Alternative titles; symbols
HGNC Approved Gene Symbol: PLD3
SNOMEDCT: 1279839002;
Cytogenetic location: 19q13.2 Genomic coordinates (GRCh38): 19:40,348,695-40,378,485 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.2 | ?Spinocerebellar ataxia 46 | 617770 | Autosomal dominant | 3 |
PLD3 is a member of the phospholipase D (PLD) family of enzymes that catalyze the hydrolysis of membrane phospholipids (Munck et al., 2005).
By searching an EST database for sequences similar to the vaccinia virus K4L gene product, Cao et al. (1997) identified partial human cDNAs encoding PLD3, which they called HUK4. The 437-amino acid partial HUK4 protein shares 48.1% identity with vaccinia virus K4L protein and weaker similarity with the group of poxvirus p37 proteins. All of these proteins contain 2 repeats of 4 characteristic motifs of the PLD protein superfamily. Database analysis predicted that HUK4 was widely expressed in human tissues.
Munck et al. (2005) extended the HUK4 ORF in the 5-prime direction, revealing a full-length 490-amino acid protein with a putative transmembrane domain near the N terminus. HUK4 was predicted to have a cytoplasmic N terminus and a large C-terminal luminal or extracellular domain with 2 PLD motifs. The C-terminal domain also contains 7 potential glycosylation sites and a putative C-terminal prenylation motif. EST database analysis revealed extensive alternative splicing involving exons 1 through 5, affecting the 5-prime UTR of HUK4. Northern blot analysis detected an approximately 2.2-kb transcript that was variably expressed in all 12 tissues examined, with highest expression in skeletal muscle, heart, and brain. A 1.7-kb transcript was also detected and showed highest expression in brain. RNA dot blot analysis confirmed ubiquitous HUK4 expression, with highest expression in adult and fetal brain regions. Munck et al. (2005) stated that the murine homolog, Sam9, is also widely expressed, with highest level in brain. Immunohistochemical analysis of transfected COS-7 cells showed colocalization of HUK4 with protein disulfide isomerase (see 608012), a marker for the endoplasmic reticulum.
Nibbeling et al. (2017) noted that the human PLD3 gene is highly expressed in cerebellum.
Munck et al. (2005) found that the PLD3 gene contains at least 15 exons, with extensive alternative splicing at the 5-prime end affecting the 5-prime UTR. Translation was expected to initiate in exon 5 or 7, but there are several additional putative start codons in upstream exons. The 5-prime UTR has low GC content. Exon 15 contains the stop codon and 2 noncanonical polyadenylation signals.
By genomic sequence analysis, Munck et al. (2005) mapped the PLD3 gene to chromosome 19q13.2.
Cruchaga et al. (2014) determined that PLD3 is highly expressed in brain regions that are vulnerable to Alzheimer disease (104300) pathology, including hippocampus and cortex, and that PLD3 is expressed at significantly lower levels in neurons from Alzheimer disease brains compared to control brains. Overexpression of PLD3 led to a significant decrease in intracellular amyloid-beta precursor protein (APP; 104760) and extracellular amyloid-beta-42 and amyloid-beta-40, and knockdown of PLD3 led to a significant increase in extracellular amyloid-beta-42 and amyloid-beta-40. Cruchaga et al. (2014) concluded that, taken together, their genetic and functional data indicated that carriers of PLD3 coding variants have a 2-fold increased risk for late-onset Alzheimer disease and that PLD3 influences APP processing.
Using purified recombinant mouse protein, Gavin et al. (2018) showed that Pld3 functioned as a 5-prime exonuclease that was indistinguishable from classical spleen acid exonuclease. Pld3 digested single-stranded oligodeoxynucleotides, including those with phosphorothioate linkages. Analysis with Pld3 -/- macrophages showed that the nuclease activity of Pld3 limited the cellular responses to exogenous ligands of ssDNA sensor Tlr9 (605474). The exonuclease activities of Pld3 and Pld4 (618488) were overlapping and redundant, and ligands of Tlr9, particularly those lacking phosphorothioate linkages, had enhanced stability and diminished turnover in cells lacking Pld3 and Pld4.
