PLS3

Summary

PLS3 (plastin 3, HGNC:9091) is a protein-coding gene on chromosome Xq23, encoding Plastin-3 (P13797). Actin-bundling protein.

Plastins are a family of actin-binding proteins that are conserved throughout eukaryote evolution and expressed in most tissues of higher eukaryotes. In humans, two ubiquitous plastin isoforms (L and T) have been identified. Plastin 1 (otherwise known as Fimbrin) is a third distinct plastin isoform which is specifically expressed at high levels in the small intestine. The L isoform is expressed only in hemopoietic cell lineages, while the T isoform has been found in all other normal cells of solid tissues that have replicative potential (fibroblasts, endothelial cells, epithelial cells, melanocytes, etc.). The C-terminal 570 amino acids of the T-plastin and L-plastin proteins are 83% identical. It contains a potential calcium-binding site near the N terminus. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 5358 — RefSeq curated summary.

At a glance

• Gene–disease (curated): X-linked osteoporosis with fractures (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 5
• Clinical variants (ClinVar): 435 total — 33 pathogenic, 16 likely-pathogenic
• Phenotypes (HPO): 2
• MANE Select transcript: NM_005032

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9091
Approved symbol	PLS3
Name	plastin 3
Location	Xq23
Locus type	gene with protein product
Status	Approved
Aliases	T-plastin
Ensembl gene	ENSG00000102024
Ensembl biotype	protein_coding
OMIM	300131
Entrez	5358

Gene structure

Transcript identifiers

Ensembl transcripts: 51 — 48 protein_coding, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000289290, ENST00000355899, ENST00000466150, ENST00000473026, ENST00000481823, ENST00000489283, ENST00000497870, ENST00000539310, ENST00000626746, ENST00000876571, ENST00000876572, ENST00000876573, ENST00000876574, ENST00000876575, ENST00000876576, ENST00000876577, ENST00000876578, ENST00000876579, ENST00000876580, ENST00000876581, ENST00000876582, ENST00000876583, ENST00000876584, ENST00000876585, ENST00000876586, ENST00000876587, ENST00000876588, ENST00000876589, ENST00000876590, ENST00000876591, ENST00000876592, ENST00000876593, ENST00000876594, ENST00000932471, ENST00000932472, ENST00000932473, ENST00000932474, ENST00000932475, ENST00000932476, ENST00000969757, ENST00000969758, ENST00000969759, ENST00000969760, ENST00000969761, ENST00000969762, ENST00000969763, ENST00000969764, ENST00000969765, ENST00000969766, ENST00000969767, ENST00000969768

RefSeq mRNA: 5 — MANE Select: NM_005032 NM_001136025, NM_001172335, NM_001282337, NM_001282338, NM_005032

CCDS: CCDS14568, CCDS78499

Canonical transcript exons

ENST00000355899 — 16 exons

Exon	Start	End
ENSE00001414639	115649429	115650861
ENSE00001939469	115561174	115561260
ENSE00003461672	115647550	115647673
ENSE00003467388	115647893	115648017
ENSE00003474665	115634881	115635046
ENSE00003478160	115645021	115645099
ENSE00003533191	115636836	115636978
ENSE00003559418	115646402	115646535
ENSE00003595813	115643313	115643508
ENSE00003642889	115629198	115629327
ENSE00003656685	115646072	115646186
ENSE00003695887	115622246	115622409
ENSE00003698848	115640408	115640503
ENSE00003701605	115629835	115629967
ENSE00003701945	115610243	115610323
ENSE00003790270	115634000	115634081

Expression profiles

Bgee: expression breadth ubiquitous, 297 present calls, max score 99.82.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 115.9358 / max 3855.8045, expressed in 1482 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
197330	97.7874	1409
197333	11.8800	969
197334	3.5462	673
197332	2.2241	572
197338	0.2073	77
197329	0.1929	93
197327	0.0534	25
197328	0.0446	16

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
blood vessel layer	UBERON:0004797	99.82	gold quality
calcaneal tendon	UBERON:0003701	99.77	gold quality
visceral pleura	UBERON:0002401	99.75	gold quality
pleura	UBERON:0000977	99.66	gold quality
parietal pleura	UBERON:0002400	99.66	gold quality
amniotic fluid	UBERON:0000173	99.40	gold quality
skin of hip	UBERON:0001554	99.40	gold quality
ascending aorta	UBERON:0001496	99.38	gold quality
thoracic aorta	UBERON:0001515	99.38	gold quality
descending thoracic aorta	UBERON:0002345	99.38	gold quality
right coronary artery	UBERON:0001625	99.36	gold quality
aorta	UBERON:0000947	99.32	gold quality
tongue squamous epithelium	UBERON:0006919	99.32	gold quality
oral cavity	UBERON:0000167	99.30	gold quality
upper leg skin	UBERON:0004262	99.30	gold quality
popliteal artery	UBERON:0002250	99.28	gold quality
tibial artery	UBERON:0007610	99.28	gold quality
artery	UBERON:0001637	99.23	gold quality
esophagus squamous epithelium	UBERON:0006920	99.22	gold quality
penis	UBERON:0000989	99.16	gold quality
synovial joint	UBERON:0002217	99.13	gold quality
saphenous vein	UBERON:0007318	99.10	gold quality
squamous epithelium	UBERON:0006914	99.07	gold quality
epithelium of esophagus	UBERON:0001976	98.97	gold quality
pericardium	UBERON:0002407	98.93	gold quality
coronary artery	UBERON:0001621	98.89	gold quality
gingiva	UBERON:0001828	98.89	gold quality
left coronary artery	UBERON:0001626	98.88	gold quality
lower lobe of lung	UBERON:0008949	98.84	gold quality
upper arm skin	UBERON:0004263	98.83	gold quality

