PLD3

Summary

PLD3 (phospholipase D family member 3, HGNC:17158) is a protein-coding gene on chromosome 19q13.2, encoding 5’-3’ exonuclease PLD3 (Q8IV08). 5’->3’ exonuclease that hydrolyzes the phosphodiester bond of single-stranded DNA (ssDNA) and RNA molecules to form nucleoside 3’-monophosphates and 5’-end 5’-hydroxy deoxyribonucleotide/ribonucleotide fragments.

This gene encodes a member of the phospholipase D (PLD) family of enzymes that catalyze the hydrolysis of membrane phospholipids. The encoded protein is a single-pass type II membrane protein and contains two PLD phosphodiesterase domains. This protein influences processing of amyloid-beta precursor protein. Mutations in this gene are associated with Alzheimer disease risk. Alternatively spliced transcript variants encoding the same protein have been found for this gene.

Source: NCBI Gene 23646 — RefSeq curated summary.

At a glance

• Gene–disease (curated): leukodystrophy (Moderate, GenCC) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 218 total — 1 pathogenic
• Phenotypes (HPO): 13
• Druggable target: yes
• MANE Select transcript: NM_012268

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17158
Approved symbol	PLD3
Name	phospholipase D family member 3
Location	19q13.2
Locus type	gene with protein product
Status	Approved
Aliases	HU-K4
Ensembl gene	ENSG00000105223
Ensembl biotype	protein_coding
OMIM	615698
Entrez	23646

Gene structure

Transcript identifiers

Ensembl transcripts: 88 — 70 protein_coding, 12 retained_intron, 4 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000356508, ENST00000359274, ENST00000392032, ENST00000409281, ENST00000409419, ENST00000409587, ENST00000409735, ENST00000464586, ENST00000475983, ENST00000480030, ENST00000485448, ENST00000486134, ENST00000488311, ENST00000492243, ENST00000493006, ENST00000594085, ENST00000594908, ENST00000596682, ENST00000598962, ENST00000599353, ENST00000599685, ENST00000600479, ENST00000600948, ENST00000602131, ENST00000700616, ENST00000700617, ENST00000700618, ENST00000700619, ENST00000700620, ENST00000700621, ENST00000700622, ENST00000700623, ENST00000700624, ENST00000700625, ENST00000700626, ENST00000700627, ENST00000700628, ENST00000700629, ENST00000700630, ENST00000700631, ENST00000700632, ENST00000700633, ENST00000700634, ENST00000700635, ENST00000700636, ENST00000700637, ENST00000700638, ENST00000700639, ENST00000853076, ENST00000853077, ENST00000853078, ENST00000853079, ENST00000853080, ENST00000853081, ENST00000853082, ENST00000853083, ENST00000853084, ENST00000853085, ENST00000853086, ENST00000853087, ENST00000853088, ENST00000853089, ENST00000853090, ENST00000853091, ENST00000853092, ENST00000853093, ENST00000853094, ENST00000853095, ENST00000853096, ENST00000853097, ENST00000853098, ENST00000853099, ENST00000853100, ENST00000853101, ENST00000853102, ENST00000853103, ENST00000853104, ENST00000924547, ENST00000924548, ENST00000924549, ENST00000952049, ENST00000952050, ENST00000952051, ENST00000952052, ENST00000952053, ENST00000952054, ENST00000952055, ENST00000952056

RefSeq mRNA: 3 — MANE Select: NM_012268 NM_001031696, NM_001291311, NM_012268

CCDS: CCDS33027

Canonical transcript exons

ENST00000409735 — 13 exons

Exon	Start	End
ENSE00000706539	40367696	40367879
ENSE00000706588	40371673	40371873
ENSE00000706599	40374481	40374620
ENSE00000706612	40376609	40376774
ENSE00001510480	40365718	40365930
ENSE00003503700	40366419	40366510
ENSE00003550901	40377786	40377885
ENSE00003624934	40366610	40366684
ENSE00003643428	40369908	40370028
ENSE00003689969	40370110	40370237
ENSE00003788487	40366773	40366915
ENSE00003980334	40348695	40348768
ENSE00003980341	40377986	40378485

Expression profiles

Bgee: expression breadth ubiquitous, 282 present calls, max score 99.65.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 170.3300 / max 1989.3844, expressed in 1827 samples.

FANTOM5 promoters (17 alternative TSS)

Promoter ID	TPM avg	Samples expressed
175832	104.7714	1497
175826	55.5251	1825
175841	1.3126	701
175839	1.0832	627
175827	1.0167	592
175828	0.9327	568
175842	0.8854	454
175836	0.8619	445
175838	0.8028	465
175825	0.7862	488

