HGNC Approved Gene Symbol: PLD1
Cytogenetic location: 3q26.31 Genomic coordinates (GRCh38): 3:171,600,404-171,810,483 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q26.31 | Cardiac valvular dysplasia 1 | 212093 | Autosomal recessive | 3 |
Phosphatidylcholine (PC)-specific phospholipases D (PLDs; EC 3.1.4.4) catalyze the hydrolysis of PC to produce phosphatidic acid and choline. A range of agonists acting through G protein-coupled receptors and receptor tyrosine kinases stimulate this hydrolysis. PC-specific PLD activity has been implicated in numerous cellular pathways, including signal transduction, membrane trafficking, and the regulation of mitosis (Hammond et al., 1995).
Using primers specific for an EST that showed similarity to a yeast PC-specific PLD gene, Hammond et al. (1995) performed PCR on HeLa cDNA and then screened a HeLa cDNA library with the PCR product to clone a cDNA encoding PLD1. The 1,072-amino acid protein does not contain previously recognized domain structures and shows no similarity to PLC (see 600810) or PIGPLD (602515). A database search identified homologs in numerous widely disparate organisms, demonstrating that PLD1 is a member of a novel but highly conserved gene family. Expression of PLD1 in insect cells produces a 120-kD protein, matching closely the theoretical size of 124 kD and suggesting that little if any posttranslational processing occurs.
Hammond et al. (1997) identified an evolutionarily conserved splice variant of PLD1 that arises from regulated splicing of a 38-amino acid alternate exon.
By Northern blot analysis, Colley et al. (1997) detected mouse Pld1 expression in all tissues examined, with highest levels in kidney and lung. The ratio of Pld1 and Pld2 (602384) in each tissue varied. In situ hybridization of mouse embryo and adult brain showed that Pld1 is expressed in a restricted manner.
Liscovitch et al. (2000) stated that PLD1 contains 4 core domains, a putative PX domain, and a C-terminal motif conserved in all eukaryotic PLDs. PLD1 has a 116-amino acid loop between core domains I and II that is not found in PLD2.
By whole-mount in situ hybridization in chick embryos, Ta-Shma et al. (2017) studied PLD1 expression during the cardiogenesis period, embryonic days (E) 2 to 8. PLD1 was homogeneously present all over the heart during days E2 to E3. Thereafter, its expression decreased, remaining primarily at the interventricular septum, adjacent to the atrioventricular valves and the right ventricular outflow tract (RVOT). PLD1 expression in the RVOT dynamically shifted over E4 to E8 before completely disappearing. These findings were verified in a separate set of experiments on histologic sections of chick embryo hearts, where PLD1 expression was noted on days E6 to E8 in several myocardial locations, most prominently in the myocardial layer of the RVOT. The signal gradually diminished in a proximal to distal direction, with the subpulmonic area being the last to express PLD1. The signal finally disappeared only after the pulmonary valve completed its separation and formation. Furthermore, PLD1 was not expressed to a significant degree in any other organ during this developmental period, except for the neural tube.
By somatic cell hybrid analysis, Colley et al. (1997) mapped the human PLD1 gene to chromosome 3. By FISH, Park et al. (1998) refined the assignment to 3q26. By interspecific backcross analysis, Colley et al. (1997) mapped the mouse Pld1 gene to the proximal region of chromosome 3.
Hammond et al. (1995) showed that recombinant PLD1 activity is located both in the cytoplasm and in association with the membrane. They suggested that PLD1 can exist as a stable soluble protein and that controlled interaction with substrate-containing phospholipid surfaces may be a physiologically important mode of regulation. Hammond et al. (1995) demonstrated that PLD1 is stimulated by phosphatidylinositol 4,5-bisphosphate and strongly inhibited by oleate in vitro. They found that ADP-ribosylation factor-1 (ARF1; 103180) activates PLD1, suggesting that PLD1 is involved in intravesicular membrane trafficking.
Hammond et al. (1997) found that both PLD1 variants have identical catalytic and regulatory properties. They demonstrated that PLD1 can be activated in vitro by PKCA (176960) and the monomeric GTP-binding proteins RHO A, RAC1 (602048), and CDC42 (116952). Hammond et al. (1997) suggested that PLD1 may be involved in cell morphology alterations as well as intracellular protein trafficking.
Sung et al. (1999) showed that the C-terminal 99 amino acids of PLD1 are required for PLD activity.
