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Inheritance

1

X-linked HP:0001417

X-linked inheritance with a dose-dependent, non-strictly-recessive phenotype. Hemizygous males are consistently and more severely affected; heterozygous females range from normal bone mineral density through osteopenia to overt osteoporosis with fractures, so carrier status is not clinically silent. PLS3 is at Xq23.

X-linked inheritance Expressivity: VARIABLE

Show evidence (3 references)

PMID:25209159 SUPPORT Human Clinical

"Osteoporosis had its onset in childhood and was characterized by recurrent peripheral fractures, low bone mineral density (BMD), vertebral compression fractures, and significant height loss in adulthood. Males were in general more severely affected than females."

Establishes both the childhood onset and the male-predominant severity gradient that the X-linked assignment rests on, in a large multigenerational pedigree.

PMID:40353206 SUPPORT Human Clinical

"had normal BMD, two had osteoporosis and one osteopenia. Moreover, men experienced a higher total number of fractures than women (men: 12.0, IQR: 6.7, 18.5, women: 2.0, IQR: 0.7, 5.2)."

Quantifies the sex difference and shows that heterozygous females are mostly but not uniformly spared, which is why this is recorded as X-linked rather than X-linked recessive.

PMID:24088043 SUPPORT Human Clinical

"This variant was also associated with a risk of fracture among elderly heterozygous women that was two times as high as that among noncarriers"

Independent evidence that heterozygosity carries measurable fracture risk, supporting a dosage-sensitive rather than fully recessive X-linked model.

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Mechanistic Hypotheses

3

Osteoblast mineralization and mechanosensation defect

osteoblast_mineralization_mechanosensing_model CANONICAL

PLS3 acts in the osteoblast/osteocyte lineage, where actin bundling at focal adhesions is required for the cell to sense the stiffening collagen matrix and to sustain the second, mineralizing phase of bone formation. Loss of PLS3 leaves collagen deposition intact but blocks mineralization, which is what patient bone biopsies show. This is the best-supported account and the one most directly anchored in human tissue.

Pathograph links

PLS3 Loss of Actin-Bundling Function -> Impaired Osteoblast Mechanosensation DIRECT PLS3 localizes to the proximal end of mature focal adhesions where they transition into actin stress fibers, so loss of bundling activity is directly upstream of the cell's ability to read matrix stiffness.

Impaired Osteoblast Mechanosensation -> Defective Bone Matrix Mineralization DIRECT Failure to respond to increasing matrix stiffness removes the feed-forward signal that sustains hydroxyapatite deposition on the already-deposited collagen scaffold.

Osteoclast NKRF-NFkB-NFATc1 dysregulation

osteoclast_nkrf_nfatc1_model ALTERNATIVE

In Pls3-null mice the primary lesion is placed in the osteoclast: reduced nuclear NKRF de-represses Nfatc1 transcription and augments resorption. This predicts a high-resorption disease, which is the opposite of the low-turnover, reduced-osteoclast-number picture reported in human PLS3 bone biopsies, so it is curated as a competing account rather than as an additional step.

Pathograph links

PLS3 Loss of Actin-Bundling Function -> Dysregulated Osteoclast NFATc1 Signaling INDIRECT KNOWN INTERMEDIATES Via reduced nuclear translocation of the PLS3 interactor NKRF and consequent de-repression of Nfatc1. Demonstrated in mouse osteoclasts only.

Dysregulated Osteoclast NFATc1 Signaling -> Cortical and Trabecular Bone Deficit INDIRECT KNOWN INTERMEDIATES Under this model, augmented Nfatc1-driven osteoclast activity removes bone faster than it is replaced. Shown in mice; the human low-turnover picture is not consistent with it.

Endosteal vascular niche contribution

endosteal_vascular_niche_model EMERGING

Cross-species single-cell mapping of the endosteal compartment places Pls3 among genes expressed in bone endothelial and vascular smooth muscle cells, and Pls3-deficient mice have smaller bone blood vessels, with a pls3 zebrafish vascular phenotype preceding bone cells. Under this model the vascular lesion is upstream of the remodeling defect. Shares its identifier with the group of the same name in the osteoporosis_bone_resorption module, whose Endosteal Vascular Niche Dysfunction node this entry conforms to.

Pathograph links

PLS3 Loss of Actin-Bundling Function -> Endosteal Vascular Niche Dysfunction INDIRECT UNKNOWN INTERMEDIATES Pls3 is expressed in bone endothelial and vascular smooth muscle cells and its loss produces smaller bone blood vessels in mice; the intervening steps between actin bundling and vascular patterning are not defined.

Endosteal Vascular Niche Dysfunction -> Defective Bone Matrix Mineralization DIRECT Mirrors the module edge from the endosteal vascular node to impaired osteoblastic bone formation: endothelial and vascular smooth muscle cells are predicted to signal directly to osteoblast lineage cells, so loss of that input would blunt the formation arm.

Endosteal Vascular Niche Dysfunction -> Low-Turnover Bone Remodeling INDIRECT UNKNOWN INTERMEDIATES The module's parallel claim that a niche vascular lesion shifts the remodeling balance without an osteoblast- or osteoclast-intrinsic primary defect. Intermediates are undefined.

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Discussions and Knowledge Gaps

4

Which bone cell type carries the primary lesion in PLS3-related osteoporosis - the osteoblast, the osteocyte, the osteoclast, or the endosteal vascular cell?

KNOWLEDGE GAP pls3_primary_cell_type

Attached to

pathophysiology#PLS3 Loss of Actin-Bundling Function pathophysiology#Impaired Osteoblast Mechanosensation pathophysiology#Dysregulated Osteoclast NFATc1 Signaling pathophysiology#Endosteal Vascular Niche Dysfunction

PLS3 is expressed in osteoblasts, osteocytes and osteoclasts, and in bone endothelial and vascular smooth muscle cells, so expression cannot adjudicate. Each candidate arm has a study behind it and none has a conditional knockout. The four arms make different predictions - an osteoclast-primary mechanism predicts high turnover, which human biopsies contradict; an osteocyte-primary mechanism predicts altered sclerostin or DMP1, which the one human immunohistochemistry study did not find; the vascular arm predicts a bone vascular abnormality that has never been looked for in a patient. The resolving experiment is cell-type-conditional deletion, which has not been published for any lineage.

Proposed experiments

Lineage-restricted conditional Pls3 deletion series

pls3_conditional_knockouts

Generate osteoblast (Col1a1-Cre or Osx-Cre), osteocyte (Dmp1-Cre), osteoclast (Ctsk-Cre or LysM-Cre) and endothelial (Cdh5-CreERT2) conditional Pls3 knockouts on one background, phenotyped with the same undecalcified histology, dynamic histomorphometry, micro-CT and CD31 bone vascular imaging.

Decision criterion

An arm is supported if its conditional deletion reproduces reduced mineral apposition rate and cortical thinning at a magnitude comparable to the germline null, and refuted if that lineage's deletion is indistinguishable from wild-type.

Would support

pathophysiology#Impaired Osteoblast Mechanosensation pathophysiology#Endosteal Vascular Niche Dysfunction

Would refute

pathophysiology#Dysregulated Osteoclast NFATc1 Signaling

Supporting outcome

Osteoblast- or osteocyte-restricted deletion reproduces the low mineral apposition rate and cortical deficit; endothelial deletion reproduces the small-vessel phenotype and a bone deficit.

Refuting outcome

Only osteoclast-restricted deletion produces a bone phenotype, and it is resorption-dominant, which would overturn the low-turnover model built from human biopsies.

Show evidence (2 references)

PMID:32655496 SUPPORT Human Clinical

"the exact pathomechanisms of impaired PLS3 function in bone are still unknown"

Explicit statement from the field that the mechanism is unresolved, which is the gap this discussion records.

PMID:37083757 SUPPORT Model Organism

"Immunohistochemical staining of femoral sections also unraveled that PLS3 was present in osteocytes, osteoblasts, and osteoclasts in cortical and trabecular bone of WT rats"

Shows that expression pattern cannot narrow the candidate cell types, which is why a conditional-deletion series rather than more expression work is proposed.

Do the available Pls3 animal models reproduce human PLS3 osteoporosis well enough to support mechanistic inference, given that they are cortical-selective while the human disease is dominated by trabecular and vertebral collapse?

HUMAN MODEL MISMATCH pls3_mouse_human_mismatch

Attached to

animal_models#Pls3-null mouse (cortical-restricted phenotype) animal_models#PLS3 E10-16del rat pathophysiology#Cortical and Trabecular Bone Deficit

Deep-phenotyped Pls3-null mice show reduced cortical thickness at every age but no trabecular bone loss and no histomorphometric abnormality at 12 weeks; the patient-allele rat is likewise cortical and explicitly milder than the human disease. Patients, by contrast, present with severe vertebral compression from early childhood, and HR-pQCT finds the largest deviations in trabecular number and separation as well as cortical thickness. Two Pls3-null mouse studies also disagree with each other on osteoclasts. This is not a general caveat about mouse models: it means that the compartment where the human disease does its damage is the one the models do not reproduce, so any mechanism inferred from a mouse trabecular readout - including the osteoclast NFATc1 arm - is not anchored in the human phenotype.

Proposed experiments

Vertebral and site-matched phenotyping of Pls3 models

pls3_vertebral_phenotyping

Phenotype the vertebral bodies, not only long bones, in the Pls3-null mouse and the PLS3 E10-16del rat, using micro-CT trabecular morphometry and dynamic histomorphometry at the same skeletal site sampled in human transiliac and vertebral studies, with sex as an explicit variable.

Decision criterion

Model fidelity is supported if vertebral trabecular number and mineral apposition rate are reduced in the models, and the mismatch stands if vertebral bone is spared as long bone trabecular bone was.