Top tissues by expression

294 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
adenohypophysis	UBERON:0002196	99.65	gold quality
pituitary gland	UBERON:0000007	99.58	gold quality
right frontal lobe	UBERON:0002810	99.22	gold quality
stromal cell of endometrium	CL:0002255	99.18	gold quality
prefrontal cortex	UBERON:0000451	99.17	gold quality
right ovary	UBERON:0002118	98.90	gold quality
descending thoracic aorta	UBERON:0002345	98.86	gold quality
right coronary artery	UBERON:0001625	98.84	gold quality
thoracic aorta	UBERON:0001515	98.81	gold quality
left ovary	UBERON:0002119	98.81	gold quality
ascending aorta	UBERON:0001496	98.80	gold quality
nucleus accumbens	UBERON:0001882	98.78	gold quality
right adrenal gland	UBERON:0001233	98.77	gold quality
right hemisphere of cerebellum	UBERON:0014890	98.77	gold quality
cingulate cortex	UBERON:0003027	98.76	gold quality
right adrenal gland cortex	UBERON:0035827	98.76	gold quality
left adrenal gland	UBERON:0001234	98.73	gold quality
anterior cingulate cortex	UBERON:0009835	98.72	gold quality
left adrenal gland cortex	UBERON:0035825	98.68	gold quality
amygdala	UBERON:0001876	98.66	gold quality
apex of heart	UBERON:0002098	98.66	gold quality
cerebellar hemisphere	UBERON:0002245	98.66	gold quality
cerebellar cortex	UBERON:0002129	98.64	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.56	gold quality
right lung	UBERON:0002167	98.55	gold quality
upper lobe of left lung	UBERON:0008952	98.54	gold quality
mucosa of stomach	UBERON:0001199	98.52	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	98.51	gold quality
Brodmann (1909) area 9	UBERON:0013540	98.50	gold quality
right atrium auricular region	UBERON:0006631	98.48	gold quality

Single-cell (SCXA)

Detected in 11 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-MTAB-9801	yes	1926.31
E-HCAD-13	yes	1284.56
E-MTAB-8142	yes	46.29
E-GEOD-81547	yes	26.92
E-MTAB-10553	yes	25.01
E-CURD-112	yes	19.06
E-HCAD-10	yes	16.18
E-MTAB-6678	yes	12.30
E-MTAB-10042	yes	9.51
E-HCAD-25	yes	8.07
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

32 targeting PLD3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-4500	99.99	72.72	2367
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-6752-5P	99.59	67.32	1243
HSA-MIR-6751-5P	99.56	64.99	1145
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-6731-5P	99.28	67.42	2375
HSA-MIR-8085	99.28	67.56	2362
HSA-MIR-449B-3P	99.20	67.24	1047
HSA-MIR-6803-5P	99.19	63.90	1026
HSA-MIR-4651	99.06	67.57	2002
HSA-MIR-608	98.93	67.83	2013
HSA-MIR-4718	98.55	68.61	814
HSA-MIR-6880-5P	98.08	65.59	1282
HSA-MIR-4640-5P	97.42	66.33	1543
HSA-MIR-4726-5P	97.24	65.67	1299

Literature-anchored findings (GeneRIF, showing 17)

• Our data do not support the hypothesis that the HindIII(+/-) site of the Y chromosome is a marker of cardiovascular risk in white men, highlighting the need for replication in genetic association studies. (PMID:16580565)
• receptor stimulation leads to sequestration of recycling endosomes in a classical protein kinase C- and phospholipase D-dependent manner (PMID:19525236)
• PLD3 overexpression may inhibit Akt phosphorylation and further block the transduction of insulin signaling in C2C12 cells. (PMID:20112697)
• PLD3 localizes to lysosomes (PMID:21752829)
• genetic and functional data indicate that carriers of PLD3 coding variants have a twofold increased risk for late-onset Alzheimer’s disease and that PLD3 influences APP processing (PMID:24336208)
• The rare coding variant might not play an important role in AD risk in mainland China. (PMID:24866402)
• PLD3 variant V232M was associated with Alzheimer’s disease risk in overall sample sets. (PMID:26189833)
• main findings of our this provide evidence that support the possible role of PLD3 common variants in influencing AD-related neuroimaging phenotypes. (PMID:26232066)
• one PLD3 variant (rs11667768) was associated with amyloid burden detected by CSF in normal individuals, suggesting the potential role of PLD3 in Abeta pathology (PMID:26402410)
• Rare Variants in PLD3 Do Not Affect Risk for Early-Onset Alzheimer Disease in a European Consortium Cohort (PMID:26411346)
• Data show that phospholipase D3 (PLD3) functions in endosomal protein sorting and plays an important role in regulating amyloid precursor protein (APP) processing. (PMID:29368044)
• The results of this study indicated that rare variants of PLD3 may play an important role in late-onset Alzheimer’s Disease in northern Han Chinese. (PMID:29865074)
• rs11667768 was significantly associated with CSF total-tau levels and hippocampal volumes at baseline and six-year follow-up in the total non-demented elderly group and the mild cognitive impairment subgroup, indicating a potential role of PLD3 common variants in influencing cognitive function through changing CSF total-tau levels and hippocampal volumes. (PMID:30103332)
• PLD3 gene is downregulated in the hippocampus of Alzheimer’s disease (AD) cases. Altered epigenetic mechanisms, such as differential DNA methylation within an alternative promoter of the gene, may be involved in the pathology of AD. PLD3 mRNA expression inversely correlates with hippocampal beta-amyloid burden, adding evidence that PLD3 protein may contribute to AD development by modifying APP processing. (PMID:30208929)
• the V232M mutation of PLD3 may affect Alzheimer’s disease pathogenesis (PMID:31121321)
• PLD3 is a neuronal lysosomal phospholipase D associated with beta-amyloid plaques and cognitive function in Alzheimer’s disease. (PMID:33830999)
• Structural analysis of PLD3 reveals insights into the mechanism of lysosomal 5’ exonuclease-mediated nucleic acid degradation. (PMID:37994783)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	pld3	ENSDARG00000068199
mus_musculus	Pld3	ENSMUSG00000003363
rattus_norvegicus	Pld3	ENSRNOG00000018390
drosophila_melanogaster	Pld3	FBGN0032923
drosophila_melanogaster	CG43345	FBGN0263050
caenorhabditis_elegans		WBGENE00013080
caenorhabditis_elegans		WBGENE00017124
caenorhabditis_elegans		WBGENE00017316
caenorhabditis_elegans		WBGENE00020256

