recruitment of trans-Golgi network-phosphatidylinositol 4-phosphate-containing vesicles at mitochondria contact sites may trigger final events leading to mitochondrial scission.
Crystal Structure
Burke et al. (2014) described crystal structures of PI4KIII-beta bound to the small GTPase RAB11A (605570) without and with the RAB11 effector protein FIP3 (300248). The RAB11-PI4KIII-beta interface is distinct compared with structures of RAB complexes and does not involve switch regions used by GTPase effectors. Burke et al. (2014) concluded that their data provided a mechanism for how PI4KIII-beta coordinates RAB11 and its effectors on phosphatidylinositol 4-phosphate-enriched membranes and also provided strategies for the design of specific inhibitors that could potentially target plasmodial PI4KIII-beta to combat malaria.
By somatic cell hybrid analysis, radiation hybrid analysis, and fluorescence in situ hybridization (FISH), Saito et al. (1997) mapped the PIK4CB gene to 1q21. Suzuki et al. (1997) mapped the PIK4CB gene to 1q21.1-q21.3 by FISH.
In a large 5-generation Chinese family from Inner Mongolia with prelingual profound deafness and inner ear malformations mapping to chromosome 1q22 (DFNA87; 620281), Su et al. (2020) identified heterozygosity for a missense mutation in the PI4KB gene (Q121R; 602758.0001). Sanger sequencing confirmed the mutation, which segregated fully with disease in the family and was not found in controls; the variant was present in gnomAD at very low minor allele frequency. Screening the PI4KB gene in 57 unrelated deaf children from a boarding school in the same area of Inner Mongolia identified 5 who were heterozygous for 3 missense mutations, V434G (602758.0002), E667K (602758.0003), and M739R (602758.0004). None of the 3 variants was found in controls or public variant databases; family members were unavailable for segregation analysis. The authors demonstrated a dominant-negative effect of the mutations in zebrafish larvae, which developed varying degrees of inner ear defects; and morphant phenotypes in zebrafish with pi4kb knockdown could not be rescued by injection of mRNA carrying any of the 4 mutations.
Using a morpholino antisense oligonucleotide (MO)-mediated strategy, Su et al. (2020) generated zebrafish with knockdown of pi4kb and observed that the semicircular canals of the morphant inner ear were unable to form the characteristic cruciform pattern, resulting in a lack of canal outgrowths and failure of the pillar to properly fuse. In addition the otic vesicles were smaller in the morphants than in wildtype larvae. Coinjection of exogenous wildtype human PI4KB mRNA and zebrafish pi4kb MO rescued the developmental defects in the otic vesicles and semicircular canals. The morphants also showed reduced hearing ability, lacking the brisk startle response observed in wildtype zebrafish at 4 days postfertilization. Injection of wildtype human PI4KB mRNA preserved the normal response to sound stimulation.
In a large 5-generation Chinese family from Inner Mongolia with nonsyndromic prelingual profound sensorineural hearing loss and inner ear malformations (DFNA87; 620281), Su et al. (2020) identified heterozygosity for a c.362A-G transition (c.362A-G, ENST00000368874) in the PI4KB gene, resulting in a gln121-to-arg (Q121R) substitution within the helical domain. Sanger sequencing confirmed the mutation, which segregated fully with disease in the family and was not found in 600 Chinese controls from the same region of Inner Mongolia; the variant was present in gnomAD at very low minor allele frequency (2/248,146). The authors demonstrated a dominant-negative effect of the Q121R mutation in zebrafish larvae, which developed varying degrees of inner ear defects; and morphant phenotypes, including reduced hearing ability in zebrafish with pi4kb knockdown, could not be rescued by injection of Q121R mRNA.
In an unrelated Chinese girl and boy (F35 and F37) from Inner Mongolia with nonsyndromic prelingual profound sensorineural hearing loss and inner ear malformations (DFNA87; 620281), Su et al. (2020) identified heterozygosity for a c.1301T-G transversion (c.1301T-G, ENST00000368874) in the PI4KB gene, resulting in a val434-to-gly (V434G) substitution within the serine-rich domain. The variant was not found in 600 Chinese controls from the same region of Inner Mongolia or in public variant databases; family members were unavailable for segregation analysis. The authors demonstrated a dominant-negative effect of the V434G mutation in zebrafish larvae, which developed varying degrees of inner ear defects; and morphant phenotypes, including reduced hearing ability in zebrafish with pi4kb knockdown, could not be rescued by injection of V434G mRNA. CT scan of patient F35 showed inner ear malformations, including incomplete partition and enlarged vestibular aqueduct; patient F37 did not undergo inner ear CT scan.
In an unrelated Chinese boy and girl (J3 and J5) from Inner Mongolia with nonsyndromic prelingual profound sensorineural hearing loss (DFNA87; 620281), Su et al. (2020) identified heterozygosity for a c.1999G-A transition (c.1999G-A, ENST00000368874) in the PI4KB gene, resulting in a glu667-to-lys (E667K) substitution within the kinase domain. The variant was not found in 600 Chinese controls from the same region of Inner Mongolia or in public variant databases; family members were unavailable for segregation analysis. The authors demonstrated a dominant-negative effect of the E667K mutation in zebrafish larvae, which developed varying degrees of inner ear defects; and morphant phenotypes, including reduced hearing ability in zebrafish with pi4kb knockdown, could not be rescued by injection of E667K mRNA. Patients J3 and J5 did not undergo inner ear CT scan.