Would support

pathophysiology#Cortical and Trabecular Bone Deficit

Would refute

pathophysiology#Dysregulated Osteoclast NFATc1 Signaling

Supporting outcome

Vertebral trabecular deficits appear in both models, making them usable for mechanistic inference about the human spinal disease.

Refuting outcome

Vertebral bone is spared in both models, confining them to cortical bone acquisition and leaving the dominant human lesion without an animal model.

Show evidence (2 references)

PMID:31678489 SUPPORT Model Organism

"Pls3-deficiency in mice only recapitulates the cortical bone phenotype of individuals with X-linked osteoporosis by negatively affecting the early stage of cortical bone acquisition"

The authors' own statement of the scope limit that this mismatch records.

PMID:28777485 SUPPORT Human Clinical

"The 3 patients presented in early childhood with severe spinal compression fractures involving all vertebral bodies."

The human phenotype the models do not reproduce, stated at its most severe.

Is bone vasculature abnormal in humans carrying PLS3 loss-of-function variants, as it is in Pls3-deficient mice?

KNOWLEDGE GAP pls3_bone_vasculature_in_humans

Attached to

pathophysiology#Endosteal Vascular Niche Dysfunction mechanistic_hypotheses#endosteal_vascular_niche_model

The entire vascular arm rests on mouse and zebrafish observations plus a computationally predicted endothelial-to-osteoblast interaction. Transiliac bone biopsy is already part of the diagnostic workup in this disease, so vascular assessment could be added to material that is being collected anyway rather than requiring a new invasive procedure. Until it is done, the arm stays EMERGING and no human-anchored causal claim can be made from it.

Proposed experiments

Bone vascular assessment in PLS3 variant carriers

pls3_human_bone_vascular_imaging

Assess vessel density and calibre by CD31 immunohistochemistry on archived and prospectively collected transiliac biopsies from PLS3 variant carriers against age- and sex-matched controls, with dynamic contrast-enhanced MRI of marrow perfusion as a non-invasive comparator.

Decision criterion

The vascular arm is supported if vessel calibre or density is reduced relative to matched controls, and weakened if bone vasculature is indistinguishable while the mineralization defect is present in the same biopsy.

Would support

pathophysiology#Endosteal Vascular Niche Dysfunction

Would refute

mechanistic_hypotheses#endosteal_vascular_niche_model

Supporting outcome

Reduced bone vessel calibre or density in carriers, matching the murine finding.

Refuting outcome

Normal bone vasculature alongside the expected osteoid and mineralization abnormalities, confining the vascular phenotype to the mouse.

Show evidence (1 reference)

PMID:42432248 SUPPORT Model Organism

"These data suggest that X-linked osteoporosis might result from abnormalities in bone vasculature."

The hypothesis, stated by its authors in hedged form, that this gap proposes to test in humans.

Why do antiresorptives raise bone mineral density in a disease whose tissue lesion is a formation and mineralization defect with low turnover, and do they reduce fractures?

OPEN QUESTION pls3_antiresorptive_mechanism_mismatch

Attached to

treatments#Bisphosphonate Therapy pathophysiology#Low-Turnover Bone Remodeling

Bisphosphonates are first-line here and reliably raise densitometric measures, yet they suppress a resorption limb that histomorphometry shows is already low. Densitometric gain under an antiresorptive can reflect secondary mineralization of retained matrix rather than restored bone formation, which in a disease of defective mineralization is not obviously the same as improved strength. No study has reported fracture outcomes, and the one anabolic trial reported a cortical volumetric density loss at the radius. The question is practical, not academic: it determines whether antiresorptive or anabolic therapy should be first-line.

Show evidence (2 references)

PMID:37083757 SUPPORT Model Organism

"Treatment with alendronate (1.0 µg/kg/day) or teriparatide (40 µg/kg five times weekly) for 8 weeks significantly improves bone mass and bone microarchitecture, and bone strength is significantly increased after teriparatide treatment"

The only head-to-head comparison in a PLS3 model, and it separates mass from strength: both agents improved mass and microarchitecture, only the anabolic significantly improved strength.

PMID:27732335 SUPPORT Human Clinical

"Future studies are needed to evaluate whether observed changes translate to fracture resistance."

The pilot study's own statement that densitometric response has not been shown to translate into fracture reduction, which is the core of this question.

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Pathophysiology

7

PLS3 Loss of Actin-Bundling Function

Loss-of-function variants in PLS3 remove or disable plastin 3, a calcium-regulated F-actin bundling protein expressed in osteoblasts, osteocytes and osteoclasts and, in bone, also in vascular endothelial and smooth muscle cells. Patient-derived missense alleles retain protein but have aberrant calcium-sensitive actin-bundling activity, so the shared molecular lesion across nonsense, frameshift, deletion and missense alleles is loss of F-actin crosslinking rather than loss of the transcript alone.

Endosteal vascular niche contribution Osteoblast mineralization and mechanosensation defect Osteoclast NKRF-NFkB-NFATc1 dysregulation

Genetic context PLS3 hgnc:9091 variant_origin: GERMLINE zygosity: HEMIZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Hemizygous in affected males; heterozygous in females, where the phenotype is variable rather than absent.

Actin filament bundling GO:0051017 ↓ DECREASED

F-actin binding by plastin 3 GO:0051015 ↓ DECREASED

Downstream

Impaired Osteoblast Mechanosensation PLS3 localizes to the proximal end of mature focal adhesions where they transition into actin stress fibers, so loss of bundling activity is directly upstream of the cell's ability to read matrix stiffness.

Dysregulated Osteoclast NFATc1 Signaling Via reduced nuclear translocation of the PLS3 interactor NKRF and consequent de-repression of Nfatc1. Demonstrated in mouse osteoclasts only.

Endosteal Vascular Niche Dysfunction Pls3 is expressed in bone endothelial and vascular smooth muscle cells and its loss produces smaller bone blood vessels in mice; the intervening steps between actin bundling and vascular patterning are not defined.

Show evidence (3 references)

PMID:24088043 SUPPORT Human Clinical

"Plastin 3 (PLS3), a protein involved in the formation of filamentous actin (F-actin) bundles, 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."

Names the molecular activity of the protein and ties its loss to the human bone phenotype, which is the claim this node makes.

PMID:38089885 SUPPORT In Vitro

"Defective cell spreading of PLS3 KD cells on stiff substrates could be rescued by expression of wildtype PLS3, but not by expression of three PLS3 mutations that were identified in patients with early onset osteoporosis and that have aberrant actin-bundling activity."

Rescue with wild-type but not with patient actin-bundling-defective alleles is what makes loss of bundling, rather than loss of the protein per se, the operative molecular lesion.

PMID:37083757 SUPPORT Model Organism

"Immunohistochemical staining of femoral sections also unraveled that PLS3 was present in osteocytes, osteoblasts, and osteoclasts in cortical and trabecular bone of WT rats"

Establishes that the protein is present in all three bone cell lineages, which is why the downstream arms of this node are curated as competing cell-type hypotheses rather than resolved.

Impaired Osteoblast Mechanosensation

In osteoblasts, PLS3 concentrates at focal adhesions, the structures through which the cell reads the stiffness of the extracellular matrix it is building. Osteoblasts depleted of PLS3 no longer scale their spreading or focal-adhesion number and length with substrate stiffness, so the feed-forward loop in which progressive matrix mineralization stiffens the substrate and drives further mineral deposition is broken. The same mechanosensory argument has been extended to osteocytes, where PLS3 is abundant in dendritic processes, but that step is inference rather than measurement in this disease.

Osteoblast mineralization and mechanosensation defect

Osteoblast CL:0000062 Osteocyte CL:0000137

Cellular response to matrix stiffness GO:0071260 ↓ DECREASED

Experimental models

PLS3-knockdown MC3T3-E1 pre-osteoblast line CELL LINE PLS3-depleted osteoblasts lose the scaling of cell size and focal-adhesion number and length with substrate stiffness that control cells show, and wild-type but not patient actin-bundling-defective PLS3 restores it.

Downstream

Defective Bone Matrix Mineralization Failure to respond to increasing matrix stiffness removes the feed-forward signal that sustains hydroxyapatite deposition on the already-deposited collagen scaffold.

Show evidence (4 references)

PMID:38089885 SUPPORT In Vitro

"we observed that depletion of PLS3 rendered osteoblasts unresponsive to changes in ECM stiffness"

The direct measurement behind this node: loss of PLS3 abolishes the osteoblast's stiffness response.

PMID:38089885 SUPPORT In Vitro

"PLS3 prominently localizes to focal adhesions (FAs), which are intricately linked to mechanosensation."

Localizes the protein to the structure that carries the mechanosensory function, which is what makes this a mechanistic node rather than a correlation.

PMID:28379384 SUPPORT INDIRECT Human Clinical

"Abnormal osteocyte function may play a role in the pathogenesis of monogenetic forms of osteoporosis."

Human iliac-crest immunohistochemistry framing osteocyte dysfunction as contributory; marked INDIRECT because the study's own PLS3-specific finding is that sclerostin, DMP1 and phospho-beta-catenin did not differ from the WNT1 comparison group.

+ 1 more reference

Endosteal Vascular Niche Dysfunction

Mechanism confidence: Hypothetical

An emerging arm in which the primary lesion is vascular rather than osteoblastic. Cross-species single-cell mapping of the endosteal compartment prioritized endothelial cells and vascular smooth muscle cells as skeletal-disease-relevant lineages and named Pls3 among the genes expressed in them; Pls3-deficient mice have smaller bone blood vessels, and pls3 knockdown in zebrafish disturbs vascular patterning before bone cells are present. No human study has yet examined bone vasculature in PLS3 variant carriers.

Endosteal vascular niche contribution

Bone vascular endothelial cell CL:0000115 Bone vascular smooth muscle cell CL:0000359

Skeletal angiogenesis GO:0001525 ↕ DYSREGULATED Bone blood vessel morphogenesis GO:0048514 ↕ DYSREGULATED

endosteum UBERON:0009859 bone blood vessel UBERON:0001981

Animal models

Pls3-deficient mouse (bone vascular phenotype) Mouse recapitulates Loss of the gene that causes this disease produces abnormal bone vasculature in mice, which is the entire observational basis of the vascular arm.