Spinocerebellar Ataxia 46
In 8 affected members of a family (RF28) with spinocerebellar ataxia-46 (SCA46; 617770), Nibbeling et al. (2017) identified a heterozygous missense mutation in the PLD3 gene (L308P; 615698.0002). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression studies showed that the L308P protein was normally expressed, had normal cellular localization, and was stable. However, phospholipase D activity of the mutant protein was significantly decreased compared to wildtype. The family was 1 of 20 unrelated families with autosomal dominant SCA who underwent whole-exome sequencing.
Reclassified Variants
The V239M variant in the PLD3 gene (615698.0001) has been reclassified as a variant of unknown significance. Cruchaga et al. (2014) had identified this variant in 2 independent families with late-onset Alzheimer disease (AD19; 615711).
Gavin et al. (2018) found that double-knockout Pld3 -/- Pld4 -/- mice were undersized compared with controls and died between 12 and 21 days of age with severe liver inflammation. Livers from double-knockout mice developed a lethal hepatic autoinflammatory disease, which could be prevented by a single allele of either Pld3 or Pld4.
This variant, formerly titled ALZHEIMER DISEASE 19, SUSCEPTIBILITY TO, based on the report of Cruchaga et al. (2014), has been reclassified because its contribution to the phenotype has not been confirmed (see, e.g., Lambert et al. (2015) and Heilmann et al. (2015).)
Among 29 individuals with Alzheimer disease and 11 unaffected individuals from 14 families of European American ancestry, Cruchaga et al. (2014) identified a single variant, rs145999145, which resulted in a val232-to-met (V232M) substitution and segregated with disease in 2 independent families with late-onset Alzheimer disease (AD19; 615711). Cruchaga et al. (2014) then determined the risk of sporadic Alzheimer disease associated with this variant in 7 independent datasets comprising 4,998 Alzheimer disease cases and 6,356 controls (p = 2.93 x 10(-05), odds ratio = 2.10, 95% CI = 1.47-2.99). The frequency of the V232M mutation was higher in Alzheimer disease cases compared to controls in each age/gender/ethnicity-matched dataset, with a similar estimated odds ratio for each dataset, suggesting that the association was unlikely to be a false positive due to population stratification. The association of the V232M variant with Alzheimer disease risk was also independent of the APOE (107741) genotype. As predicted for an Alzheimer disease risk allele, V232M showed age-dependent differences in frequency among controls, with the lowest frequency (1/376, 0.27%) in the Wellderly dataset, a series composed of healthy individuals without dementia who were older than 80 years. Similarly, no V232M carriers were found among the 303 individuals without dementia who had normal cerebrospinal fluid amyloid-beta-42 (see APP, 104760) and tau (MAPT; 157140) profiles, suggesting that the calculated odds ratio for the V232M variant when compared to all controls may be an underestimation. As proposed, the frequency of V232M was higher in familial cases than in sporadic cases (2.62% in familial vs 1.36% in sporadic cases).
Lambert et al. (2015), van der Lee et al. (2015), and Heilmann et al. (2015) found no association between rare and common variants in PLD3, including the V232M substitution, in large studies of French, Danish, Spanish, and German populations with late-onset AD. Cruchaga and Goate (2015) suggested that the failure of replication in these studies was due to lack of population stratification and/or to population/regional differences. They concluded that the V232M variant is a late-onset AD susceptibility allele, although the odds ratio may be lower than that reported by Cruchaga et al. (2014).
In 8 affected members of a family (RF28) with spinocerebellar ataxia-46 (SCA46; 617770), Nibbeling et al. (2017) identified a heterozygous c.923T-C transition (chr19.40880431, GRCh37) in the PLD3 gene, resulting in a leu308-to-pro (L308P) substitution at a highly conserved residue in the PLD phosphodiesterase domain 2. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the 1000 Genomes Project or ExAC databases. The family had previously been reported by van Dijk et al. (1995). In vitro functional expression studies showed that the L308P protein was normally expressed, had normal cellular localization, and was stable. However, phospholipase D activity of the mutant protein was significantly decreased compared to wildtype.
Hamosh (2017) noted that the c.923T-C variant was reported once in the gnomAD database, in a non-Finnish European individual (November 20, 2017).