Single-cell (SCXA)

Detected in 14 experiment(s), a significant marker in 12.

Experiment	Marker?	Max mean expression
E-GEOD-93593	yes	2097.40
E-MTAB-8894	yes	823.47
E-HCAD-5	yes	606.10
E-MTAB-8142	yes	145.65
E-HCAD-10	yes	46.19
E-MTAB-10287	yes	45.86
E-CURD-112	yes	15.52
E-GEOD-135922	yes	11.25
E-MTAB-10137	yes	6.71
E-GEOD-84465	yes	6.07
E-GEOD-130148	yes	5.81
E-MTAB-7008	no	485.80
E-MTAB-4850	no	1.14
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTNNB1

miRNA regulators (miRDB)

100 targeting PLS3, 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-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-5688	99.96	73.23	4504
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-3682-5P	99.93	67.97	1163
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-4779	99.86	66.50	1583

Literature-anchored findings (GeneRIF, showing 40)

• expression of T-plastin in the placental context may indeed be associated with the enhanced replicative potential of placental trophoblasts. (PMID:14567899)
• T-plastin has the potential to be a Sezary cell-specific marker valuable for diagnostic and treatment of Sezary syndrome. (PMID:14612505)
• T-plastin increases Arp2/3-mediated actin-based movement (PMID:15741236)
• T-fimbrin has a role in the response to DNA damage (PMID:16142308)
• unaffected SMN1-deleted females exhibit significantly higher expression of PLS3 than their spinal muscular atrophy-affected counterparts (PMID:18440926)
• Increased T-plastin is associated with leukemic cutaneous T-cell lymphoma (PMID:18569641)
• The PLS3 gene may be an age- and/or puberty-specific and sex-specific modifier of spinal muscular atrophy. (PMID:20937953)
• PLS3 is expressed in the majority of SS patients and provide insight into the molecular regulation of PLS3 expression in CTCL (PMID:22495182)
• T-plastin is a marker restricted to malignant lymphocytes from Sezary syndrome patients and plays a role for cell survival and migration. (PMID:22627769)
• PLS3 over-expression led to a stabilization of axons which, in turn, results in a significant delay of axon pruning, counteracting poor axonal connectivity in spinal muscular atrophy neuromuscular junctions. (PMID:23263861)
• Overexpression of PLS3 is associated with epithelial-mesenchymal transition and is associated with metastasis in colorectal cancer (PMID:23378342)
• PLS3, Twist, KIR3DL2 and NKp46 gene expression can model efficient molecular Sezary syndrome diagnosis. (PMID:23429988)
• study identified a common gene variant in PLS3 as an independent prognostic marker in female patients with stage II and III colon cancer (PMID:23549633)
• Plastin 3 (PLS3) appears to be important in human bone health, on the basis of pathogenic variants in PLS3 in five families with X-linked osteoporosis and osteoporotic fractures that we report here. (PMID:24088043)
• Data suggest that several single-nucleotide polymorphisms (SNPs) of the plastin genes PLS3 and LCP1 could serve as gender- and/or stage-specific molecular predictors of tumor recurrence in stage II/III colorectal cancer as well as therapeutic targets. (PMID:24170770)
• PLS3 gene may have an age- and gender-specific role in the clinical severity of SMA in children afflicted with this condition. (PMID:24172247)
• PLS3 overexpression is associated with colorectal cancer. (PMID:24217791)
• Loss of PLS3 is associated with spinal muscular atrophy. (PMID:24271012)
• PLS3 expression and SMA phenotype: a commentary on correlation of PLS3 expression with disease severity in children with spinal muscular atrophy. (PMID:24284364)
• results confirm the role of PLS3 mutations in early onset osteoporosis. The mechanism whereby PLS3 affects bone health is unclear, but it may be linked to osteocyte dendrite function and skeletal mechanosensing (PMID:25209159)
• T-plastin expression downstream to the calcineurin/NFAT pathway is involved in keratinocyte migration. (PMID:25226517)
• PLS3 was expressed in circulating tumor cells undergoing the epithelial-mesenchymal transition in patients with breast cancer; an excellent biomarker for identifying groups at risk of recurrence or with a poor prognosis (PMID:25880010)
• plastin 3 is a regulator of actin microfilament bundles at the ES in which it dictates the configuration of the filamentous actin network (PMID:26048141)
• Measurements of SMN and PLS3 transcript and protein levels in induced pluripotent stem cell-derived motor neurons show limited value as Spinal muscular atrophy biomarkers. (PMID:26114395)
• High levels of recombinant hPLS3 mRNA were expressed in motor neurons of SMA mice and an increased level of PLS3 protein in total spinal cord, yet neither survival nor the fundamental electrophysiological aspects of the neuromuscular junction improved. (PMID:26134627)
• t is beyond doubt that PL S3 must be further investigated to determine its role in diagnostics, prediction, treatment and monitoring of treatment of colorectal cancer. (PMID:26146096)
