Alternative titles; symbols
HGNC Approved Gene Symbol: PITPNA
Cytogenetic location: 17p13.3 Genomic coordinates (GRCh38): 17:1,517,718-1,562,792 (from NCBI)
Phosphatidylinositol transfer protein is a member of a diverse set of cytosolic phospholipid transfer proteins that are distinguished by their ability to transfer phospholipids between membranes in vitro (Wirtz, 1991).
The rat Pitpna gene encodes a polypeptide of 271 amino acids and is expressed in a wide range of tissues (Dickeson et al., 1989). The protein predicted by the human PITPNA gene cloned and sequenced by Dickeson et al. (1994) showed only 3 amino acid sequence differences from the rat protein, 2 of which represented conservative substitutions. Hay and Martin (1993) reported studies suggesting that PITPNA is identical to priming-specific factor-3, one of the 3 priming factors involved in the ATP-dependent priming of Ca(2+)-activated secretion. Rat Pitpna shares 40% amino acid homology over its entire length with the Drosophila retinal degeneration B (rdgB) protein (Vihtelic et al., 1993). Flies carrying the rdgB mutation undergo light-enhanced retinal degeneration.
As a first step toward investigations of possible involvement of the PITPNA locus in retinal degeneration, Fitzgibbon et al. (1994) mapped the PITPNA gene to human chromosome 17p13.3 by PCR analysis of a somatic cell hybrid panel followed by fluorescence in situ hybridization. They mapped the homologous gene to mouse chromosome 11 by interspecific mouse backcross mapping.
The mouse 'vibrator' (vb) mutation causes an early-onset progressive action tremor, degeneration of brainstem and spinal cord neurons, and juvenile death. Hamilton et al. (1997) cloned the vb mutation using an in vivo positional complementation approach followed by complete resequencing of the resulting 76-kb critical region in vb and its progenitor strain. The authors showed that the vb mutation is an intracisternal A particle retroposon insertion in intron 4 of the Pitpn gene, causing a 5-fold reduction in Pitpn RNA and protein levels. Expression of neurofilament light chain (NEFL; 162280) was also reduced in vb mice, suggesting 1 signaling pathway that may underlie vb pathology. The vb phenotype was suppressed in 1 intercross. By a complete genome scan, they mapped a major suppressor locus (Mvb1) to proximal mouse chromosome 19.
The modifier-of-vibrator-1 locus (Mvb1) controls levels of correctly processed mRNA from genes mutated by endogenous retrovirus insertions into introns, including the Pitpn(vb) tremor mutation. By positional complementation cloning, Floyd et al. (2003) identified Mvb1 as the nuclear export factor Nxf1 (602647), providing an unexpected link between the mRNA export receptor and pre-mRNA processing.
By examining lipid profiles, Monaco et al. (2004) observed increased neutral lipids, including cholesterol esters, triglycerides, and free fatty acids, in vb/vb liver compared with wildtype. No changes were detected in vb/vb liver phospholipid content or in the vb/vb brain lipid profile. Mammary glands of vb/vb mice were significantly underdeveloped compared with wildtype, and vb/vb mammary fat pads contained brown rather than white adipose tissue. No defect in phospholipid-mediated signaling was observed in isolated vb/vb fibroblasts. In Ptpa-null mice, Monaco et al. (2004) found reduced circulating triglycerides, overall reduction in body fat, low ATP/ADP ratio, and histologic evidence of steatosis in liver and duodenal tissue. Monaco et al. (2004) suggested that reduced Ptpa activity may result in biochemical uncoupling of mitochondrial fuel metabolism from energy production.
Dickeson, S. K., Helmkamp, G. M., Jr., Yarbrough, L. R. Sequence of a human cDNA encoding phosphatidylinositol transfer protein and occurrence of a related sequence in widely divergent eukaryotes. Gene 142: 301-305, 1994. [PubMed: 8194769] [Full Text: https://doi.org/10.1016/0378-1119(94)90279-8]
Dickeson, S. K., Lim, C. N., Schuyler, G. T., Dalton, T. P., Helmkamp, G. M., Jr., Yarbrough, L. R. Isolation and sequence of cDNA clones encoding rat phosphatidylinositol transfer protein. J. Biol. Chem. 264: 16557-16564, 1989. [PubMed: 2777797]
Fitzgibbon, J., Pilz, A., Gayther, S., Appukuttan, B., Dulai, K. S., Delhanty, J. D. A., Helmkamp, G. M., Jr., Yarbrough, L. R., Hunt, D. M. Localization of the gene encoding human phosphatidylinositol transfer protein (PITPN) to 17p13.3: a gene showing homology to the Drosophila retinal degeneration B gene (rdgB). Cytogenet. Cell Genet. 67: 205-207, 1994. [PubMed: 7914867] [Full Text: https://doi.org/10.1159/000133823]
Floyd, J. A., Gold, D. A., Concepcion, D., Poon, T. H., Wang, X., Keithley, E., Chen, D., Ward, E. J., Chinn, S. B., Friedman, R. A., Yu, H.-T., Moriwaki, K., Shiroishi, T., Hamilton, B. A. A natural allele of Nxf1 suppresses retrovirus insertional mutations. Nature Genet. 35: 221-228, 2003. [PubMed: 14517553] [Full Text: https://doi.org/10.1038/ng1247]
Hamilton, B. A., Smith, D. J., Mueller, K. L., Kerrebrock, A. W., Bronson, R. T., van Berkel, V., Daly, M. J., Kruglyak, L., Reeve, M. P., Nemhauser, J. L., Hawkins, T. L., Rubin, E. M., Lander, E. S. The vibrator mutation causes neurodegeneration via reduced expression of PITP-alpha: positional complementation cloning and extragenic suppression. Neuron 18: 711-722, 1997. [PubMed: 9182797] [Full Text: https://doi.org/10.1016/s0896-6273(00)80312-8]
Hay, J. C., Martin, T. F. J. Phosphatidylinositol transfer protein required for ATP-dependent priming of Ca(2+)-activated secretion. Nature 366: 572-575, 1993. [PubMed: 8255295] [Full Text: https://doi.org/10.1038/366572a0]
Monaco, M. E., Kim, J., Ruan, W., Wieczorek, R., Kleinberg, D. L., Walden, P. D. Lipid metabolism in phosphatidylinositol transfer protein alpha-deficient vibrator mice. Biochem. Biophys. Res. Commun. 317: 444-450, 2004. [PubMed: 15063778] [Full Text: https://doi.org/10.1016/j.bbrc.2004.03.054]
Vihtelic, T. S., Goebl, M., Milligan, S., O'Tousa, J. E., Hyde, D. R. Localization of Drosophila retinal degeneration B, a membrane-associated phosphatidylinositol transfer protein. J. Cell Biol. 122: 1013-1022, 1993. [PubMed: 8354691] [Full Text: https://doi.org/10.1083/jcb.122.5.1013]
Wirtz, K. W. A. Phospholipid transfer proteins. Annu. Rev. Biochem. 60: 73-99, 1991. [PubMed: 1883207] [Full Text: https://doi.org/10.1146/annurev.bi.60.070191.000445]