Paralogs (2): PLD4 (ENSG00000166428), PLD5 (ENSG00000180287)

Protein

Protein identifiers

5’-3’ exonuclease PLD3 — Q8IV08 (reviewed: Q8IV08)

Alternative names: (S,S)-bis(monoacylglycero)phosphate synthase PLD3, HindIII K4L homolog, Hu-K4, Phospholipase D3

All UniProt accessions (16): Q8IV08, A0A0A0MS28, A0A8V8TPY8, A0A8V8TQH4, A0A8V8TQH6, A0A8V8TRD4, E2QRG1, M0QX50, M0QX99, M0QY94, M0QYJ4, M0QZK2, M0R1F7, M0R2E7, M0R2W7, M0R3G9

UniProt curated annotations — full annotation on UniProt →

Function. 5’->3’ exonuclease that hydrolyzes the phosphodiester bond of single-stranded DNA (ssDNA) and RNA molecules to form nucleoside 3’-monophosphates and 5’-end 5’-hydroxy deoxyribonucleotide/ribonucleotide fragments. Partially redundant with PLD4, can cleave all four nucleotides displaying higher efficiency for ssDNA and RNA fragments initiated with uridine and guanosine residues and lower efficiency for cytidine-initiated substrates. As a result, it does not always degrade polynucleotides to the single nucleotide level, it can stall at specific sites sparing certain fragments from exonucleolytic degradation. Processes self and pathogenic ssDNA and RNA molecules that reach the endolysosomal compartment via phagocytosis or autophagy and may serve as ‘danger’ signals for recognition by innate immune receptors such as toll-like receptors (TLRs). Degrades mitochondrial CpG-rich ssDNA fragments to prevent TLR9 activation and autoinflammatory response, but it can cleave viral RNA to generate ligands for TLR7 activation and initiate antiviral immune responses. In plasmacytoid dendritic cells, it cooperates with endonuclease RNASET2 to release 2’,3’-cyclic guanosine monophosphate (2’,3’-cGMP), a potent stimulatory ligand for TLR7. Produces 2’,3’-cGMPs and cytidine-rich RNA fragments that occupy TLR7 ligand-binding pockets and trigger a signaling-competent state. Can exert polynucleotide phosphatase activity toward 5’-phosphorylated ssDNA substrates although at a slow rate. Transphosphatidylase that catalyzes the exchange with R to S stereo-inversion of the glycerol moiety between (S,R)-lysophosphatidylglycerol (LPG) and monoacylglycerol (MAG) substrates to yield (S,S)-bis(monoacylglycero)phosphate (BMP). Can synthesize a variety of (S,S)-BMPs representing the main phospholipid constituent of lysosomal intralumenal vesicle (ILV) membranes that bind acid hydrolases for lipid degradation. Regulates the homeostasis and interorganellar communication of the endolysosomal system with an overall impact on cellular removal of dysfunctional organelles via autophagy as well as proper protein and lipid turnover. May play a role in myotube formation in response to ER stress.

Subunit / interactions. Homodimer. Interacts with APP.

Subcellular location. Endoplasmic reticulum membrane. Lysosome lumen. Early endosome membrane. Late endosome membrane. Golgi apparatus membrane. Endosome membrane.

Tissue specificity. Widely expressed. In the brain, high levels of expression are detected in the frontal, temporal and occipital cortices and hippocampus. Expressed at low level in corpus callosum. Expressed in plasmacytoid dendritic cells and monocytes (at protein level).

Post-translational modifications. N-glycosylated. Proteolytically processed to a soluble active form that is stable within endosomes and lysosomes. During transport through the secretory pathway becomes proteolysed by cysteine proteases, thereby releasing a stable soluble lysosomal lumenal polypeptide, whereas the transmembrane-bound fragment is rapidly degraded. Its transport route to lysosomes involves ubiquitination and the ESCRT complex. Ubiquitinated at N-terminus. Ubiquitination mediates sorting into lysosomes.

Disease relevance. Spinocerebellar ataxia 46 (SCA46) [MIM:617770] A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA46 is a slowly progressive, autosomal dominant form with onset in adulthood. The disease may be caused by variants affecting the gene represented in this entry. There is limited evidences for implication of PLD3 in SCA46. Knockout mice do not present signs of cerebellar degeneration or spinocerebellar ataxia at 9 months of age, challenging the interpretation of the suggested loss-of-function mechanism for PLD3 as the SCA46-causative gene. Genetic variants in PLD3 have been suggested to be associated with an increased risk for Alzheimer disease. Further studies, however, did not support PLD3 involvement in this disease. Futhermore, it is controversial whether PLD3 plays a role in amyloid precursor protein processing (APP) or not. In a relevant Alzheimer’s disease mouse model PLD3 deficiency does not affect APP metabolism or amyloid plaque burden. However one study shown that PLD3 influences APP processing.