• PLS3 is a genuine spinal muscular atrophy protective modifier in SMN1-deleted individuals (PMID:26573968)
• We show that genes of the classical apoptosis pathway are involved in the smn-1-mediated neuronal death, and that this phenotype can be rescued by the expression of human SMN1, indicating a functional conservation between the two orthologs. Finally, we determined that Plastin3/plst-1 genetically interacts with smn-1 to prevent degeneration, and that treatment with valproic acid is able to rescue the degenerative phenotype (PMID:27260405)
• PLS3 expression does not always modify SMA phenotype (PMID:27279027)
• findings emphasize the power of genetic modifiers, PLS3 and CORO1C, to unravel the cellular pathomechanisms underlying spinal muscular atrophy (SMA)–and the power of combinatorial therapy based on splice correction of SMN2 and endocytosis improvement to efficiently treat SMA (PMID:27499521)
• Patients with PLS3 mutation-related osteoporosis respond to teriparatide treatment. (PMID:27732335)
• T-plastin mediates the hypoxia-induced membrane trafficking (PMID:28218996)
• PLS3 mutation plays a role in low turnover osteoporosis pathophysiology. (PMID:28379384)
• In this study, the authors found that the actin filament bundling abilities of PLS1 and PLS2 were similarly sensitive to Ca(2+) (pCa50 ~6.4), whereas PLS3 was less sensitive (pCa50 ~5.9). (PMID:28694070)
• PLS3 sequencing in childhood-onset primary osteoporosis identifies two novel disease-causing variants. (PMID:28748388)
• PLS3 deletions lead to severe childhood-onset osteoporosis resulting from defective bone matrix mineralization. (PMID:28777485)
• PLS3 mutation is associated with X-linked osteoporosis. (PMID:29736964)
• Regulation of osteoclastogenesis and bone remodeling via the PLS3-NKRF-NFkappaB-NFATC1 axis unveils a novel possibility to counteract osteoporosis. (PMID:30204862)
• study identifies PLS3 as a potential target for enhancing the p38 MAPK-mediated apoptosis induced by paclitaxel. (PMID:30829071)
• PLS3 polymorphisms are genetic loci for osteoporosis in postmenopausal Chinese women. (PMID:30837644)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	pls3	ENSDARG00000037655
mus_musculus	Pls3	ENSMUSG00000016382
rattus_norvegicus	Pls3	ENSRNOG00000027520
drosophila_melanogaster	Fim	FBGN0024238
caenorhabditis_elegans		WBGENE00022223
caenorhabditis_elegans		WBGENE00022425

Paralogs (2): PLS1 (ENSG00000120756), LCP1 (ENSG00000136167)

Protein

Protein identifiers

Plastin-3 — P13797 (reviewed: P13797)

Alternative names: T-fimbrin, T-plastin

All UniProt accessions (5): P13797, B4DPW9, F2Z2Z9, H7C4N2, U3KQI3

UniProt curated annotations — full annotation on UniProt →

Function. Actin-bundling protein.

Subunit / interactions. Monomer.

Subcellular location. Cytoplasm.

Tissue specificity. Expressed in a variety of organs, including muscle, brain, uterus and esophagus.

Disease relevance. Osteoporosis (OSTEOP) [MIM:166710] A systemic skeletal disorder characterized by decreased bone mass and deterioration of bone microarchitecture without alteration in the composition of bone. The result is fragile bones and an increased risk of fractures, even after minimal trauma. Osteoporosis is a chronic condition of multifactorial etiology and is usually clinically silent until a fracture occurs. Disease susceptibility is associated with variants affecting the gene represented in this entry. It has been proposed that loss-of-function variants may be associated with X-linked osteoporosis, while missense variants affecting the actin-binding domains might have a gain-of-function effect and may cause X-linked diaphragmatic hernia. Variants in PLS3 have been suggested to be associated with a variety of abnormalities of the skeletal system, ranging from non-syndromic childhood-onset osteoporosis to osteogenesis imperfecta. Diaphragmatic hernia 5, X-linked (DIH5) [MIM:306950] A form of congenital diaphragmatic hernia, a posterolateral defect of the diaphragm, generally located on the left side, that permits the herniation of abdominal viscera into the thorax. The lungs are hypoplastic and have abnormal vessels that cause respiratory insufficiency and persistent pulmonary hypertension with high mortality. About one third of cases have cardiovascular malformations and lesser proportions have skeletal, neural, genitourinary, gastrointestinal or other defects. DIH5 is usually transmitted in an X-linked recessive pattern with males being severely affected. Early death is frequent. The disease is caused by variants affecting the gene represented in this entry. It has been proposed that loss-of-function variants may be associated with X-linked osteoporosis, while missense variants affecting the actin-binding domains might have a gain-of-function effect and may cause X-linked diaphragmatic hernia.