Downstream

Defective Bone Matrix Mineralization Mirrors the module edge from the endosteal vascular node to impaired osteoblastic bone formation: endothelial and vascular smooth muscle cells are predicted to signal directly to osteoblast lineage cells, so loss of that input would blunt the formation arm.

Low-Turnover Bone Remodeling The module's parallel claim that a niche vascular lesion shifts the remodeling balance without an osteoblast- or osteoclast-intrinsic primary defect. Intermediates are undefined.

Show evidence (5 references)

PMID:42432248 SUPPORT Model Organism

"mice showed smaller blood vessels in bone compared to controls (CTRLs) (Fig. 6a), which was confirmed by backscattered scanning electron microscopy (SEM) and micro-CT analysis"

The structural vascular measurement in Pls3-deficient mice that this node rests on, replicated across three imaging modalities.

PMID:42432248 SUPPORT Model Organism

"These data suggest that X-linked osteoporosis might result from abnormalities in bone vasculature."

The authors' own statement of the hypothesis, named for this disease specifically. Its hedged phrasing is why mechanism_confidence is HYPOTHETICAL and the node sits in an EMERGING hypothesis group.

PMID:42432248 SUPPORT Model Organism

"Knockdown of pls3 in zebrafish embryos49 resulted in mild cardiac edema and defects in intersegmental vessel (ISV) formation, including disconnections from the dorsal aorta or posterior cardinal vein, ectopic vessel connections and smaller lumens"

The zebrafish vascular patterning defect, in a second species and by an independent perturbation, that the mouse vessel-calibre measurement alone would not establish.

+ 2 more references

Dysregulated Osteoclast NFATc1 Signaling

Mechanism confidence: Hypothetical

A competing, mouse-derived arm in which the primary lesion is in the osteoclast. PLS3 binds NFkB repressing factor (NKRF); in Pls3-null osteoclasts less NKRF reaches the nucleus, Nfatc1 - the master regulator of osteoclastogenesis - is de-repressed, and resorption is augmented. The reciprocal experiment supports the axis: PLS3-overexpressing mice show increased nuclear NKRF, suppressed osteoclast function and thicker, stronger cortical bone. This arm is deliberately not conformed to the module's RANKL-Driven Osteoclastogenesis node, because human PLS3 bone biopsies show the opposite phenotype - reduced osteoclast number and low turnover.

Osteoclast NKRF-NFkB-NFATc1 dysregulation

Osteoclast CL:0000092

Osteoclast differentiation GO:0030316 ↑ INCREASED

Downstream

Cortical and Trabecular Bone Deficit Under this model, augmented Nfatc1-driven osteoclast activity removes bone faster than it is replaced. Shown in mice; the human low-turnover picture is not consistent with it.

Show evidence (5 references)

PMID:30204862 SUPPORT Model Organism

"We show that unbalanced PLS3 levels affect osteoclast development and function, by misregulating the NFκB pathway."

States the osteoclast-centred claim this node encodes, in the mouse system where it was demonstrated.

PMID:30204862 SUPPORT Model Organism

"We found the opposite in Pls3 knockout osteoclasts, where decreased nuclear NKRF augmented Nfatc1 transcription, causing osteoporosis."

Gives the specific NKRF-to-Nfatc1 step and directionality that make this a mechanistic arm rather than a general osteoclast observation.

PMID:30204862 SUPPORT Model Organism

"while Pls3 knockout mice exhibit osteoporosis, PLS3 overexpressing mice show thickening of cortical bone and increased bone strength"

The bidirectional dosage experiment; gain and loss of PLS3 move bone mass in opposite directions, which is the strongest support for the axis.

+ 2 more references

Defective Bone Matrix Mineralization

The defining tissue lesion. Osteoblasts deposit a normal collagen matrix but fail to mineralize it: patient transiliac biopsies show increased osteoid volume and thickness with a prolonged mineralizing lag time, and quantitative backscattered electron imaging plus Raman microspectroscopy show frank hypomineralization. This is the mirror image of osteogenesis imperfecta, where the collagen defect produces hypermineralized matrix, and is the basis for separating this entry from the OI group.

Osteoblast CL:0000062

Bone mineralization GO:0030282 ↓ DECREASED Ossification GO:0001503 ↓ DECREASED

bone tissue UBERON:0002481

Experimental models

PLS3-knockdown MC3T3-E1 pre-osteoblast line CELL LINE Reproduces the human tissue finding that collagen matrix is deposited normally but is not subsequently mineralized.

Downstream

Low-Turnover Bone Remodeling A block at the mineralizing step slows the whole formation limb of the remodeling cycle, which is what the reduced mineral apposition rate measures.

Cortical and Trabecular Bone Deficit Mirrors the module edge from impaired osteoblastic bone formation to net bone loss: matrix that is not mineralized does not carry load.

Show evidence (5 references)

PMID:28777485 SUPPORT Human Clinical

"Extensive analyses of a transiliac bone biopsy from 1 patient showed a prominent increase in osteoid volume, osteoid thickness, and in mineralizing lag time."

The human histomorphometric signature of a mineralization block: osteoid accumulates because it is not being mineralized on schedule.

PMID:28777485 SUPPORT Human Clinical

"Results from quantitative backscattered electron imaging and Raman microspectroscopy showed a significant hypomineralization of the bone."

Two independent physical measurements of mineral content confirming the histomorphometric inference.

PMID:38089885 SUPPORT In Vitro

"depletion of PLS3 does not alter the first stage of osteoblast mineralization in which a collagen matrix is deposited, but severely affects the subsequent mineralization of that matrix"

Separates the two phases of bone formation and shows the defect is confined to the mineralizing phase, which is exactly what the patient biopsies show.

+ 2 more references

Low-Turnover Bone Remodeling

Bone remodeling in PLS3-related osteoporosis is slow on both limbs, not resorption-dominant. Histomorphometry shows a reduced mineral apposition rate, scant osteoid, and reduced osteoblast and osteoclast numbers, while serum bone turnover markers are typically normal.

Osteoblast CL:0000062 Osteocyte CL:0000137 Osteoclast CL:0000092

Bone remodeling GO:0046849 ↓ DECREASED

Animal models

PLS3 E10-16del rat Rat recapitulates Reproduces the reduced mineral apposition rate that is the defining histomorphometric abnormality in patients.

Downstream

Cortical and Trabecular Bone Deficit Sustained low formation against ongoing resorption yields net negative bone balance and progressive structural deterioration.

Show evidence (4 references)

PMID:25209159 SUPPORT Human Clinical

"Bone histomorphometry findings in 4 males and 1 female showed severe trabecular osteoporosis, low amount of osteoid, and decreased mineral apposition rate, indicating impaired bone formation"

The primary human measurement of a slow formation limb, in five biopsied members of one pedigree.

PMID:32655496 SUPPORT Human Clinical

"Bone tissue is characterized by low bone turnover with reduced osteoblast and osteoclast numbers and disturbed matrix mineralization"

States the low-turnover, both-limbs-reduced tissue phenotype that distinguishes this node from the module's resorption-dominant default.

PMID:31968132 SUPPORT Human Clinical

"Results confirmed normal concentrations of conventional metabolic bone markers in both groups."

Normal serum turnover markers alongside severe skeletal disease is the clinical correlate of low, balanced turnover, and is why circulating markers cannot be used to monitor this disease.

+ 1 more reference

Cortical and Trabecular Bone Deficit

The structural end state, and one with a distinctive geometry. HR-pQCT in adults with PLS3 variants shows a large total bone area driven by an enlarged trabecular compartment with a small, thin cortex, low volumetric bone mineral density in both compartments, fewer and more widely separated trabeculae with normal trabecular thickness, and low failure load. Cortical porosity is normal, so the cortical deficit is one of thickness rather than of intracortical remodeling. Women deviate less from reference data than men.

Bone remodeling GO:0046849 ↕ DYSREGULATED

compact bone tissue UBERON:0001439 trabecular bone tissue UBERON:0002483

Animal models

Pls3-null mouse (cortical-restricted phenotype) Mouse partially recapitulates Reproduces the cortical-thinning half of the human structural phenotype at every age examined, and nothing else.

PLS3 E10-16del rat Rat partially recapitulates Reproduces thinner cortical bone and reduced mechanical strength at three ages.

Downstream

Reduced Bone Mineral Density Low volumetric density in both compartments is what densitometry measures as a low areal bone mineral density Z-score.

Recurrent Peripheral Fractures Reduced failure load at the distal radius and tibia is the mechanical basis for long-bone fragility fractures under ordinary loading.

Vertebral Compression Fractures Loss of trabecular number in the vertebral body, whose strength is trabecular-dominated, produces compression fractures from childhood.

Show evidence (4 references)

PMID:39658012 SUPPORT Human Clinical

"In men, total bone area was large (median Z-score: 1.33 radius; 1.46 tibia) due to a large trabecular area (+1.73 radius; +1.87 tibia), while the cortical area was small (-2.61 radius; -2.84 tibia)."

The compartment-resolved geometry of the deficit, which a DXA areal density cannot show.

PMID:39658012 SUPPORT Human Clinical

"the largest deviations were found in trabecular number (-2.18 radius; -1.64 tibia), trabecular separation (+2.32 radius; +1.65 tibia), and cortical thickness (-2.99 radius; -2.46 tibia), whereas trabecular thickness and cortical porosity were normal"

Locates the microarchitectural lesion in trabecular number and cortical thickness while excluding intracortical porosity, which constrains which mechanisms are plausible.

PMID:39658012 SUPPORT Human Clinical

"Additionally, failure load was low (-2.39 radius; -2.2 tibia)."