Liscovitch et al. (2000) reviewed the structure, localization, regulation, and functions of PLDs, including PLD1.
Interaction of PLD1 with actin microfilaments regulates cell proliferation, vesicle trafficking, and secretion. Kusner et al. (2002) found that highly purified globular actin (G-actin) inhibited both basal and stimulated PLD1 activity, whereas filamentous actin (F-actin) had the opposite effect. Actin-induced modulation of PLD1 activity was independent of the activating stimulus. The effects of actin on PLD1 were isoform specific: human platelet actin, which exists in a 5:1 ratio of beta- (ACTB; 102630) and gamma-actin (ACTG1; 102560), was only 45% as potent and 40% as efficacious as rabbit skeletal muscle alpha-actin (ACTA1; 102610).
Cai et al. (2006) showed that presenilin-1 (PSEN1; 104311), a major component of gamma-secretase, binds PLD1 and recruits it to the Golgi/trans-Golgi network (TGN). Overexpression of PLD1 in mouse neuroblastoma (N2a) cells decreased gamma-secretase-mediated beta-amyloid (APP; 104760) generation, whereas downregulation of PLD1 increased beta-amyloid production. Further studies showed that PLD1 disrupted association of gamma-secretase protein components, independent of PLD1 catalytic activity. In a companion paper, Cai et al. (2006) found that overexpression of catalytically active PLD1 promoted generation of beta-amyloid-containing vesicles from the TGN. Although PLD1 enzymatic activity was decreased in N2a cells with familial Alzheimer disease-3 (AD3; 607822) PSEN1 mutations, overexpression of wildtype PLD1, but not catalytically inactive PLD1, in these cells increased cell surface delivery of beta-amyloid at axonal terminals and rescued impaired axonal growth and neurite branching. The findings showed that PLD1 regulates intracellular trafficking of beta-amyloid, distinct from its effect on gamma-secretase activity.
In affected individuals from 2 unrelated consanguineous families with cardiac valvular dysplasia (CVDP1; 212093), Ta-Shma et al. (2017) identified homozygosity or compound heterozygosity for mutations in the PLD1 gene (602382.0001-602382.0003) that segregated with disease and were not found in the ExAC database.
In Pld1 knockout (KO) mice, Ta-Shma et al. (2017) observed marked tricuspid regurgitation (TR), with increased velocity across the valve compared to wildtype mice. Consistent with TR, the right atrial area was larger in KO mice, and the right atrial to left atrial area ratio was also larger compared to wildtype mice. Pulmonary valve (PV) peak velocity was abnormally high in KO mice, and mean PV diameter was smaller than in wildtype mice. In addition, histologic evaluation of the PV revealed thickened valve leaflets in KO mice compared with wildtype mice.
In 2 brothers from a consanguineous family (family A) with cardiac valvular dysplasia-1 (CVDP1; 212093), Ta-Shma et al. (2017) identified homozygosity for a c.1325A-C transversion (c.1325A-C, NM_002662) in the PLD1 gene, resulting in a his442-to-pro (H442P) substitution at a highly conserved residue within the first catalytic domain. The mutation was present in heterozygosity in their unaffected parents and an unaffected sib; it was not found in the ExAC database. Functional analysis in a yeast strain homozygous for the homologous mutation (H774P) showed total absence of sporulation, indicating a strong loss-of-function phenotype in yeast that was consistent with pathogenicity of the H442P mutation in humans.
In a 2-year-old girl from a consanguineous family (family B) with cardiac valvular dysplasia-1 (CVDP1; 212093), Ta-Shma et al. (2017) identified homozygosity for a 2-bp deletion (c.1484_1485delTG, NM_002662) in the PLD1 gene, causing a frameshift predicted to result in a premature termination codon (Thr495fs32Ter) with loss of 2 catalytic domains. The mutation was present in heterozygosity in her unaffected parents. In another branch of family B, an affected 17-year-old boy was compound heterozygous for the 2-bp deletion and a splice site mutation in intron 25 of the PLD1 gene (c.2882+2T-C; 602382.0003); his unaffected parents were each heterozygous for 1 of the mutations, neither of which was found in the ExAC database.
For discussion of the splice site mutation (c.2282+2T-C, NM_002662) in intron 25 of the PLD1 gene that was found in compound heterozygous state in a patient with cardiac valvular dysplasia-1 (CVDP1; 212093) by Ta-Shma et al. (2017), see 602382.0002.