Polymorphism. Genetic variations in PLS3 define the bone mineral density quantitative trait locus 18 (BMND18) [MIM:300910]. Variance in bone mineral density influences bone mass, contributes to size determination in the general population, and is a susceptibility factor for osteoporotic fractures.

Isoforms (3)

UniProt ID	Names	Canonical?
P13797-1	1	yes
P13797-2	2
P13797-3	3

RefSeq proteins (5): NP_001129497, NP_001165806, NP_001269266, NP_001269267, NP_005023* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001589	Actinin_actin-bd_CS	Conserved_site
IPR001715	CH_dom	Domain
IPR002048	EF_hand_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR018247	EF_Hand_1_Ca_BS	Binding_site
IPR036872	CH_dom_sf	Homologous_superfamily
IPR039959	Fimbrin/Plastin	Family

Pfam: PF00307, PF13499

UniProt features (81 total): helix 27, sequence variant 15, turn 10, binding site 9, domain 6, modified residue 5, splice variant 3, strand 3, region of interest 2, chain 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
1AOA	X-RAY DIFFRACTION	2.4
7R94	ELECTRON MICROSCOPY	2.6
7SXA	ELECTRON MICROSCOPY	6.87
7SX8	ELECTRON MICROSCOPY	9
7SX9	ELECTRON MICROSCOPY	10
1WJO	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P13797-F1	89.01	0.67

Functional residue map

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

Ligand- & substrate-binding residues (9): 27; 29; 36; 65; 67; 69; 71; 76; 25

Post-translational modifications (5): 268, 293, 326, 339, 391

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 272 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, RRAGTTGT_UNKNOWN, LIANG_HEMATOPOIESIS_STEM_CELL_NUMBER_SMALL_VS_HUGE_UP, GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GEORGES_CELL_CYCLE_MIR192_TARGETS, YANG_BREAST_CANCER_ESR1_LASER_DN, GOBP_VESICLE_MEDIATED_TRANSPORT, GGGTGGRR_PAX4_03, CAGCTG_AP4_Q5, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, SENESE_HDAC1_AND_HDAC2_TARGETS_DN

GO Biological Process (5): actin filament bundle assembly (GO:0051017), actin filament network formation (GO:0051639), bone development (GO:0060348), regulation of synaptic vesicle cycle (GO:0098693), presynaptic actin cytoskeleton organization (GO:0099140)

GO Molecular Function (6): calcium ion binding (GO:0005509), actin filament binding (GO:0051015), structural constituent of presynaptic actin cytoskeleton (GO:0098699), actin binding (GO:0003779), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (6): cytoplasm (GO:0005737), cytosol (GO:0005829), actin filament (GO:0005884), plasma membrane (GO:0005886), neuromuscular junction (GO:0031594), actin filament bundle (GO:0032432)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
actin cytoskeleton	2
cellular component assembly	1
actin filament bundle organization	1
actin filament organization	1
skeletal system development	1
animal organ development	1
regulation of vesicle-mediated transport	1
synaptic vesicle cycle	1
actin cytoskeleton organization	1
presynaptic cytoskeleton organization	1
metal ion binding	1
actin binding	1
protein-containing complex binding	1
structural constituent of cytoskeleton	1
presynaptic actin cytoskeleton organization	1
presynaptic actin cytoskeleton	1
structural constituent of presynapse	1
cytoskeletal protein binding	1
binding	1
cation binding	1
intracellular anatomical structure	1
cytoplasm	1
polymeric cytoskeletal fiber	1
membrane	1
cell periphery	1
synapse	1
actin filament	1

Protein interactions and networks

STRING

1882 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PLS3	SMN1	Q16637	846
PLS3	CORO1C	Q9ULV4	795
PLS3	FSCN1	Q16658	760
PLS3	TMEM38B	Q9NVV0	678
PLS3	NCALD	P29554	640
PLS3	CRTAP	O75718	630
PLS3	IFITM5	A6NNB3	610
PLS3	P3H1	Q32P28	600
PLS3	FKBP10	Q96AY3	596
PLS3	CHP1	Q99653	593
PLS3	PLSCR3	Q9NRY6	574
PLS3	PFN1	P07737	572
PLS3	SEC24D	O94855	562
PLS3	ZPR1	O75312	542
PLS3	HNRNPR	O43390	542