Converts the structural findings into a mechanical strength deficit, the quantity that actually predicts fracture.

+ 1 more reference

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Pathograph

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Phenotypes

7

Eye 1

Blue Sclerae FREQUENT HP:0000592

Show evidence (1 reference)

PMID:40353206 SUPPORT Human Clinical

"Extra-skeletal characteristics such as (mild) blue discoloration of the sclerae (men: 33.3%, women: 30.0%), joint hypermobility (44.4%, 70.0%) and skin hyperlaxity (50.0%, 20.0%) were observed."

Gives sex-stratified frequencies for the extra-skeletal features in the 28-patient cohort.

Integument 1

Skin Hyperlaxity FREQUENT Hyperextensible skin HP:0000974

Show evidence (1 reference)

PMID:40353206 SUPPORT Human Clinical

"Extra-skeletal characteristics such as (mild) blue discoloration of the sclerae (men: 33.3%, women: 30.0%), joint hypermobility (44.4%, 70.0%) and skin hyperlaxity (50.0%, 20.0%) were observed."

Source of the reported frequency for skin hyperlaxity in the 28-patient cohort.

Musculoskeletal 5

Reduced Bone Mineral Density FREQUENT HP:0004349

Course: PROGRESSIVE

Show evidence (2 references)

PMID:24616189 SUPPORT Human Clinical

"Lumbar spine areal bone mineral density (LS-aBMD) Z-scores ranged from -1.7 to -3.5, but height was normal."

Quantifies the densitometric deficit in affected boys and records that it is not accompanied by short stature.

PMID:40353206 SUPPORT Human Clinical

"had normal BMD, two had osteoporosis and one osteopenia. Moreover, men experienced a higher total number of fractures than women (men: 12.0, IQR: 6.7, 18.5, women: 2.0, IQR: 0.7, 5.2)."

Shows that most adult heterozygous women in the largest cohort had normal bone mineral density, supporting the sex-dependent penetrance recorded here.

Recurrent Peripheral Fractures VERY_FREQUENT Recurrent fractures HP:0002757

Show evidence (1 reference)

PMID:24616189 SUPPORT Human Clinical

"When first evaluated between 4 and 8 years of age, these boys had a history of one to four long-bone fractures. Mild vertebral compression fractures were identified in each boy."

Documents both the age of onset and the peripheral fracture burden in four affected boys from two families.

Vertebral Compression Fractures VERY_FREQUENT HP:0002953

Course: PROGRESSIVE

Sequelae: Thoracic Kyphosis

Show evidence (2 references)

PMID:28777485 SUPPORT Human Clinical

"The 3 patients presented in early childhood with severe spinal compression fractures involving all vertebral bodies."

The most severe reported presentation, in boys carrying PLS3 deletions, establishing pan-vertebral involvement in childhood.

PMID:32655496 SUPPORT Human Clinical

"Compromised PLS3 function introduces severe and progressive changes to spinal structures that are present already in childhood, in both sexes and most abundant in upper thoracic spine."

Blinded spinal MRI in 15 variant-positive versus 13 variant-negative family members, giving the level distribution and confirming involvement in both sexes.

Thoracic Kyphosis FREQUENT HP:0002942

Show evidence (1 reference)

PMID:25209159 SUPPORT Human Clinical

"Osteoporosis had its onset in childhood and was characterized by recurrent peripheral fractures, low bone mineral density (BMD), vertebral compression fractures, and significant height loss in adulthood. Males were in general more severely affected than females."

Records the adult height loss that is the clinical expression of accumulated thoracic vertebral collapse in this pedigree.

Joint Hypermobility FREQUENT HP:0001382

Show evidence (1 reference)

PMID:40353206 SUPPORT Human Clinical

"Extra-skeletal characteristics such as (mild) blue discoloration of the sclerae (men: 33.3%, women: 30.0%), joint hypermobility (44.4%, 70.0%) and skin hyperlaxity (50.0%, 20.0%) were observed."

Source of the reported frequency, in the same cohort assessment as the other extra-skeletal features.

🧬

Genetic Associations

1

PLS3 loss-of-function variants (Causative)

Gene: PLS3 (plastin 3, T-plastin) hgnc:9091 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (4 references)

PMID:24088043 SUPPORT Human Clinical

"Plastin 3 (PLS3), a protein involved in the formation of filamentous actin (F-actin) bundles, 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."

The founding gene-disease report, identifying PLS3 as causative in five independent X-linked osteoporosis families.

PMID:28777485 SUPPORT Human Clinical

"In family 1, the 2 affected brothers had a deletion of exons 4-16 (NM_005032) in PLS3, inherited from their healthy mother."

Documents whole-exon deletion as a disease mechanism, establishing that the allelic spectrum extends beyond point variants to copy-number loss.

PMID:40353206 SUPPORT Human Clinical

"No relation was found between types and locations of variants and various clinical endpoints in men, using data from our cohort and the literature."

The largest genotype-phenotype analysis to date finds no variant-class rule for clinical outcome, which is why no allele-stratified subtypes are curated.

+ 1 more reference

💊

Medical Actions

2

Bisphosphonate Therapy

Action: Pharmacotherapy NCIT:C15986

Agent: alendronate CHEBI:2567 zoledronic acid CHEBI:46557

Platform: Small molecule

Oral alendronate or intravenous zoledronic acid, the mainstay of treatment. Both raise bone mineral density and zoledronic acid has been reported to reshape already-compressed vertebral bodies in a growing child. Note the mechanistic mismatch: bisphosphonates suppress resorption, but the underlying lesion here is a formation and mineralization defect with low turnover, so the density gain does not follow from correcting the mechanism. No trial has tested fracture reduction in this disease.

Mechanism Target:

Cortical and Trabecular Bone Deficit — Antiresorptive therapy acts on the structural end state by slowing further loss, not on the upstream mineralization defect.

Show evidence (1 reference)

PMID:24616189 SUPPORT Human Clinical

"The 2 boys from family 1 received oral alendronate for 6 years, which normalized LS-aBMD."

Densitometric normalisation under long-term oral alendronate in two affected boys; the outcome measured is bone mineral density, not fracture.

Show evidence (3 references)

PMID:28620780 SUPPORT Human Clinical

"Zoledronic acid treatment could significantly increase the Z-score of BMD and reshape the compressed vertebral bodies."

Single-patient report of the intravenous option, including vertebral reshaping, which is the outcome that matters most in childhood spinal disease.

PMID:40353206 SUPPORT Human Clinical

"Adult men demonstrated a 16.6% mean increase in the BMD of the lumbar spine (p = .03)"

Cohort-level confirmation of the densitometric response, in adult men mostly treated with oral bisphosphonates.

PMID:37083757 SUPPORT Model Organism

"Treatment with alendronate (1.0 µg/kg/day) or teriparatide (40 µg/kg five times weekly) for 8 weeks significantly improves bone mass and bone microarchitecture, and bone strength is significantly increased after teriparatide treatment"

Controlled comparison in a rat carrying a patient-derived PLS3 deletion; both agents improve mass and microarchitecture, but only teriparatide significantly improved strength.

Teriparatide

Action: Pharmacotherapy NCIT:C15986

Agent: teriparatide NCIT:C61966

Platform: Peptide

Recombinant PTH(1-34), an anabolic agent, given off-label. A 24-month uncontrolled pilot in adults with WNT1 or PLS3 variants showed rises in formation and resorption markers and gains at the lumbar spine and femoral neck. Two cautions are recorded on the evidence itself: distal radius cortical volumetric density fell in the same study, and the histomorphometric osteoid response was less consistent in the PLS3 patients than in the WNT1 patients - which is what a primary mineralization defect would predict.

Mechanism Target:

Low-Turnover Bone Remodeling — An anabolic agent is the mechanistically motivated choice against a low-formation, low-turnover lesion, in contrast to antiresorptives.

Show evidence (1 reference)

PMID:27732335 SUPPORT Human Clinical

"All patients showed increases in formation markers procollagen type 1 amino-terminal propeptide (90% to 398%) and osteocalcin (50% to 280%)"

Direct evidence that the drug lifts the suppressed formation limb, which is the mechanism this link asserts.

Show evidence (3 references)

PMID:27732335 SUPPORT Human Clinical

"Lumbar spine BMD increased 5.2% to 7.9% in 5 patients and femoral neck BMD 2.6% to 7.8% in 4 patients in 24 months."

The primary densitometric result of the pilot study, in six adults of whom three carried the PLS3 c.73-24T>A splice variant.

PMID:27732335 REFUTE Human Clinical

"Distal radius cortical volumetric BMD decreased 5.4% to 26.1%."

A site-discordant loss at the cortical radius in the same study, quoted as a REFUTE item because it argues against an unqualified benefit claim - and the cortex is the compartment most affected in this disease.

PMID:27732335 SUPPORT INDIRECT Human Clinical

"In histomorphometric analyses, osteoid indices increased more consistently in patients with WNT1 vs PLS3 mutation."

Genotype-differential tissue response; supports treating PLS3 osteoporosis as mechanistically distinct from WNT1 osteoporosis rather than as one monogenic-osteoporosis treatment class.

🔬

Biochemical Markers

2

Serum dickkopf-1 (DKK1) (Elevated)

Show evidence (2 references)

PMID:31968132 SUPPORT Human Clinical

"DKK1 concentrations were significantly elevated in PLS3 mutation-positive subjects compared with WNT1 mutation-positive subjects"

Establishes the elevation and, by contrasting with the WNT1 group, that it is not a generic feature of monogenic osteoporosis.

PMID:31968132 SUPPORT Human Clinical

"Both intact and C-terminal FGF23 were significantly elevated in WNT1 mutation-positive subjects (p = .039 and p = .027, respectively) and normal in PLS3 subjects."

The reciprocal negative result: FGF23 separates WNT1 from PLS3 osteoporosis, so the two monogenic forms have distinguishable biochemical signatures.