Cai, D., Netzer, W. J., Zhong, M., Lin, Y., Du, G., Frohman, M., Foster, D. A., Sisodia, S. S., Xu, H., Gorelick, F. S., Greengard, P. Presenilin-1 uses phospholipase D1 as a negative regulator of beta-amyloid formation. Proc. Nat. Acad. Sci. 103: 1941-1946, 2006. [PubMed: 16449386] [Full Text: https://doi.org/10.1073/pnas.0510708103]
Cai, D., Zhong, M., Wang, R., Netzer, W. J., Shields, D., Zheng, H., Sisodia, S. S., Foster, D. A., Gorelick, F. S., Xu, H., Greengard, P. Phospholipase D1 corrects impaired beta-APP trafficking and neurite outgrowth in familial Alzheimer's disease-linked presenilin-1 mutant neurons. Proc. Nat. Acad. Sci. 103: 1936-1940, 2006. [PubMed: 16449385] [Full Text: https://doi.org/10.1073/pnas.0510710103]
Colley, W. C., Altshuller, Y. M., Sue-Ling, C. K., Copeland, N. G., Gilbert, D. J., Jenkins, N. A., Branch, K. D., Tsirka, S. E., Bollag, R. J., Bollag, W. B., Frohman, M. A. Cloning and expression analysis of murine phospholipase D1. Biochem. J. 326: 745-753, 1997. [PubMed: 9307024] [Full Text: https://doi.org/10.1042/bj3260745]
Hammond, S. M., Altshuller, Y. M., Sung, T.-C., Rudge, S. A., Rose, K., Engebrecht, J., Morris, A. J., Frohman, M. A. Human ADP-ribosylation factor-activated phosphatidylcholine-specific phospholipase D defines a new and highly conserved gene family. J. Biol. Chem. 270: 29640-29643, 1995. [PubMed: 8530346] [Full Text: https://doi.org/10.1074/jbc.270.50.29640]
Hammond, S. M., Jenco, J. M., Nakashima, S., Cadwallader, K., Gu, Q., Cook, S., Nozawa, Y., Prestwich, G. D., Frohman, M. A., Morris, A. J. Characterization of two alternately spliced forms of phospholipase D1: activation of the purified enzymes by phosphatidylinositol 4,5-bisphosphate, ADP-ribosylation factor, and RHO family monomeric GTP-binding proteins and protein kinase C-alpha. J. Biol. Chem. 272: 3860-3868, 1997. [PubMed: 9013646] [Full Text: https://doi.org/10.1074/jbc.272.6.3860]
Kusner, D. J., Barton, J. A., Wen, K.-K., Wang, X., Rubenstein, P. A., Iyer, S. S. Regulation of phospholipase D activity by actin: actin exerts bidirectional modulation of mammalian phospolipase (sic) D activity in a polymerization-dependent, isoform-specific manner. J. Biol. Chem. 277: 50683-50692, 2002. [PubMed: 12388543] [Full Text: https://doi.org/10.1074/jbc.M209221200]
Liscovitch, M., Czarny, M., Fiucci, G., Tang, X. Phospholipase D: molecular and cell biology of a novel gene family. Biochem. J. 345: 401-415, 2000. [PubMed: 10642495]
Park, S. H., Chun, Y. H., Ryu, S. H., Suh, P. G., Kim, H. Assignment of human PLD1 to human chromosome band 3q26 by fluorescence in situ hybridization. Cytogenet. Cell Genet. 82: 224 only, 1998. [PubMed: 9858822] [Full Text: https://doi.org/10.1159/000015105]
Sung, T.-C., Zhang, Y., Morris, A. J., Frohman, M. A. Structural analysis of human phospholipase D1. J. Biol. Chem. 274: 3659-3666, 1999. [PubMed: 9920915] [Full Text: https://doi.org/10.1074/jbc.274.6.3659]
Ta-Shma, A., Zhang, K., Salimova, E., Zernecke, A., Sieiro-Mosti, D., Stegner, D., Furtado, M., Shaag, A., Perles, Z., Nieswandt, B., Rein, A. J. J. T., Rosenthal, N., Neiman, A. M., Elpeleg, O. Congenital valvular defects associated with deleterious mutations in the PLD1 gene. J. Med. Genet. 54: 278-286, 2017. [PubMed: 27799408] [Full Text: https://doi.org/10.1136/jmedgenet-2016-104259]