IntAct

107 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
LCP1	PLS3	psi-mi:“MI:0914”(association)	0.640
PLS3	LCP1	psi-mi:“MI:0914”(association)	0.640
PLS3	PLS1	psi-mi:“MI:0914”(association)	0.530
SERPINB13	TTC4	psi-mi:“MI:0914”(association)	0.530
HNRNPH2	PLS3	psi-mi:“MI:0914”(association)	0.460
HNRNPH2	PLS3	psi-mi:“MI:0403”(colocalization)	0.460
ATXN2	PLS3	psi-mi:“MI:0915”(physical association)	0.460
PLS3	ATXN2	psi-mi:“MI:0403”(colocalization)	0.460
Pafah1b1	EDIL3	psi-mi:“MI:0915”(physical association)	0.400
Sass6		psi-mi:“MI:0915”(physical association)	0.400
PLS3		psi-mi:“MI:0915”(physical association)	0.370
OTUB1	EPM2A	psi-mi:“MI:0914”(association)	0.350
Actb		psi-mi:“MI:0914”(association)	0.350
PLEKHA7	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
DLD	NFKBIE	psi-mi:“MI:0914”(association)	0.350
DNM1L		psi-mi:“MI:0914”(association)	0.350
IMPA2	KRT1	psi-mi:“MI:0914”(association)	0.350
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
CUL5	DDX3X	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350

BioGRID (306): PLS3 (Affinity Capture-MS), PLS3 (Affinity Capture-MS), PLS3 (Affinity Capture-RNA), ARHGDIA (Co-fractionation), ENO2 (Co-fractionation), FKBP14 (Co-fractionation), HSPE1 (Co-fractionation), PLS3 (Co-fractionation), PLS3 (Co-fractionation), PLS3 (Co-fractionation), PLS3 (Co-fractionation), PLS3 (Co-fractionation), PLS3 (Co-fractionation), PLS3 (Co-fractionation), PLS3 (Co-fractionation)

ESM2 similar proteins: A6H742, A7E3Q8, O13728, O14134, O14185, O59945, O88818, P05095, P13796, P13797, P19179, P19966, P32599, P37803, P37804, P37805, P41810, P53585, P53978, P54680, P78820, P87078, Q00955, Q01995, Q08873, Q14651, Q3V0K9, Q3ZBY2, Q4R5J4, Q54BC6, Q54HG2, Q550R2, Q55BP5, Q5R6R2, Q61233, Q63598, Q6DG81, Q6FIR8, Q6FM46, Q6P698

Diamond homologs: A0A2I0BVG8, A6H742, A7E3Q8, O23184, O50064, O59945, O88818, P13796, P13797, P19179, P28470, P32599, P48451, P54680, P62343, P62344, P87072, Q0DJ94, Q14651, Q24214, Q25088, Q338P8, Q3E9C0, Q3V0K9, Q61233, Q63598, Q63811, Q6DG81, Q6P698, Q6Z2M9, Q7F0J0, Q7G188, Q7XHW4, Q84UL5, Q8C5W0, Q96LZ3, Q99K51, Q9FI19, Q9FJ70, Q9FKI0

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 119 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
Signaling by SCF-KIT	5	14.3×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of gene expression	10	6.8×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	33
Likely pathogenic	16
Uncertain significance	104
Likely benign	78
Benign	54

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1172590	NM_005032.7(PLS3):c.1512-1G>T	Pathogenic
1201464	NM_005032.7(PLS3):c.1511+1G>A	Pathogenic
1335789	NM_005032.7(PLS3):c.766C>T (p.Arg256Ter)	Pathogenic
1356620	NM_005032.7(PLS3):c.618del (p.Ile207fs)	Pathogenic
1407720	NM_005032.7(PLS3):c.1067del (p.Ala356fs)	Pathogenic
1453605	NM_005032.7(PLS3):c.1375_1376del (p.Lys459fs)	Pathogenic
1453791	NM_005032.7(PLS3):c.1326G>A (p.Trp442Ter)	Pathogenic
1517731	NM_005032.7(PLS3):c.367+1G>A	Pathogenic
1706551	NM_005032.7(PLS3):c.672_673del (p.His225fs)	Pathogenic
2032457	NM_005032.7(PLS3):c.683del (p.Leu228fs)	Pathogenic
2090539	NM_005032.7(PLS3):c.865_866delinsG (p.Ile289fs)	Pathogenic
2111137	NM_005032.7(PLS3):c.1050_1053del (p.Arg350fs)	Pathogenic
2119651	NM_005032.7(PLS3):c.1169G>A (p.Trp390Ter)	Pathogenic
2425280	NC_000023.10:g.(?114844563)(114883881_?)del	Pathogenic
2425281	NC_000023.10:g.(?114844563)(114844655_?)del	Pathogenic
2571376	NM_005032.7(PLS3):c.748+1G>A	Pathogenic
2699544	NM_005032.7(PLS3):c.352C>T (p.Gln118Ter)	Pathogenic
2811444	NM_005032.7(PLS3):c.323del (p.Gly108fs)	Pathogenic
2833036	NM_005032.7(PLS3):c.394del (p.Trp132fs)	Pathogenic
3008381	NM_005032.7(PLS3):c.1142_1145del (p.Thr381fs)	Pathogenic
3254618	NM_005032.7(PLS3):c.696G>A (p.Trp232Ter)	Pathogenic
3649100	NM_005032.7(PLS3):c.243dup (p.Gln82fs)	Pathogenic
3657672	NM_005032.7(PLS3):c.1620del (p.Ile541fs)	Pathogenic
3664413	NM_005032.7(PLS3):c.1252del (p.His418fs)	Pathogenic
3675123	NM_005032.7(PLS3):c.1303C>T (p.Arg435Ter)	Pathogenic
3723900	NM_005032.7(PLS3):c.1580G>A (p.Trp527Ter)	Pathogenic
3724122	NM_005032.7(PLS3):c.1613C>A (p.Ser538Ter)	Pathogenic
3724418	NM_005032.7(PLS3):c.994_995del (p.Thr331_Asp332insTer)	Pathogenic
4085997	NM_005032.7(PLS3):c.985_987+6delinsG	Pathogenic
431450	NM_005032.7(PLS3):c.256del (p.Ser86fs)	Pathogenic