In a Chinese girl (J37) from Inner Mongolia with nonsyndromic prelingual profound sensorineural hearing loss (DFNA87; 620281), Su et al. (2020) identified heterozygosity for a c.2216T-G transversion (c.2216T-G, ENST00000368874) in the PI4KB gene, resulting in a met739-to-arg (M739R) substitution within the kinase domain. The variant was not found in 600 Chinese controls from the same region of Inner Mongolia or in public variant databases; family members were unavailable for segregation analysis. The authors demonstrated a dominant-negative effect of the M739R mutation in zebrafish larvae, which developed varying degrees of inner ear defects; and morphant phenotypes, including reduced hearing ability in zebrafish with pi4kb knockdown, could not be rescued by injection of M739R mRNA. Patient J37 did not undergo inner ear CT scan.
Burke, J. E., Inglis, A. J., Perisic, O., Masson, G. R., McLaughlin, S. H., Rutaganira, F., Shokat, K. M., Williams, R. L. Structures of PI4KIII-beta complexes show simultaneous recruitment of Rab11 and its effectors. Science 344: 1035-1038, 2014. [PubMed: 24876499] [Full Text: https://doi.org/10.1126/science.1253397]
Gromada, J., Bark, C., Smidt, K., Efanov, A. M., Janson, J., Mandic, S. A., Webb, D.-L., Zhang, W., Meister, B., Jeromin, A., Berggren, P.-O. Neuronal calcium sensor-1 potentiates glucose-dependent exocytosis in pancreatic beta cells through activation of phosphatidylinositol 4-kinase beta. Proc. Nat. Acad. Sci. 102: 10303-10308, 2005. [PubMed: 16014415] [Full Text: https://doi.org/10.1073/pnas.0504487102]
Jovic, M., Kean, M. J., Szentpetery, Z., Polevoy, G., Gingras, A.-C., Brill, J. A., Balla, T. Two phosphatidylinositol 4-kinases control lysosomal delivery of the Gaucher disease enzyme, beta-glucocerebrosidase. Molec. Biol. Cell 23: 1533-1545, 2012. [PubMed: 22337770] [Full Text: https://doi.org/10.1091/mbc.E11-06-0553]
Meyers, R., Cantley, L. C. Cloning and characterization of a wortmannin-sensitive human phosphatidylinositol 4-kinase. J. Biol. Chem. 272: 4384-4390, 1997. [PubMed: 9020160] [Full Text: https://doi.org/10.1074/jbc.272.7.4384]
Mora, S., Durham, P. L., Smith, J. R., Russo, A. F., Jeromin, A., Pessin, J. E. NCS-1 inhibits insulin-stimulated GLUT4 translocation in 3T3L1 adipocytes through a phosphatidylinositol 4-kinase-dependent pathway. J. Biol. Chem. 277: 27494-27500, 2002. [PubMed: 12011096] [Full Text: https://doi.org/10.1074/jbc.M203669200]
Nagashima, S., Tabara, L.-C., Tilokani, L., Paupe, V., Anand, H., Pogson, J. H., Zunino, R., McBride, H. M., Prudent, J. Golgi-derived PI(4)P-containing vesicles drive late steps of mitochondrial division. Science 367: 1366-1371, 2020. [PubMed: 32193326] [Full Text: https://doi.org/10.1126/science.aax6089]
Nakanishi, S., Catt, K. J., Balla, T. A wortmannin-sensitive phosphatidylinositol 4-kinase that regulates hormone-sensitive pools of inositolphospholipids. Proc. Nat. Acad. Sci. 92: 5317-5321, 1995. [PubMed: 7777504] [Full Text: https://doi.org/10.1073/pnas.92.12.5317]
Saito, T., Seki, N., Ishii, H., Ohira, M., Hayashi, A., Kozuma, S., Hori, T. Complementary DNA cloning and chromosomal mapping of a novel phosphatidylinositol kinase gene. DNA Res. 4: 301-305, 1997. [PubMed: 9405938] [Full Text: https://doi.org/10.1093/dnares/4.4.301]
Su, X., Feng, Y., Rahman, S. A., Wu, S., Li, G., Ruschendorf, F., Zhao, L., Cui, H., Liang, J., Fang, L., Hu, H., Froehler, S., and 11 others. Phosphatidylinositol 4-kinase beta mutations cause nonsyndromic sensorineural deafness and inner ear malformation. J. Genet. Genomics 47: 618-626, 2020. [PubMed: 33358777] [Full Text: https://doi.org/10.1016/j.jgg.2020.07.008]
Suzuki, K., Hirano, H., Okutomi, K., Suzuki, M., Kuga, Y., Fujiwara, T., Kanemoto, N., Isono, K., Horie, M. Identification and characterization of a novel human phosphatidylinositol 4-kinase. DNA Res. 4: 273-280, 1997. [PubMed: 9405935] [Full Text: https://doi.org/10.1093/dnares/4.4.273]