Conventional serum bone turnover markers (Normal)

Show evidence (2 references)

PMID:31968132 SUPPORT Human Clinical

"Results confirmed normal concentrations of conventional metabolic bone markers in both groups."

Direct measurement of the conventional marker panel in 14 PLS3 variant carriers against 34 variant-negative relatives.

PMID:28379384 SUPPORT Human Clinical

"DMP1, sclerostin, and phospho-β-catenin expression did not differ between groups."

Tissue-level counterpart: the osteocyte regulatory proteins most often proposed as mechanistic mediators were not differentially expressed in PLS3 bone relative to the WNT1 comparison group.

🔬

Diagnosis

4

Molecular Genetic Testing

Diagnosis is established by identifying a hemizygous or heterozygous PLS3 variant, in practice through a next-generation sequencing panel aimed at osteogenesis imperfecta and other monogenic bone disease rather than through a PLS3-directed test. Because PLS3 is absent from many first-line fragility-fracture panels, families are typically ascertained on the OI diagnostic pathway and reach the PLS3 diagnosis only once collagen genes return negative. Sequence analysis alone is not sufficient: partial and whole-gene PLS3 deletions are an established cause, so a panel without exon-level copy-number calling can return negative in an affected boy.

next-generation sequencing panel for monogenic bone disease NCIT:C19770

Results: Hemizygous (males) or heterozygous (females) PLS3 variant

Show evidence (3 references)

PMID:40353206 SUPPORT Human Clinical

"Genetic analysis was performed, in most of the patients, through next generation sequencing (NGS), followed by analysis of variants implicated in OI and other monogenic bone diseases."

Establishes the testing modality actually used to diagnose the largest reported cohort, and that PLS3 is reached through an OI-oriented panel.

PMID:24088043 SUPPORT Human Clinical

"in an additional five families (described in less detail) referred for diagnosis or ruling out of osteogenesis imperfecta type I, a rare variant (rs140121121) in PLS3 was found"

Documents the referral route: these families entered testing as suspected osteogenesis imperfecta, which is why the diagnosis depends on PLS3 being present on the panel that is ordered.

PMID:28777485 SUPPORT Human Clinical

"Here we describe for the first time PLS3 deletions as the underlying cause for childhood-onset primary osteoporosis in 3 boys from 2 families."

Establishes gene deletion as a disease-causing allele class, which is why a sequencing-only panel is an incomplete test for this gene.

Bone Densitometry

Dual-energy X-ray absorptiometry of the lumbar spine and femoral neck, reported as age- and sex-adjusted Z-scores, is the primary quantitative measure and the basis for monitoring. A normal scan does not exclude the diagnosis in a female carrier, and axial DXA can miss the appendicular cortical deficit that peripheral quantitative CT detects.

dual-energy X-ray absorptiometry of lumbar spine and femoral neck NCIT:C48789

Results: Low lumbar spine and femoral neck areal BMD Z-scores in affected males

Show evidence (2 references)

PMID:40353206 SUPPORT Human Clinical

"BMD measurements by DXA were for most of the patients performed using GE Lunar Prodigy Advance equipment (H8950AN enCORE, Version 17 SP4); Z-scores were calculated using equipment-specific and age- and sex adjusted reference data"

Specifies DXA as the densitometric modality and age- and sex-adjusted Z-scores as the reported metric in the largest cohort.

PMID:24616189 SUPPORT Human Clinical

"However, one of these mothers had low bone mass at the distal radius, as measured by peripheral quantitative computed tomography (pQCT)."

Shows that a carrier with unremarkable axial densitometry can still have a detectable peripheral cortical deficit, which is the limitation of relying on DXA alone to assess carriers.

Transiliac Bone Biopsy with Histomorphometry

Tetracycline-labelled transiliac biopsy resolves the tissue-level lesion and is the investigation that separates this disease from osteogenesis imperfecta. It shows accumulated unmineralized osteoid with a prolonged mineralizing lag time on a low-turnover background - the opposite mineralization direction to collagen type I defects.

transiliac bone biopsy with tetracycline labelling NCIT:C15189

Results: Increased osteoid volume and thickness, prolonged mineralizing lag time, low trabecular bone volume, normal-to-reduced osteoclast surface

Show evidence (2 references)

PMID:28777485 SUPPORT Human Clinical

"Extensive analyses of a transiliac bone biopsy from 1 patient showed a prominent increase in osteoid volume, osteoid thickness, and in mineralizing lag time."

The mineralization-defect signature that the biopsy is performed to demonstrate.

PMID:24616189 SUPPORT Human Clinical

"Iliac bone histomorphometry in 2 patients showed low trabecular bone volume and a low osteoid maturation time but normal bone formation rate and osteoclast surface."

Records the normal osteoclast surface, which is the histomorphometric finding that argues against a resorption-driven mechanism.

Spinal Magnetic Resonance Imaging

Spinal MRI detects the vertebral compression burden, which is present in both sexes from childhood and is systematically under-recognised because carriers are often asymptomatic. In the one systematic series the readers were blinded to genotype, so the reported findings are not the product of expectation.

magnetic resonance imaging of the spine NCIT:C16809

Results: Biconcave vertebral compression fractures, most abundant in upper thoracic spine

Show evidence (2 references)

PMID:32655496 SUPPORT Human Clinical

"we set out to evaluate their spinal pathology using magnetic resonance imaging (MRI)"

Establishes spinal MRI as the modality used to assess the vertebral disease.

PMID:32655496 SUPPORT Human Clinical

"The MRIs were first independently assessed for spinal changes by an orthopedic surgeon and three experienced radiologists who were blinded to the subjects' genotype and phenotype."

Records the blinded read, which is what makes the MRI findings usable as a diagnostic characterisation rather than a genotype-driven impression.

📊

Prevalence

1

Worldwide, families reported in the literature

Cases In Literature Ultra Rare

No population-based prevalence estimate exists. The literature count is the only occurrence measure available and is a lower bound on true frequency, since PLS3 is not on many first-line fragility-fracture gene panels.

Show evidence (2 references)

PMID:40353206 SUPPORT Human Clinical

"To date, only 47 families have been described with 47 different genetic variants."

Gives the cumulative published family count as of 2025, the basis for the ULTRA_RARE band and for recording this as a literature-case count rather than a rate.

PMID:40353206 SUPPORT Human Clinical

"Our cohort comprises of 28 patients from 11 families, 18 men and 10 women, with a different PLS3 variant in each family."

The largest single reported series, which also shows the near one-variant-per-family allelic heterogeneity of the disease.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from PLS3-Related X-Linked Osteoporosis:

Osteogenesis Imperfecta Type I

Overlapping Features The main clinical mimic: childhood fractures, low bone mineral density, blue sclerae and joint hypermobility occur in both, and PLS3 families have been referred for OI testing. The discriminating tissue finding is mineralization direction - collagen type I defects give hypermineralized matrix, PLS3 gives hypomineralized matrix with prolonged mineralizing lag time.

Show evidence (2 references)

PMID:24616189 SUPPORT Human Clinical

"in contrast to bone fragility caused by mutations in collagen type I encoding genes, there is no hypermineralization of mineralized bone matrix"

The tissue-level discriminator between PLS3 osteoporosis and collagen-related osteogenesis imperfecta.

PMID:24088043 SUPPORT Human Clinical

"in an additional five families (described in less detail) referred for diagnosis or ruling out of osteogenesis imperfecta type I, a rare variant (rs140121121) in PLS3 was found"

Documents that PLS3 families present through the OI diagnostic pathway, which is why the differential matters operationally.

🧫

Experimental Models

1

PLS3-knockdown MC3T3-E1 pre-osteoblast line CELL_LINE

MC3T3-E1 murine pre-osteoblasts stably depleted of PLS3 by lentiviral shRNA, differentiated on polyacrylamide hydrogels spanning the stiffness range from unmineralized to mineralized bone. The system that separates matrix deposition from matrix mineralization and tests rescue with patient alleles.

Publication

PMID:38089885

Pathograph links

Impaired Osteoblast Mechanosensation recapitulates fidelity: moderate PLS3-depleted osteoblasts lose the scaling of cell size and focal-adhesion number and length with substrate stiffness that control cells show, and wild-type but not patient actin-bundling-defective PLS3 restores it.

Limitations: A murine immortalised pre-osteoblast line, not patient-derived cells, and substrate stiffness on a hydrogel is a proxy for the in vivo mineralizing front. Osteocyte mechanosensation, which senses fluid shear rather than substrate stiffness, is not modelled at all.

Readouts

Cell spreading response to substrate stiffness

Cell area and focal-adhesion metrics on 6 kPa versus 100 kPa Matrigel-coated polyacrylamide hydrogels.

Direction: ABOLISHED

Interpretation: Loss of the stiffness response, rather than a shifted setpoint, is what makes this a mechanosensation defect.

Show evidence (1 reference)

PMID:38089885 SUPPORT In Vitro

"we observed that depletion of PLS3 rendered osteoblasts unresponsive to changes in ECM stiffness"

The measurement this readout records.

Rescue of spreading by wild-type versus patient PLS3 alleles

Re-expression of EGFP-tagged wild-type PLS3 or the patient alleles A368D, N446S and L478P in the knockdown background on stiff substrate.

Direction: RESTORED

Interpretation: Rescue by wild-type but not by bundling-defective patient alleles ties the cellular phenotype to the disease-causing molecular lesion.

Show evidence (1 reference)

PMID:38089885 SUPPORT In Vitro

"Defective cell spreading of PLS3 KD cells on stiff substrates could be rescued by expression of wildtype PLS3, but not by expression of three PLS3 mutations that were identified in patients with early onset osteoporosis and that have aberrant actin-bundling activity."

The allele-specific rescue experiment.

Defective Bone Matrix Mineralization recapitulates fidelity: moderate Reproduces the human tissue finding that collagen matrix is deposited normally but is not subsequently mineralized.