SpliceAI

2856 predictions. Top by Δscore:

Variant	Effect	Δscore
X:115561256:TTTAC:T	donor_gain	1.0000
X:115561257:TTAC:T	donor_gain	1.0000
X:115561258:TAC:T	donor_gain	1.0000
X:115561259:AC:A	donor_gain	1.0000
X:115561260:CGTA:C	donor_loss	1.0000
X:115561261:G:GA	donor_loss	1.0000
X:115561261:G:GG	donor_gain	1.0000
X:115561262:TAAG:T	donor_loss	1.0000
X:115603506:G:GT	donor_gain	1.0000
X:115610237:CTTTA:C	acceptor_loss	1.0000
X:115610240:TAGAT:T	acceptor_loss	1.0000
X:115610241:A:AG	acceptor_gain	1.0000
X:115610242:G:GA	acceptor_gain	1.0000
X:115610242:GAT:G	acceptor_gain	1.0000
X:115610320:GTTG:G	donor_gain	1.0000
X:115610322:TGGTG:T	donor_loss	1.0000
X:115610323:GGT:G	donor_loss	1.0000
X:115610324:G:GG	donor_gain	1.0000
X:115610324:G:T	donor_loss	1.0000
X:115610325:T:TC	donor_loss	1.0000
X:115610326:GA:G	donor_loss	1.0000
X:115610327:AG:A	donor_loss	1.0000
X:115622222:T:A	acceptor_gain	1.0000
X:115622226:T:A	acceptor_gain	1.0000
X:115622240:A:AG	acceptor_gain	1.0000
X:115622241:C:G	acceptor_gain	1.0000
X:115622242:A:AG	acceptor_gain	1.0000
X:115622243:A:G	acceptor_gain	1.0000
X:115622244:A:G	acceptor_gain	1.0000
X:115622244:A:T	acceptor_loss	1.0000

AlphaMissense

4216 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:115629850:C:A	A128D	1.000
X:115629955:G:A	G163E	1.000
X:115634909:C:A	A204D	1.000
X:115634921:G:A	G208E	1.000
X:115634992:T:A	W232R	1.000
X:115634992:T:C	W232R	1.000
X:115636905:T:A	L273Q	1.000
X:115636905:T:C	L273P	1.000
X:115636913:T:A	W276R	1.000
X:115636913:T:C	W276R	1.000
X:115636915:G:C	W276C	1.000
X:115636915:G:T	W276C	1.000
X:115640430:T:C	L305P	1.000
X:115640433:T:C	L306P	1.000
X:115643335:C:A	A337D	1.000
X:115643347:T:C	L341P	1.000
X:115643355:G:C	A344P	1.000
X:115643379:T:C	F352L	1.000
X:115643381:T:A	F352L	1.000
X:115643381:T:G	F352L	1.000
X:115643383:T:A	V353D	1.000
X:115643398:T:A	V358D	1.000
X:115643419:T:A	L365H	1.000
X:115643419:T:C	L365P	1.000
X:115643428:C:A	A368D	1.000
X:115643436:G:C	A371P	1.000
X:115643437:C:A	A371D	1.000
X:115643443:T:C	L373P	1.000
X:115643445:T:C	F374L	1.000
X:115643447:T:A	F374L	1.000

dbSNP variants (sampled 300 via entrez): RS1000058798 (X:115636156 T>C), RS1000086250 (X:115570426 T>G), RS1000214415 (X:115648514 C>T), RS1000270783 (X:115639996 T>C), RS1000293594 (X:115631366 C>T), RS1000307372 (X:115608712 T>G), RS1000409163 (X:115631671 G>A,T), RS1000485170 (X:115574844 A>G,T), RS1000534596 (X:115591520 A>G), RS1000593003 (X:115566835 C>T), RS1000628190 (X:115623948 G>A), RS1000725812 (X:115639511 A>G), RS1000751491 (X:115574653 C>T), RS1000803459 (X:115615519 G>A,C,T), RS1000914125 (X:115607200 C>T)