Activity regulation. The exonuclease activity toward ssDNA substrate is Ca(2+) and Mg(2+)-independent, but it is inhibited by Fe(2+), Cu(2+) and to a lesser extent Zn(2+) ions.

Domain organisation. The catalytic domain contains two conserved PLD phosphodiesterase HxK(x4)D(E) motifs that accomodate the phosphate group of the nucleic acid substrates, with one nucleophile histidine residue forming a phosphohistidine intermediate and the other histidine protonating the leaving 5’-OH ssDNA/RNA fragment, resulting in the cleavage of the phosphodiester bond. The homodimer has two independent catalytic domains arranged at the dimer interface.

Similarity. Belongs to the phospholipase D family.

RefSeq proteins (3): NP_001026866, NP_001278240, NP_036400* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001736	PLipase_D/transphosphatidylase	Domain
IPR032803	PLDc_3	Domain
IPR050874	Diverse_PLD-related	Family

Pfam: PF13918

Catalyzed reactions (Rhea), 6 shown:

• a ribonucleoside 3’-phosphate-2’-3’-cyclophospho-GMP + H2O = a ribonucleoside 3’-phosphate + 2’,3’-cyclophospho-GMP + H(+) (RHEA:81319)
• a 5’-end 5’-dephospho-ribonucleotidyl-ribonucleotide-RNA + H2O = a ribonucleoside 3’-phosphate + a 5’-end dephospho-ribonucleoside-RNA + H(+) (RHEA:81375)
• a 5’-end 5’-dephospho-2’-deoxyribonucleotidyl-2’-deoxyribonucleotide in single-stranded DNA + H2O = a 5’-end dephospho-2’-deoxyribonucleoside in single-stranded DNA + a 2’-deoxyribonucleoside 3’-phosphate + H(+) (RHEA:81379)
• a 5’-end 5’-phospho-2’-deoxyribonucleotide in single-stranded DNA + H2O = a 5’-end 5’-dephospho-2’-deoxyribonucleotide in single-stranded DNA + phosphate (RHEA:82335)
• an (R,S)-glycero-3-phospho-(3’-acyl-1’-glycerol) + a 1-acyl-sn-glycerol = a 3-acyl-sn-glycero-1-phospho-(3’-acyl-1’-sn-glycerol) + glycerol (RHEA:82563)
• 3-lyso-sn-glycero-1-phospho-(3’-(9Z-octadecenoyl)-1’-sn-glycerol) + 1-(9Z-octadecenoyl)-sn-glycerol = 3-(9Z-octadecenoyl)-sn-glycero-1-phospho-(3’-(9Z-octadecenoyl)-1’-sn-glycerol) + glycerol (RHEA:82567)

UniProt features (117 total): mutagenesis site 29, strand 21, sequence variant 20, helix 18, active site 5, binding site 5, glycosylation site 5, turn 3, disulfide bond 3, topological domain 2, domain 2, chain 1, site 1, transmembrane region 1, sequence conflict 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
8Q1K	X-RAY DIFFRACTION	1.51
8Q1X	X-RAY DIFFRACTION	1.85
8V5T	X-RAY DIFFRACTION	2.3
8S86	ELECTRON MICROSCOPY	2.8
9VBH	ELECTRON MICROSCOPY	2.85
9VBI	ELECTRON MICROSCOPY	2.87
9VBG	ELECTRON MICROSCOPY	2.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IV08-F1	91.15	0.81

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (6): 416 (nucleophile); 71–72 (cleavage; by lysosomal cysteine proteases); 201; 201 (proton donor); 203; 208

Ligand- & substrate-binding residues (5): 201; 203; 218; 416; 438

Disulfide bonds (3): 77–239, 81–237, 366–487

Glycosylation sites (5): 97, 132, 236, 284, 387

Mutagenesis-validated functional residues (29):