Limitations: In vitro alizarin-red mineralization in a murine cell line; no osteoclasts, osteocytes, vasculature or mechanical loading are present.

Readouts

Hydroxyapatite deposition on deposited collagen matrix

Picrosirius red for collagen and alizarin red for mineral over 1-3 weeks of osteogenic differentiation.

Direction: DECREASED

Interpretation: Collagen output is preserved while mineral output collapses, which is the in vitro image of the patient biopsy.

Show evidence (1 reference)

PMID:38089885 SUPPORT In Vitro

"depletion of PLS3 does not alter the first stage of osteoblast mineralization in which a collagen matrix is deposited, but severely affects the subsequent mineralization of that matrix"

The phase-resolved mineralization result.

🐁

Animal Models

3

Pls3-null mouse (cortical-restricted phenotype)

Deep-phenotyped Pls3-deficient mice studied at several ages with undecalcified histology and bone-specific histomorphometry, the analysis missing from earlier micro-CT-only reports. The result is a selectively cortical model.

Species

Mouse

Genotype

Pls3 knockout

Publication

PMID:31678489

Pathograph links

Cortical and Trabecular Bone Deficit partially recapitulates fidelity: moderate Reproduces the cortical-thinning half of the human structural phenotype at every age examined, and nothing else.

Limitations: Trabecular bone mass and every histomorphometric parameter at 12 weeks were indistinguishable from wild-type littermates, whereas severe trabecular and vertebral disease is the dominant human finding. The authors themselves scope the model to cortical bone acquisition.

Readouts

Cortical thickness of tibia and femur

Undecalcified histology and bone histomorphometry across age groups.

Direction: DECREASED

Interpretation: The one structural parameter that tracks the human disease in this model.

Show evidence (1 reference)

PMID:31678489 SUPPORT Model Organism

"Remarkably however, the cortical thickness in both, tibia and femur, was significantly reduced in Pls3-deficient mice in all age groups."

Reports the measurement and its consistency across ages.

Trabecular bone mass

Undecalcified histology with full histomorphometry at 12 weeks.

Direction: UNCHANGED

Interpretation: A genuine negative result: the compartment most affected in patients is unaffected in this model.

Show evidence (1 reference)

PMID:31678489 SUPPORT Model Organism

"Surprisingly, we did not detect significant differences between wildtype and Pls3-deficient littermates with respect to trabecular bone mass, and the same was the case for all histomorphometric parameters determined at 12 weeks of age."

The negative trabecular and histomorphometric result.

Show evidence (1 reference)

PMID:31678489 SUPPORT Model Organism

"Pls3-deficiency in mice only recapitulates the cortical bone phenotype of individuals with X-linked osteoporosis by negatively affecting the early stage of cortical bone acquisition"

The authors' own scoping of what this model does and does not model, which is the basis for PARTIALLY_RECAPITULATES.

Pls3-deficient mouse (bone vascular phenotype)

Male hemizygous Pls3-null mice used in the endosteal single-cell mapping study to ask which cell type Pls3 acts through. The reported phenotype is vascular rather than osteoblast-intrinsic. The same model is curated in the osteoporosis_bone_resorption module against the generic module node; here it is linked to this disease's own vascular node.

Species

Mouse

Genotype

Pls3 hemizygous null (Pls3y/-)

Publication

PMID:42432248

Pathograph links

Endosteal Vascular Niche Dysfunction recapitulates fidelity: moderate Loss of the gene that causes this disease produces abnormal bone vasculature in mice, which is the entire observational basis of the vascular arm.

Limitations: No human study has examined bone vasculature in PLS3 variant carriers, so the translational step is untested; the authors state it as "might result from". Pls3 is expressed in osteoblast lineage cells as well as in the vasculature, so the model does not isolate the vascular contribution. Male hemizygous only, giving no information about heterozygous carriers.

Readouts

Bone blood vessel size

Anti-CD31 immunohistochemistry of mid-femur sections, confirmed by backscattered scanning electron microscopy and micro-CT.

Direction: DECREASED

Interpretation: Smaller bone blood vessels are the structural correlate of the vascular node.

Show evidence (1 reference)

PMID:42432248 SUPPORT Model Organism

"mice showed smaller blood vessels in bone compared to controls (CTRLs) (Fig. 6a), which was confirmed by backscattered scanning electron microscopy (SEM) and micro-CT analysis"

The measurement, across three independent modalities.

Show evidence (1 reference)

PMID:42432248 SUPPORT Model Organism

"These data suggest that X-linked osteoporosis might result from abnormalities in bone vasculature."

Names this disease as the intended target of the inference; the hedged phrasing is why fidelity is MODERATE.

PLS3 E10-16del rat

The only animal model carrying a patient-derived PLS3 allele - a deletion of exons 10-16 matching a reported human large-fragment deletion - rather than a complete gene knockout. Used both to phenotype and to compare antiresorptive with anabolic treatment.

Species

Rat

Genotype

PLS3 E10-16del hemizygous (PLS3E10-16del/0)

Publication

PMID:37083757

Pathograph links

Cortical and Trabecular Bone Deficit partially recapitulates fidelity: moderate Reproduces thinner cortical bone and reduced mechanical strength at three ages.

Limitations: As with the mouse, the deficit is cortical and the bone phenotype is milder than the human disease; the authors attribute the mildness to residual truncated PLS3 protein, since exon 1-9 transcript levels were comparable to wild-type. Vertebral disease, the dominant human feature, is not the reported readout.

Readouts

Femoral cortical thickness and failure loads

Micro-CT and three-point bending at 3, 6 and 9 months.

Direction: DECREASED

Interpretation: Couples the structural deficit to a measured loss of mechanical strength.

Show evidence (1 reference)

PMID:37083757 SUPPORT Model Organism

"we have constructed a novel rat model with clinically relevant hemizygous E10-16del mutation in PLS3 (PLS3E10-16del/0) that recapitulates the osteoporotic phenotypes with obviously thinner cortical thickness"

Reports the structural and biomechanical measurements.

Low-Turnover Bone Remodeling recapitulates fidelity: moderate Reproduces the reduced mineral apposition rate that is the defining histomorphometric abnormality in patients.

Limitations: Histomorphometry in this model was reported for long bone; the human measurements come from transiliac biopsy, so the skeletal site differs.

Readouts

Mineral apposition rate

Dynamic bone histomorphometry.

Direction: DECREASED

Interpretation: The direct animal counterpart of the human low-formation finding.

Show evidence (1 reference)

PMID:37083757 SUPPORT Model Organism

"Histomorphometric analysis indicates a significantly lower mineral apposition rate in PLS3E10-16del/0 rats."

Reports the measurement.