Cao, J. X., Koop, B. F., Upton, C. A human homolog of the vaccinia virus HindIII K4L gene is a member of the phospholipase D superfamily. Virus Res. 48: 11-18, 1997. [PubMed: 9140189] [Full Text: https://doi.org/10.1016/s0168-1702(96)01422-0]
Cruchaga, C., Goate, A. M. Cruchaga and Goate reply. Nature 520: E5-E6, 2015. Note: Electronic Article. [PubMed: 25832412] [Full Text: https://doi.org/10.1038/nature14037]
Cruchaga, C., Karch, C. M., Jin, S. C., Benitez, B. A., Cai, Y., Guerreiro, R., Harari, O., Norton, J., Budde, J., Bertelsen, S., Jeng, A. T., Cooper, B., and 48 others. Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease. Nature 505: 550-554, 2014. [PubMed: 24336208] [Full Text: https://doi.org/10.1038/nature12825]
Gavin, A. L., Huang, D., Huber, C., Martensson, A., Tardif, V., Skog, P. D., Blane, T. R., Thinnes, T. C., Osborn, K., Chong, H. S., Kargaran, F., Kimm, P., and 15 others. PLD3 and PLD4 are single-stranded acid exonucleases that regulate endosomal nucleic-acid sensing. Nature Immun. 19: 942-953, 2018. [PubMed: 30111894] [Full Text: https://doi.org/10.1038/s41590-018-0179-y]
Hamosh, A. Personal Communication. Baltimore, Md. 11/20/2017.
Heilmann, S., Drichel, D., Clarimon, J., Fernandez, V., Lacour, A., Wagner, H., Thelen, M., Hernandez, I., Fortea, J., Alegret, M., Blesa, R., Mauleon, A., and 20 others. PLD3 in non-familial Alzheimer's disease. Nature 520: E3-E4, 2015. Note: Electronic Article. [PubMed: 25832411] [Full Text: https://doi.org/10.1038/nature14039]
Lambert, J.-C., Grenier-Boley, B., Bellenguez, C., Pasquier, F., Campion, D., Dartigues, J.-F., Berr, C., Tzourio, C., Amouyel, P. PLD3 and sporadic Alzheimer's disease risk. Nature 520: E1, 2015. Note: Electronic Article. [PubMed: 25832408] [Full Text: https://doi.org/10.1038/nature14036]
Munck, A., Bohm, C., Seibel, N. M., Hashemol Hosseini, Z., Hampe, W. Hu-K4 is a ubiquitously expressed type 2 transmembrane protein associated with the endoplasmic reticulum. FEBS J. 272: 1718-1726, 2005. [PubMed: 15794758] [Full Text: https://doi.org/10.1111/j.1742-4658.2005.04601.x]
Nibbeling, E. A. R., Duarri, A., Verschuuren-Bemelmans, C. C., Fokkens, M. R., Karjalainen, J. M., Smeets, C. J. L. M., de Boer-Bergsma, J. J., van der Vries, G., Dooijes, D., Bampi, G. B., van Diemen, C., Brunt, E., and 9 others. Exome sequencing and network analysis identifies shared mechanisms underlying spinocerebellar ataxia. Brain 140: 2860-2878, 2017. [PubMed: 29053796] [Full Text: https://doi.org/10.1093/brain/awx251]
van der Lee, S. J., Holstege, H., Wong, T. H., Jakobsdottir, J., Bis, J. C., Chouraki, V., van Rooij, J. G. J., Grove, M. L., Smith, A. V., Amin, N., Choi, S.-H., Beiser, A. S., and 26 others. PLD3 variants in population studies. Nature 520: E2-E3, 2015. Note: Electronic Article. [PubMed: 25832410] [Full Text: https://doi.org/10.1038/nature14038]
van Dijk, G. W., Wokke, J. H. J., Oey, P. L., Franssen, H., Ippel, P. F., Veldman, H. A new variant of sensory ataxic neuropathy with autosomal dominant inheritance. Brain 118: 1557-1563, 1995. [PubMed: 8595484] [Full Text: https://doi.org/10.1093/brain/118.6.1557]