Position	Phenotype
6	no effect on protein maturation or trafficking to lysosomes. decreases exonuclease activity toward mitochondrial cpg-ric
7	slightly increases plasma membrane localization, does not affect delivery to lysosomes.
163	tends to form aggregates. decreases exonuclease activity toward ssdna.
201	loss of (s,s)-bmp synthase activity. no effect on protein expression or localization to lysosomes.
201	decreases rna binding; when associated with d-337 and n-416. almost complete loss of rna binding; when associated with d
203	loss of (s,s)-bmp synthase activity. no effect on protein expression or localization to lysosomes.
208	loss of (s,s)-bmp synthase activity. no effect on protein expression or localization to lysosomes.
228	decreases exonuclease activity toward cpg-free or cpg-rich ssdna substrates. increases mitophagy rate. no effect on prot
236	increases exonuclease activity toward cpg-free ssdna substrates. slightly decreases exonuclease activity toward a cpg-ri
300	no effect on proteolytical processing or localization to lysosomes.
337	decreases exonuclease activity toward rna. decreases rna binding; when associated with n-201 and n-416. results in a 10-
339	results in a 10-fold reduction of exonuclease activity toward rna; when associated with n-337.
340	prevents dimerization resulting in decreased exonuclease activity toward rna and cpg ssdna substrates. almost complete l
350	retained in the endoplasmic reticulum. loss of exonuclease activity toward ssdna; when associated with a-354; a-377 and
354	retained in the endoplasmic reticulum. loss of exonuclease activity toward ssdna; when associated with a-350, a-377 and
356	no effect on exonuclease activity toward ssdna.
377	retained in the endoplasmic reticulum. loss of exonuclease activity toward ssdna; when associated with a-350; a-354 and
380	retained in the endoplasmic reticulum. loss of exonuclease activity toward ssdna; when associated with a-350; a-354 and
388	no effect on exonuclease activity toward rna and cpg ssdna.
390	no effect on exonuclease activity toward rna and cpg ssdna.
410	no effect on exonuclease activity toward ssdna.
411	decreases exonuclease activity toward rna and ssdna.
416	loss of (s,s)-bmp synthase activity. no effect on protein expression or localization to lysosomes.
416	decreases rna binding; when associated with n-201 and d-337. almost complete loss of rna binding; when associated with n
418	loss of (s,s)-bmp synthase activity. loss of exonuclease activity toward ssdna. no effect on protein expression or local

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-1483148	Synthesis of PG
R-HSA-2029485	Role of phospholipids in phagocytosis

MSigDB gene sets: 289 (showing top): BORCZUK_MALIGNANT_MESOTHELIOMA_UP, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOCC_VACUOLAR_MEMBRANE, GOMF_NUCLEASE_ACTIVITY, STEARMAN_LUNG_CANCER_EARLY_VS_LATE_DN, GAUSSMANN_MLL_AF4_FUSION_TARGETS_C_UP, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, GOBP_MUSCLE_STRUCTURE_DEVELOPMENT, ROSS_LEUKEMIA_WITH_MLL_FUSIONS, GOBP_PRODUCTION_OF_MOLECULAR_MEDIATOR_INVOLVED_IN_INFLAMMATORY_RESPONSE, GOBP_CYTOKINE_PRODUCTION, STEARMAN_TUMOR_FIELD_EFFECT_UP, ATGCTGG_MIR338

GO Biological Process (7): immune system process (GO:0002376), lipid metabolic process (GO:0006629), inflammatory response (GO:0006954), myotube differentiation (GO:0014902), regulation of cytokine production involved in inflammatory response (GO:1900015), DNA metabolic process (GO:0006259), lipid catabolic process (GO:0016042)

GO Molecular Function (7): D-type glycerophospholipase activity (GO:0004630), single-stranded DNA 5’-3’ DNA exonuclease activity (GO:0045145), catalytic activity (GO:0003824), nuclease activity (GO:0004518), exonuclease activity (GO:0004527), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (14): Golgi membrane (GO:0000139), lysosomal membrane (GO:0005765), endoplasmic reticulum membrane (GO:0005789), endomembrane system (GO:0012505), early endosome membrane (GO:0031901), late endosome membrane (GO:0031902), lysosomal lumen (GO:0043202), extracellular exosome (GO:0070062), lysosome (GO:0005764), endosome (GO:0005768), endoplasmic reticulum (GO:0005783), Golgi apparatus (GO:0005794), endosome membrane (GO:0010008), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Glycerophospholipid biosynthesis	1
Fcgamma receptor (FCGR) dependent phagocytosis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
endomembrane system	3
bounding membrane of organelle	2
lysosome	2
cellular anatomical structure	2
endosome membrane	2
cytoplasm	2
intracellular membrane-bounded organelle	2
biological_process	1
primary metabolic process	1
defense response	1
striated muscle cell differentiation	1
regulation of cytokine production	1
cytokine production involved in inflammatory response	1
nucleic acid metabolic process	1
lipid metabolic process	1
catabolic process	1
glycerophospholipase activity	1
phosphoric diester hydrolase activity	1
single-stranded DNA exodeoxyribonuclease activity	1
5’-3’ DNA exonuclease activity	1
molecular_function	1
catalytic activity, acting on a nucleic acid	1
nuclease activity	1
hydrolase activity, acting on ester bonds	1
binding	1
catalytic activity	1
Golgi apparatus	1
lytic vacuole membrane	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
vacuole	1
plasma membrane	1
early endosome	1
late endosome	1
vacuolar lumen	1
extracellular vesicle	1
lytic vacuole	1
cytoplasmic vesicle	1
endosome	1

Protein interactions and networks

STRING

1088 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PLD3	PLD6	Q8N2A8	701
PLD3	TREM2	Q9NZC2	680
PLD3	UNC5C	O95185	667
PLD3	PLD2	O14939	665
PLD3	ABCA7	Q8IZY2	647
PLD3	SORL1	Q92673	625
PLD3	PSEN2	P49810	613
PLD3	CD2AP	Q9Y5K6	611
PLD3	PICALM	Q13492	611
PLD3	AKAP9	Q99996	607
PLD3	ADAM10	O14672	598
PLD3	APP	P05067	574
PLD3	BIN1	O00499	544
PLD3	PSEN1	P49768	544
PLD3	CASS4	Q9NQ75	529