{ }

Source YAML

click to show

name: PLS3-Related X-Linked Osteoporosis
creation_date: "2026-09-02T00:00:00Z"
category: Mendelian
description: >-
  A monogenic, X-linked form of primary early-onset osteoporosis caused by
  loss-of-function variants in PLS3, which encodes the calcium-regulated
  actin-bundling protein plastin 3. Hemizygous males present in childhood with
  low bone mineral density, recurrent peripheral fractures and vertebral
  compression fractures, often progressing to thoracic kyphosis and height loss;
  heterozygous females range from unaffected to overtly osteoporotic. Unlike
  osteogenesis imperfecta, the lesion is not in type I collagen: bone matrix is
  laid down but is hypomineralized, with prolonged mineralizing lag time and low
  bone turnover. Which cell type carries the primary defect is unsettled - the
  osteoblast mineralization/mechanosensing arm, an osteoclast NKRF-NFkB-NFATc1
  arm seen in Pls3-null mice, and an emerging endosteal vascular arm are curated
  here as competing mechanistic hypotheses rather than as one settled chain.
parents:
- Osteoporosis
- Metabolic Bone Disease
disease_term:
  preferred_term: X-linked osteoporosis with fractures
  term:
    id: MONDO:0018315
    label: X-linked osteoporosis with fractures
synonyms:
- X-linked osteoporosis with fractures
- PLS3-related osteoporosis
- X-linked primary osteoporosis
- X-linked early-onset osteoporosis
- plastin 3 deficiency
prevalence:
- population: Worldwide, families reported in the literature
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population-based prevalence estimate exists. The literature count is the
    only occurrence measure available and is a lower bound on true frequency,
    since PLS3 is not on many first-line fragility-fracture gene panels.
  evidence:
  - reference: PMID:40353206
    reference_title: "Phenotypic and genetic characteristics of a Dutch cohort of patients with X-linked osteoporosis due to PLS3 genetic variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: To date, only 47 families have been described with 47 different genetic variants.
    explanation: >-
      Gives the cumulative published family count as of 2025, the basis for the
      ULTRA_RARE band and for recording this as a literature-case count rather
      than a rate.
  - reference: PMID:40353206
    reference_title: "Phenotypic and genetic characteristics of a Dutch cohort of patients with X-linked osteoporosis due to PLS3 genetic variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our cohort comprises of 28 patients from 11 families, 18 men and 10 women,
      with a different PLS3 variant in each family.
    explanation: >-
      The largest single reported series, which also shows the near
      one-variant-per-family allelic heterogeneity of the disease.
inheritance:
- name: X-linked
  description: >-
    X-linked inheritance with a dose-dependent, non-strictly-recessive
    phenotype. Hemizygous males are consistently and more severely affected;
    heterozygous females range from normal bone mineral density through
    osteopenia to overt osteoporosis with fractures, so carrier status is not
    clinically silent. PLS3 is at Xq23.
  inheritance_term:
    preferred_term: X-linked inheritance
    term:
      id: HP:0001417
      label: X-linked inheritance
  expressivity: VARIABLE
  evidence:
  - reference: PMID:25209159
    reference_title: A novel splice mutation in PLS3 causes X-linked early onset low-turnover osteoporosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Osteoporosis had its onset in childhood and was characterized by recurrent
      peripheral fractures, low bone mineral density (BMD), vertebral compression
      fractures, and significant height loss in adulthood. Males were in general
      more severely affected than females.
    explanation: >-
      Establishes both the childhood onset and the male-predominant severity
      gradient that the X-linked assignment rests on, in a large multigenerational
      pedigree.
  - reference: PMID:40353206
    reference_title: "Phenotypic and genetic characteristics of a Dutch cohort of patients with X-linked osteoporosis due to PLS3 genetic variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      had normal BMD, two had osteoporosis and one osteopenia. Moreover, men
      experienced a higher total number of fractures than women (men: 12.0, IQR:
      6.7, 18.5, women: 2.0, IQR: 0.7, 5.2).
    explanation: >-
      Quantifies the sex difference and shows that heterozygous females are
      mostly but not uniformly spared, which is why this is recorded as X-linked
      rather than X-linked recessive.
  - reference: PMID:24088043
    reference_title: PLS3 mutations in X-linked osteoporosis with fractures.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This variant was also associated with a risk of fracture among elderly
      heterozygous women that was two times as high as that among noncarriers
    explanation: >-
      Independent evidence that heterozygosity carries measurable fracture risk,
      supporting a dosage-sensitive rather than fully recessive X-linked model.
genetic:
- name: PLS3 loss-of-function variants
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: PLS3 (plastin 3, T-plastin)
    term:
      id: hgnc:9091
      label: PLS3
  notes: >-
    PLS3 (Xq23) encodes plastin 3, a calcium-regulated F-actin bundling protein
    of the plastin/fimbrin family with two N-terminal EF-hand domains and two
    tandem actin-binding domains. Reported disease alleles span nonsense,
    frameshift, splice, missense and whole- or partial-gene deletions, and each
    reported family typically carries a private variant. Missense alleles cluster
    in the actin-binding domains and have been shown biochemically to disturb
    calcium-sensitive actin bundling. No consistent genotype-phenotype rule has
    been established, although frameshift/nonsense alleles trend toward more
    deviant microarchitecture than missense alleles.
  evidence:
  - reference: PMID:24088043
    reference_title: PLS3 mutations in X-linked osteoporosis with fractures.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Plastin 3 (PLS3), a protein involved in the formation of filamentous actin
      (F-actin) bundles, 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.
    explanation: >-
      The founding gene-disease report, identifying PLS3 as causative in five
      independent X-linked osteoporosis families.
  - reference: PMID:28777485
    reference_title: PLS3 Deletions Lead to Severe Spinal Osteoporosis and Disturbed Bone Matrix Mineralization.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In family 1, the 2 affected brothers had a deletion of exons 4-16
      (NM_005032) in PLS3, inherited from their healthy mother.
    explanation: >-
      Documents whole-exon deletion as a disease mechanism, establishing that
      the allelic spectrum extends beyond point variants to copy-number loss.
  - reference: PMID:40353206
    reference_title: "Phenotypic and genetic characteristics of a Dutch cohort of patients with X-linked osteoporosis due to PLS3 genetic variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No relation was found between types and locations of variants and various
      clinical endpoints in men, using data from our cohort and the literature.
    explanation: >-
      The largest genotype-phenotype analysis to date finds no variant-class rule
      for clinical outcome, which is why no allele-stratified subtypes are curated.
  - reference: PMID:39658012
    reference_title: Bone microarchitecture and strength in men and women with PLS3 gene variants assessed with HR-pQCT.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Men with frameshift/nonsense variants seemed to have more deviant trabecular
      and cortical microarchitecture and strength, at both scan locations, than
      those with missense/in-frame insertion variants.
    explanation: >-
      A hedged imaging-level trend in the opposite direction to the clinical-endpoint
      analysis above; recorded because it is the only reported allele-class signal,
      not because it establishes one.
mechanistic_hypotheses:
- hypothesis_group_id: osteoblast_mineralization_mechanosensing_model
  hypothesis_label: Osteoblast mineralization and mechanosensation defect
  status: CANONICAL
  description: >-
    PLS3 acts in the osteoblast/osteocyte lineage, where actin bundling at focal
    adhesions is required for the cell to sense the stiffening collagen matrix
    and to sustain the second, mineralizing phase of bone formation. Loss of
    PLS3 leaves collagen deposition intact but blocks mineralization, which is
    what patient bone biopsies show. This is the best-supported account and the
    one most directly anchored in human tissue.
- hypothesis_group_id: osteoclast_nkrf_nfatc1_model
  hypothesis_label: Osteoclast NKRF-NFkB-NFATc1 dysregulation
  status: ALTERNATIVE
  description: >-
    In Pls3-null mice the primary lesion is placed in the osteoclast: reduced
    nuclear NKRF de-represses Nfatc1 transcription and augments resorption. This
    predicts a high-resorption disease, which is the opposite of the low-turnover,
    reduced-osteoclast-number picture reported in human PLS3 bone biopsies, so it
    is curated as a competing account rather than as an additional step.
- hypothesis_group_id: endosteal_vascular_niche_model
  hypothesis_label: Endosteal vascular niche contribution
  status: EMERGING
  description: >-
    Cross-species single-cell mapping of the endosteal compartment places Pls3
    among genes expressed in bone endothelial and vascular smooth muscle cells,
    and Pls3-deficient mice have smaller bone blood vessels, with a pls3 zebrafish
    vascular phenotype preceding bone cells. Under this model the vascular lesion
    is upstream of the remodeling defect. Shares its identifier with the group of
    the same name in the osteoporosis_bone_resorption module, whose
    Endosteal Vascular Niche Dysfunction node this entry conforms to.
pathophysiology:
- name: PLS3 Loss of Actin-Bundling Function
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    Loss-of-function variants in PLS3 remove or disable plastin 3, a
    calcium-regulated F-actin bundling protein expressed in osteoblasts,
    osteocytes and osteoclasts and, in bone, also in vascular endothelial and
    smooth muscle cells. Patient-derived missense alleles retain protein but have
    aberrant calcium-sensitive actin-bundling activity, so the shared molecular
    lesion across nonsense, frameshift, deletion and missense alleles is loss of
    F-actin crosslinking rather than loss of the transcript alone.
  genetic_context:
    gene:
      preferred_term: PLS3
      term:
        id: hgnc:9091
        label: PLS3
    variant_origin: GERMLINE
    zygosity: HEMIZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Hemizygous in affected males; heterozygous in females, where the phenotype
      is variable rather than absent.
  molecular_functions:
  - preferred_term: F-actin binding by plastin 3
    term:
      id: GO:0051015
      label: actin filament binding
    modifier: DECREASED
  biological_processes:
  - preferred_term: Actin filament bundling
    term:
      id: GO:0051017
      label: actin filament bundle assembly
    modifier: DECREASED
  evidence:
  - reference: PMID:24088043
    reference_title: PLS3 mutations in X-linked osteoporosis with fractures.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Plastin 3 (PLS3), a protein involved in the formation of filamentous actin
      (F-actin) bundles, 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.
    explanation: >-
      Names the molecular activity of the protein and ties its loss to the human
      bone phenotype, which is the claim this node makes.
  - reference: PMID:38089885
    reference_title: The actin-bundling protein, PLS3, is part of the mechanoresponsive machinery that regulates osteoblast mineralization.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Defective cell spreading of PLS3 KD cells on stiff substrates could be
      rescued by expression of wildtype PLS3, but not by expression of three PLS3
      mutations that were identified in patients with early onset osteoporosis and
      that have aberrant actin-bundling activity.
    explanation: >-
      Rescue with wild-type but not with patient actin-bundling-defective alleles
      is what makes loss of bundling, rather than loss of the protein per se, the
      operative molecular lesion.
  - reference: PMID:37083757
    reference_title: Impaired bone strength and bone microstructure in a novel early-onset osteoporotic rat model with a clinically relevant PLS3 mutation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Immunohistochemical staining of femoral sections also unraveled that PLS3
      was present in osteocytes, osteoblasts, and osteoclasts in cortical and
      trabecular bone of WT rats
    explanation: >-
      Establishes that the protein is present in all three bone cell lineages,
      which is why the downstream arms of this node are curated as competing
      cell-type hypotheses rather than resolved.
  downstream:
  - target: Impaired Osteoblast Mechanosensation