Disease associations

OMIM: gene MIM:300131 | disease phenotypes: MIM:142340, MIM:306950, MIM:166200

GenCC curated gene-disease

Disease	Classification	Inheritance
X-linked osteoporosis with fractures	Definitive	X-linked
hernia, anterior diaphragmatic	Strong	X-linked

Mondo (5): postmenopausal osteoporosis (MONDO:0008159), congenital diaphragmatic hernia (MONDO:0005711), hernia, anterior diaphragmatic (MONDO:0010606), osteogenesis imperfecta (MONDO:0019019), X-linked osteoporosis with fractures (MONDO:0018315)

Orphanet (3): Congenital diaphragmatic hernia (Orphanet:2140), Osteogenesis imperfecta (Orphanet:666), X-linked osteoporosis with fractures (Orphanet:391330)

HPO phenotypes

2 total (2 of 2 shown, HPO-id order):

HPO	Term
HP:0000776	Congenital diaphragmatic hernia
HP:0003811	Neonatal death

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST004898_4	Preterm birth (maternal effect)	1.000000e-11
GCST004899_1	Gestational age at birth (maternal effect)	7.000000e-16
GCST90002395_646	Mean platelet volume	2.000000e-20
GCST90002401_293	Platelet distribution width	8.000000e-10
GCST90002402_519	Platelet count	4.000000e-11

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0003917	premature birth
EFO:0005939	parental genotype effect measurement
EFO:0005112	gestational age
EFO:0007984	platelet component distribution width
EFO:0004309	platelet count