IntAct

111 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
ENPP6	SCAMP1	psi-mi:“MI:0914”(association)	0.640
CFTR	HAX1	psi-mi:“MI:0914”(association)	0.610
CYSLTR2	CASK	psi-mi:“MI:0914”(association)	0.590
CANX	PGRMC1	psi-mi:“MI:0914”(association)	0.570
PLD3	CNIH3	psi-mi:“MI:0915”(physical association)	0.560
PLD3	SMCO4	psi-mi:“MI:0915”(physical association)	0.560
OPRM1	PLD3	psi-mi:“MI:0915”(physical association)	0.560
	PLOD2	psi-mi:“MI:0914”(association)	0.530
NFKB1	PLD3	psi-mi:“MI:0915”(physical association)	0.520
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
FLT4	ILVBL	psi-mi:“MI:0914”(association)	0.420
	TK2	psi-mi:“MI:0915”(physical association)	0.400
PLD3	GPR35	psi-mi:“MI:0915”(physical association)	0.370
ANXA7	PLD3	psi-mi:“MI:0915”(physical association)	0.370
PLD3	BCL2L1	psi-mi:“MI:0915”(physical association)	0.370
TK1	PLD3	psi-mi:“MI:0915”(physical association)	0.370
PLD3	STK11	psi-mi:“MI:0915”(physical association)	0.370
LTN1	KIF2A	psi-mi:“MI:0914”(association)	0.350
Tyw3	PPP6C	psi-mi:“MI:0914”(association)	0.350
		psi-mi:“MI:0914”(association)	0.350
	IPO5	psi-mi:“MI:0914”(association)	0.350
	ESYT2	psi-mi:“MI:0914”(association)	0.350
E5	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (341): PLD3 (Affinity Capture-MS), PLD3 (Two-hybrid), HNRNPH3 (Co-fractionation), PLD3 (Affinity Capture-MS), PLD3 (Two-hybrid), PLD3 (Proximity Label-MS), PLD3 (Proximity Label-MS), PLD3 (Proximity Label-MS), PLD3 (Proximity Label-MS), PLD3 (Affinity Capture-MS), PLD3 (Affinity Capture-MS), PLD3 (Affinity Capture-RNA), PLD3 (Affinity Capture-MS), PLD3 (Affinity Capture-MS), PLD3 (Affinity Capture-MS)

ESM2 similar proteins: A1L1C2, A3KNW0, A6H603, A6NFQ2, A6QLU7, A9ULG4, B1H1N7, E1BE10, E2RD63, O35405, O55230, O60294, O60906, O75771, O95479, P21709, P51839, P56201, Q0V8L6, Q149M9, Q1JPJ9, Q28DT3, Q2KJJ8, Q2TBP8, Q4R583, Q5FVH2, Q5R4Y7, Q5XIA3, Q60750, Q643R3, Q6NVG1, Q6QHF9, Q80XS7, Q865R1, Q8BG07, Q8BYR1, Q8C0L6, Q8CFX1, Q8IV08, Q8N0W3

Diamond homologs: A0A7H0DN15, O17405, O35405, P18377, P20537, Q2KJJ8, Q3UNN8, Q4R583, Q54K50, Q54SA1, Q5FVH2, Q5R4Y7, Q640B3, Q6PB03, Q8BG07, Q8IV08, Q8N7P1, Q96BZ4, P36316, P26579, P63800, P63801, P63802, Q5HEB2, Q5HMD3, Q6G7M2, Q6GEY7, Q8CNK3

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PLD3	“up-regulates quantity”	APP	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 118 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
NCAM signaling for neurite out-growth	5	16.6×	5e-04
Disorders of transmembrane transporters	5	8.5×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
transmembrane transport	7	11.6×	2e-03
neuron apoptotic process	6	10.9×	9e-03
negative regulation of neuron apoptotic process	7	7.6×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

218 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	117
Likely benign	63
Benign	8

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
803558	NC_000019.10:g.40394766del	Pathogenic

SpliceAI

1958 predictions. Top by Δscore:

Variant	Effect	Δscore
19:40366372:T:TA	acceptor_gain	1.0000
19:40366602:A:AG	acceptor_gain	1.0000
19:40366603:T:G	acceptor_gain	1.0000
19:40366608:A:AG	acceptor_gain	1.0000
19:40366609:G:GA	acceptor_gain	1.0000
19:40366609:GCT:G	acceptor_gain	1.0000
19:40366681:AAAGG:A	donor_loss	1.0000
19:40366682:AAGGT:A	donor_loss	1.0000
19:40366683:AGGT:A	donor_loss	1.0000
19:40366684:GGTAG:G	donor_loss	1.0000
19:40366685:GTAGG:G	donor_loss	1.0000
19:40366686:T:A	donor_loss	1.0000
19:40366770:CAGA:C	acceptor_loss	1.0000
19:40366771:A:AG	acceptor_gain	1.0000
19:40366771:AGAA:A	acceptor_loss	1.0000
19:40366772:G:GG	acceptor_gain	1.0000
19:40366772:GA:G	acceptor_gain	1.0000
19:40366772:GAA:G	acceptor_gain	1.0000
19:40366772:GAAA:G	acceptor_gain	1.0000
19:40366912:GCGA:G	donor_gain	1.0000
19:40366913:CGA:C	donor_gain	1.0000
19:40366914:GA:G	donor_gain	1.0000
19:40366914:GAG:G	donor_gain	1.0000
19:40366914:GAGTA:G	donor_loss	1.0000
19:40366915:AGT:A	donor_loss	1.0000
19:40366916:G:GG	donor_gain	1.0000
19:40366916:GTAA:G	donor_loss	1.0000
19:40367695:GAGCA:G	acceptor_gain	1.0000
19:40367875:AGCAG:A	donor_loss	1.0000
19:40367880:G:GC	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000300232 (19:40362497 G>A), RS1000355452 (19:40352100 C>T), RS1000394675 (19:40356117 G>A), RS1000409623 (19:40351896 G>C), RS1000709964 (19:40350962 G>T), RS1000829605 (19:40350405 G>T), RS1000924109 (19:40356778 T>C,G), RS1000980487 (19:40362890 T>G), RS1001006587 (19:40346769 G>A), RS1001015213 (19:40373780 A>C), RS1001199546 (19:40378665 G>A), RS1001317945 (19:40347030 C>T), RS1001333963 (19:40378914 C>G,T), RS1001362355 (19:40353728 G>A), RS1001490419 (19:40356772 G>C)

Disease associations

OMIM: gene MIM:615698 | disease phenotypes: MIM:615711, MIM:617770, MIM:118220

GenCC curated gene-disease

Disease	Classification	Inheritance
spinocerebellar ataxia 46	Moderate	Autosomal dominant
leukodystrophy	Moderate	Autosomal recessive

Mondo (5): Alzheimer disease 19 (MONDO:0014316), spinocerebellar ataxia 46 (MONDO:0033481), Charcot-Marie-Tooth disease (MONDO:0015626), Charcot-Marie-Tooth disease type 4 (MONDO:0018995), leukodystrophy (MONDO:0019046)

Orphanet (3): Spinocerebellar ataxia type 46 (Orphanet:589522), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166), Charcot-Marie-Tooth disease type 4 (Orphanet:64749)

HPO phenotypes

13 total (13 of 13 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000514	Slow saccadic eye movements
HP:0000639	Nystagmus
HP:0001260	Dysarthria
HP:0001272	Cerebellar atrophy
HP:0001310	Dysmetria
HP:0002066	Gait ataxia
HP:0002070	Limb ataxia
HP:0002403	Positive Romberg sign
HP:0003390	Sensory axonal neuropathy
HP:0003581	Adult onset
HP:0003677	Slowly progressive
HP:0008003	Jerky ocular pursuit movements

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST003827_4	Otitis media	2.000000e-07
GCST003828_1	Otitis media (chronic)	3.000000e-08
GCST003829_4	Otitis media (recurrent)	1.000000e-07

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2769 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

1 potent at pChembl≥5 of 5 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.05	IC50	8900	nM	CHEMBL4870571

PubChem BioAssay actives

1 with measured affinity, of 27 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[1,3-dimethyl-7-[(4-methylphenyl)methyl]-2,6-dioxopurin-8-yl]sulfanylacetic acid	1768576: Inhibition of PLD3 (unknown origin) using 3’-dT-nNPP as substrate by fluorescence-based screening assay	ic50	8.9000	uM

CTD chemical–gene interactions

59 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Particulate Matter	increases abundance, increases expression	3
bisphenol F	affects cotreatment, increases expression	2
bisphenol A	decreases expression, increases expression	2
Acetaminophen	decreases expression, increases expression	2
Air Pollutants	increases abundance, increases expression	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Cisplatin	affects expression, affects cotreatment, increases expression	2
Dexamethasone	decreases expression, affects cotreatment, increases expression	2
Phenylmercuric Acetate	increases expression, affects cotreatment	2
Smoke	decreases expression, increases abundance, increases expression	2
Tretinoin	increases expression	2
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
decabromobiphenyl ether	decreases expression	1
trichostatin A	affects expression	1
beta-lapachone	decreases expression	1
sodium arsenite	increases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
nickel sulfate	increases expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
nutlin 3	affects cotreatment, increases secretion	1
ICG 001	increases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1

ChEMBL screening assays

13 unique, capped per target: 13 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4827772	Binding	Substrate activity at PLD3 (unknown origin) assessed as Km by Michaelis-Menten kinetic model based fluorescence assay	Modulators of immunoregulatory exonucleases PLD3 and PLD4 identified by high-throughput screen. — Bioorg Med Chem Lett

Cellosaurus cell lines

7 cell lines: 5 cancer cell line, 2 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B3E0	Abcam HEK293T PLD3 KO	Transformed cell line	Female
CVCL_F1PL	HyCyte HEK293T KO-hPLD3	Transformed cell line	Female
CVCL_F1PX	HyCyte HeLa KO-hPLD3	Cancer cell line	Female
CVCL_F1TJ	HyCyte SH-SY5Y KO-hPLD3	Cancer cell line	Female
CVCL_F1UC	HyCyte THP-1 KO-hPLD3	Cancer cell line	Male
CVCL_TE47	HAP1 PLD3 (-) 1	Cancer cell line	Male
CVCL_TE48	HAP1 PLD3 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