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D065630	Hernias, Diaphragmatic, Congenital	C16.131.433; C23.300.707.960.500.116
D010013	Osteogenesis Imperfecta	C05.116.099.708.685; C16.320.737; C17.300.200.540
D015663	Osteoporosis, Postmenopausal	C05.116.198.579.610; C18.452.104.579.610
C564413	Hernia, Anterior Diaphragmatic (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases methylation, decreases expression, increases expression, affects expression, affects cotreatment	5
Valproic Acid	affects expression, decreases methylation, increases expression	4
sodium arsenite	affects methylation, decreases expression, increases expression	3
Benzo(a)pyrene	affects methylation, decreases methylation, increases expression, increases mutagenesis, affects reaction	3
Tobacco Smoke Pollution	decreases expression, increases expression, affects expression	3
trichostatin A	affects cotreatment, increases expression	2
perfluorooctanoic acid	decreases expression, increases expression	2
perfluorooctane sulfonic acid	decreases expression, increases expression	2
chloropicrin	decreases expression, increases expression	2
entinostat	increases expression, affects cotreatment	2
Acetaminophen	decreases expression	2
Air Pollutants	decreases expression, increases abundance	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Particulate Matter	decreases expression, increases abundance	2
bisphenol F	increases expression	1
dicrotophos	decreases expression	1
beauvericin	affects cotreatment, decreases expression	1
methylmercuric chloride	increases expression	1
deoxynivalenol	decreases expression	1
titanium dioxide	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
terbufos	increases methylation	1
beta-lapachone	increases expression	1
arsenite	decreases reaction, affects binding	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	decreases expression	1
nickel sulfate	decreases expression	1
coumarin	increases phosphorylation	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3E5	Abcam HEK293T PLS3 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00079924	PHASE4	COMPLETED	Effects of Teriparatide in Postmenopausal Women With Osteoporosis
NCT00239629	PHASE4	COMPLETED	Teriparatide and Strontium Ranelate Head-To-Head Comparison Trial
NCT00545051	PHASE4	COMPLETED	A Study of Once Monthly Bonviva (Ibandronate) in Prevention of Glucocorticoid-Induced Osteoporosis.
NCT00545363	PHASE4	COMPLETED	A Study of Adherence to Once Monthly Ibandronate (Bonviva) in Women With Post-Menopausal Osteoporosis, Supported by a Patient Relationship Program (PRP)
NCT00545909	PHASE4	COMPLETED	BEATRIS Study: A Study of Adherence to Bonviva (Ibandronate) Once Monthly in Women With Post-Menopausal Osteoporosis
NCT00729651	PHASE4	COMPLETED	Efficacy and Safety Study of Fosamax Plus D in Postmenopausal Women With Osteoporosis (0217A-263)
NCT01544894	PHASE4	COMPLETED	Clinical Study of Raloxifene and Strontium Ranelate in Postmenopausal Osteoporosis
NCT01709110	PHASE4	COMPLETED	VERtebral Fracture Treatment Comparisons in Osteoporotic Women
NCT01750086	PHASE4	COMPLETED	Acute Effect of Teriparatide With Bisphosphonate or Denosumab on Bone Resorption
NCT02176382	PHASE4	COMPLETED	Denosumab and Teriparatide Study (DATA-HD and DATA-EX)
NCT02499237	PHASE4	COMPLETED	Zoledronic Acid to Maintain Bone Mass After Denosumab Discontinuation
NCT02598440	PHASE4	COMPLETED	A Study of Ibandronate (Bonviva) in Patients With Post-Menopausal Osteoporosis
NCT02598453	PHASE4	COMPLETED	PRIOR Study - A Study of Ibandronate (Boniva) in Postmenopausal Women With Osteoporosis or Osteopenia
NCT02604836	PHASE4	COMPLETED	A Study of Ibandronate (Boniva) to Evaluate Satisfaction in Women With Post-Menopausal Osteoporosis or Osteopenia
NCT03472846	PHASE4	COMPLETED	MiDeTe - microRNA Levels Under Denosumab and Teriparatide Therapy in Postmenopausal Osteoporosis
NCT04026256	PHASE4	COMPLETED	Bone Modeling Effects of Combined Anabolic/Antiresorptive Administration
NCT04719481	PHASE4	UNKNOWN	Pravastatin Reduces Acute Phase Response of Zoledronic Acid
NCT04719650	PHASE4	UNKNOWN	Clinical Pharmacokinetics and Pharmacodynamics Study of Different Doses of Zoledronic Acid
NCT05010590	PHASE4	ACTIVE_NOT_RECRUITING	Anabolic Therapy in Postmenopausal Osteoporosis
NCT05630768	PHASE4	COMPLETED	Efficacy and Safety of Actonel® After Denosumab Discontinuation in Postmenopausal Osteoporosis Women
NCT05645289	PHASE4	UNKNOWN	Efficacy and Safety of Minodronate in Patients With Low Back Pain
NCT05902078	PHASE4	RECRUITING	Eldecalcitol and Calcitriol in Postmenopausal Women With Low Bone Mineral Density or Mild Osteoporosis
NCT06079476	PHASE4	COMPLETED	A Study of Romosozumab (EVENITY®) in Postmenopausal Women in India With Osteoporosis at a High Risk of Fracture.
NCT06767150	PHASE4	RECRUITING	StrAtegies For Zoledronic Acid Post-dEnosumab Discontinuation in Postmenopausal oSTeoporosis
NCT06938152	PHASE4	RECRUITING	Effects of Cycle Therapy vs Sequential Therapy With Romosozumab and Denosumab in Postmenopausal Osteoporosis Patients
NCT07406685	PHASE4	NOT_YET_RECRUITING	The Comparison of Ibandronate and Zoledronic Acid After Denosumab Discontinuation
NCT05213676	PHASE4	RECRUITING	De-implementing Inhaled Nitric Oxide for Congenital Diaphragmatic Hernia
NCT07247240	PHASE4	NOT_YET_RECRUITING	Efficacy of Inhaled Nitric Oxide in Congenital Diaphragmatic Hernia
NCT00131469	PHASE4	COMPLETED	Study of Teriparatide (FORTEO) to Treat Adults With Osteogenesis Imperfecta
NCT00159419	PHASE4	COMPLETED	Bisphosphonate Therapy for Osteogenesis Imperfecta
NCT01713231	PHASE4	COMPLETED	Effect of High-Dose Vitamin D on Bone Density in Osteogenesis Imperfecta
NCT02303873	PHASE4	COMPLETED	Efficacy and Safety of Alendronate in Chinese Children or Adolescents With Osteogenesis Imperfecta
NCT03735537	PHASE4	COMPLETED	Treatment of Osteogenesis Imperfecta With Parathyroid Hormone and Zoledronic Acid
NCT04152551	PHASE4	RECRUITING	Effects of Bisphosphonates on OI-Related Hearing Loss
NCT00091793	PHASE3	COMPLETED	Study to Evaluate AMG 162 in the Prevention of Postmenopausal Osteoporosis
NCT00092014	PHASE3	COMPLETED	A Study to Evaluate and Compare Alendronate and Risedronate on Bone Mineral Density in Women With Postmenopausal Osteoporosis (MK-0217-211)
NCT00092027	PHASE3	COMPLETED	A Study to Evaluate the Safety and Tolerability of MK0217 in Women (0217-219)
NCT00092053	PHASE3	COMPLETED	Study of Investigational Drug in Osteoporosis (MK-0217-908)
NCT00165698	PHASE3	COMPLETED	Efficacy and Safety Study on Menatetrenone in the Treatment of Postmenopausal Osteoporosis Women
NCT00247273	PHASE3	COMPLETED	A Study of Monthly Risedronate for Osteoporosis