67 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04762758	PHASE3	UNKNOWN	Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients
NCT00271635	PHASE2	COMPLETED	Ascorbic Acid Treatment in CMT1A Trial (AATIC)
NCT01401257	PHASE2	COMPLETED	Phase II, Randomized, Placebo-controlled Trial in Patients With Charcot-marie-tooth Disease Type 1A
NCT02561702	PHASE2	COMPLETED	Mexiletine for Muscle Cramps in Charcot Marie Tooth Disease
NCT02967679	PHASE2	COMPLETED	SERENDEM : MD1003 in Patients Suffering From Demyelinating Neuropathies, an Open Label Pilot Study
NCT03124459	PHASE2	TERMINATED	Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease
NCT03254199	PHASE2	TERMINATED	A Study to Assess the Safety and Effectiveness of FLX-787 in Subjects With Charcot-Marie-Tooth Disease Experiencing Muscle Cramps.
NCT03943290	PHASE2	TERMINATED	Extension Study to Evaluate the Long-Term Effects of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy (FSHD) and Charcot-Marie Tooth (CMT) Disease Types 1 and X (CMT1 and CMTX)
NCT05777226	PHASE2	UNKNOWN	Research of SORD-CMT Natural History and Epalrestat Treatment
NCT06482437	PHASE2	COMPLETED	Safety and Efficacy of NMD670 in Adult Patients With Type 1 and Type 2 Charcot-Marie-Tooth Disease
NCT00889174	Not specified	COMPLETED	The Nosology and Etiology of Leukodystrophies of Unknown Causes
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT02843555	Not specified	COMPLETED	Natural History of the Leukodystrophies
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT03333200	Not specified	RECRUITING	Longitudinal Study of Neurodegenerative Disorders
NCT03639285	Not specified	RECRUITING	Natural History, Diagnosis, and Outcomes for Leukodystrophies
NCT05443906	Not specified	RECRUITING	Home Exercise for Individuals with Neurodegenerative Disease
NCT04100889	Not specified	WITHDRAWN	A Non-Interventional Pilot Study to Explore the Role of Gut Flora in Alzheimer’s Disease
NCT05637801	Not specified	ACTIVE_NOT_RECRUITING	A Pivotal Study of Sensory Stimulation in Alzheimer’s Disease (HOPE Study)
NCT01289704	PHASE2/PHASE3	UNKNOWN	Treadmill, Stretching and Proprioceptive Exercise (TreSPE) Rehabilitation Program for Charcot-Marie-Tooth Neuropathy Type 1A (CMT1A)
NCT00541164	PHASE1/PHASE2	COMPLETED	Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease
NCT05361031	PHASE1/PHASE2	COMPLETED	The Safety and Tolerability of Engensis (VM202) in Patients With Charcot-Marie-Tooth Disease Subtype 1A (CMT1A)
NCT07223632	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Treatment of Charcot-Marie-Tooth Disease, Axonal, Type 2S (CMT2S) in an Individual Patient
NCT00149045	Not specified	COMPLETED	Follow up and Observation of Charcot Marie Tooth Disease in Families
NCT01193075	Not specified	RECRUITING	Natural History Evaluation of Charcot Marie Tooth Disease (CMT) Types CMT1B, CMT2A, CMT4A, CMT4C, and Others
NCT01203085	Not specified	COMPLETED	Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale for Children With CMT
NCT01455623	Not specified	COMPLETED	Development and Validation of a Disability Severity Index for CMT
NCT01918826	Not specified	UNKNOWN	Evaluation of the Analgesic Efficiency of the Transcutaneous Neurostimulation in the Charcot Syndrome Marie Tooth on the Pains of Lower Limbs
NCT02001038	Not specified	COMPLETED	Survey of Current Management of Orthopaedic Complications in CMT Patients
NCT02011204	Not specified	COMPLETED	Study of Electrical Impedance Myography (EIM) in ALS
NCT02194010	Not specified	COMPLETED	Disability Severity Scale (DSI) and Hereditary Motor and Sensory Neuropathy Overall Disability Scale (HMSN-R-ODS)
NCT02429947	Not specified	COMPLETED	An Analysis of the Symptomatic Domains Most Relevant to Charcot Marie Tooth Neuropathy (CMT) Patients
NCT02532244	Not specified	COMPLETED	Genetics of Pediatric-Onset Motor Neuron and Neuromuscular Diseases
NCT02788734	Not specified	COMPLETED	Patient Reported Outcomes Measures (PROM) in Carpal Tunnel Therapies in Patients With Inherited Neuropathies
NCT02979145	Not specified	UNKNOWN	Charcot-Marie-Tooth Disease (CMT) Infant Scale (INC-6611)
NCT03460951	Not specified	COMPLETED	Diffusion Tensor Imaging in Chronic Inflammatory Demyelinating Polyneuropathy (PIDC)
NCT03715283	Not specified	COMPLETED	Change in MUNIX in Patients With CMT1A Undergoing a Home Ankle Strengthening Program Versus Standard of Care
NCT03782883	Not specified	COMPLETED	The Impact of Charcot-Marie-Tooth Disease in the Real World
NCT03810508	Not specified	TERMINATED	A Natural History Study of Charcot-Marie-Tooth 4J (CMT4J)