    causal_link_type: DIRECT
    hypothesis_groups:
    - osteoblast_mineralization_mechanosensing_model
    description: >-
      PLS3 localizes to the proximal end of mature focal adhesions where they
      transition into actin stress fibers, so loss of bundling activity is
      directly upstream of the cell's ability to read matrix stiffness.
  - target: Dysregulated Osteoclast NFATc1 Signaling
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - osteoclast_nkrf_nfatc1_model
    description: >-
      Via reduced nuclear translocation of the PLS3 interactor NKRF and
      consequent de-repression of Nfatc1. Demonstrated in mouse osteoclasts only.
  - target: Endosteal Vascular Niche Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - endosteal_vascular_niche_model
    description: >-
      Pls3 is expressed in bone endothelial and vascular smooth muscle cells and
      its loss produces smaller bone blood vessels in mice; the intervening steps
      between actin bundling and vascular patterning are not defined.
- name: Impaired Osteoblast Mechanosensation
  role: amplifier
  biological_scale: CELLULAR
  description: >-
    In osteoblasts, PLS3 concentrates at focal adhesions, the structures through
    which the cell reads the stiffness of the extracellular matrix it is
    building. Osteoblasts depleted of PLS3 no longer scale their spreading or
    focal-adhesion number and length with substrate stiffness, so the
    feed-forward loop in which progressive matrix mineralization stiffens the
    substrate and drives further mineral deposition is broken. The same
    mechanosensory argument has been extended to osteocytes, where PLS3 is
    abundant in dendritic processes, but that step is inference rather than
    measurement in this disease.
  cell_types:
  - preferred_term: Osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  - preferred_term: Osteocyte
    term:
      id: CL:0000137
      label: osteocyte
  biological_processes:
  - preferred_term: Cellular response to matrix stiffness
    term:
      id: GO:0071260
      label: cellular response to mechanical stimulus
    modifier: DECREASED
  evidence:
  - reference: PMID:38089885
    reference_title: The actin-bundling protein, PLS3, is part of the mechanoresponsive machinery that regulates osteoblast mineralization.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we observed that depletion of PLS3 rendered osteoblasts unresponsive to
      changes in ECM stiffness
    explanation: >-
      The direct measurement behind this node: loss of PLS3 abolishes the
      osteoblast's stiffness response.
  - reference: PMID:38089885
    reference_title: The actin-bundling protein, PLS3, is part of the mechanoresponsive machinery that regulates osteoblast mineralization.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      PLS3 prominently localizes to focal adhesions (FAs), which are intricately
      linked to mechanosensation.
    explanation: >-
      Localizes the protein to the structure that carries the mechanosensory
      function, which is what makes this a mechanistic node rather than a
      correlation.
  - reference: PMID:28379384
    reference_title: Osteocyte Protein Expression Is Altered in Low-Turnover Osteoporosis Caused by Mutations in WNT1 and PLS3.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Abnormal osteocyte function may play a role in the pathogenesis of
      monogenetic forms of osteoporosis.
    explanation: >-
      Human iliac-crest immunohistochemistry framing osteocyte dysfunction as
      contributory; marked INDIRECT because the study's own PLS3-specific finding
      is that sclerostin, DMP1 and phospho-beta-catenin did not differ from the
      WNT1 comparison group.
  - reference: PMID:25209159
    reference_title: A novel splice mutation in PLS3 causes X-linked early onset low-turnover osteoporosis.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mechanism whereby PLS3 affects bone health is unclear, but it may be
      linked to osteocyte dendrite function and skeletal mechanosensing.
    explanation: >-
      States the mechanosensing hypothesis explicitly as a hypothesis; quoted here
      so the node records that the osteocyte limb is proposed rather than shown.
  downstream:
  - target: Defective Bone Matrix Mineralization
    causal_link_type: DIRECT
    hypothesis_groups:
    - osteoblast_mineralization_mechanosensing_model
    description: >-
      Failure to respond to increasing matrix stiffness removes the feed-forward
      signal that sustains hydroxyapatite deposition on the already-deposited
      collagen scaffold.
- name: Endosteal Vascular Niche Dysfunction
  role: trigger
  biological_scale: TISSUE
  conforms_to: "osteoporosis_bone_resorption#Endosteal Vascular Niche Dysfunction"
  description: >-
    An emerging arm in which the primary lesion is vascular rather than
    osteoblastic. Cross-species single-cell mapping of the endosteal compartment
    prioritized endothelial cells and vascular smooth muscle cells as
    skeletal-disease-relevant lineages and named Pls3 among the genes expressed
    in them; Pls3-deficient mice have smaller bone blood vessels, and pls3
    knockdown in zebrafish disturbs vascular patterning before bone cells are
    present. No human study has yet examined bone vasculature in PLS3 variant
    carriers.
  cell_types:
  - preferred_term: Bone vascular endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  - preferred_term: Bone vascular smooth muscle cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  locations:
  - preferred_term: endosteum
    term:
      id: UBERON:0009859
      label: endosteum
  - preferred_term: bone blood vessel
    term:
      id: UBERON:0001981
      label: blood vessel
  biological_processes:
  - preferred_term: Skeletal angiogenesis
    term:
      id: GO:0001525
      label: angiogenesis
    modifier: DYSREGULATED
  - preferred_term: Bone blood vessel morphogenesis
    term:
      id: GO:0048514
      label: blood vessel morphogenesis
    modifier: DYSREGULATED
  mechanism_confidence: HYPOTHETICAL
  evidence:
  - reference: PMID:42432248
    reference_title: "Multiscale analysis and functional validation of the cellular and genetic determinants of skeletal disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      mice showed smaller blood vessels in bone compared to controls (CTRLs) (Fig.
      6a), which was confirmed by backscattered scanning electron microscopy (SEM)
      and micro-CT analysis
    explanation: >-
      The structural vascular measurement in Pls3-deficient mice that this node
      rests on, replicated across three imaging modalities.
  - reference: PMID:42432248
    reference_title: "Multiscale analysis and functional validation of the cellular and genetic determinants of skeletal disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These data suggest that X-linked osteoporosis might result from
      abnormalities in bone vasculature.
    explanation: >-
      The authors' own statement of the hypothesis, named for this disease
      specifically. Its hedged phrasing is why mechanism_confidence is
      HYPOTHETICAL and the node sits in an EMERGING hypothesis group.
  - reference: PMID:42432248
    reference_title: "Multiscale analysis and functional validation of the cellular and genetic determinants of skeletal disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Knockdown of pls3 in zebrafish embryos49 resulted in mild cardiac edema and
      defects in intersegmental vessel (ISV) formation, including disconnections
      from the dorsal aorta or posterior cardinal vein, ectopic vessel connections
      and smaller lumens
    explanation: >-
      The zebrafish vascular patterning defect, in a second species and by an
      independent perturbation, that the mouse vessel-calibre measurement alone
      would not establish.
  - reference: PMID:42432248
    reference_title: "Multiscale analysis and functional validation of the cellular and genetic determinants of skeletal disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The absence of bone cells at this developmental stage indicates that pls3
      might act directly to control angiogenesis and vascular patterning.
    explanation: >-
      The temporal-ordering argument this node turns on: the zebrafish vascular
      defect appears before bone cells exist, so the vascular lesion cannot be
      secondary to a bone-cell defect. This is what distinguishes the emerging
      vascular arm from the osteoblast and osteoclast accounts rather than merely
      adding to them.
  - reference: PMID:42432248
    reference_title: "Multiscale analysis and functional validation of the cellular and genetic determinants of skeletal disease."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      This provides a potential explanation for how genes expressed in ECs and
      VSMCs, such as Pls3, Nherf2 and Cbx6, regulate bone.
    explanation: >-
      Places Pls3 among the vascular-expressed skeletal genes and states the
      proposed vascular-to-osteoblast route; the interaction analysis is
      CellPhoneDB-predicted, hence COMPUTATIONAL.
  downstream:
  - target: Defective Bone Matrix Mineralization
    causal_link_type: DIRECT
    hypothesis_groups:
    - endosteal_vascular_niche_model
    description: >-
      Mirrors the module edge from the endosteal vascular node to impaired
      osteoblastic bone formation: endothelial and vascular smooth muscle cells
      are predicted to signal directly to osteoblast lineage cells, so loss of
      that input would blunt the formation arm.
  - target: Low-Turnover Bone Remodeling
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - endosteal_vascular_niche_model
    description: >-
      The module's parallel claim that a niche vascular lesion shifts the
      remodeling balance without an osteoblast- or osteoclast-intrinsic primary
      defect. Intermediates are undefined.
- name: Dysregulated Osteoclast NFATc1 Signaling
  role: amplifier
  biological_scale: CELLULAR
  description: >-
    A competing, mouse-derived arm in which the primary lesion is in the
    osteoclast. PLS3 binds NFkB repressing factor (NKRF); in Pls3-null
    osteoclasts less NKRF reaches the nucleus, Nfatc1 - the master regulator of
    osteoclastogenesis - is de-repressed, and resorption is augmented. The
    reciprocal experiment supports the axis: PLS3-overexpressing mice show
    increased nuclear NKRF, suppressed osteoclast function and thicker, stronger
    cortical bone. This arm is deliberately not conformed to the module's
    RANKL-Driven Osteoclastogenesis node, because human PLS3 bone biopsies show
    the opposite phenotype - reduced osteoclast number and low turnover.
  cell_types:
  - preferred_term: Osteoclast
    term:
      id: CL:0000092
      label: osteoclast
  biological_processes:
  - preferred_term: Osteoclast differentiation
    term:
      id: GO:0030316
      label: osteoclast differentiation
    modifier: INCREASED
  mechanism_confidence: HYPOTHETICAL
  evidence:
  - reference: PMID:30204862
    reference_title: Plastin 3 influences bone homeostasis through regulation of osteoclast activity.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We show that unbalanced PLS3 levels affect osteoclast development and
      function, by misregulating the NFκB pathway.
    explanation: >-
      States the osteoclast-centred claim this node encodes, in the mouse system
      where it was demonstrated.
  - reference: PMID:30204862
    reference_title: Plastin 3 influences bone homeostasis through regulation of osteoclast activity.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We found the opposite in Pls3 knockout osteoclasts, where decreased nuclear
      NKRF augmented Nfatc1 transcription, causing osteoporosis.
    explanation: >-
      Gives the specific NKRF-to-Nfatc1 step and directionality that make this a
      mechanistic arm rather than a general osteoclast observation.
  - reference: PMID:30204862
    reference_title: Plastin 3 influences bone homeostasis through regulation of osteoclast activity.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      while Pls3 knockout mice exhibit osteoporosis, PLS3 overexpressing mice show
      thickening of cortical bone and increased bone strength
    explanation: >-
      The bidirectional dosage experiment; gain and loss of PLS3 move bone mass in
      opposite directions, which is the strongest support for the axis.
  - reference: PMID:24616189
    reference_title: "Osteoporosis caused by mutations in PLS3: clinical and bone tissue characteristics."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Iliac bone histomorphometry in 2 patients showed low trabecular bone volume
      and a low osteoid maturation time but normal bone formation rate and
      osteoclast surface.
    explanation: >-
      Human bone histomorphometry finds normal osteoclast surface, which is what a
      primary osteoclast-activation mechanism predicts against. Recorded as REFUTE
      on this node rather than omitted, because the negative human result is the
      reason this arm is ALTERNATIVE.
  - reference: PMID:31678489
    reference_title: Mice lacking plastin-3 display a specific defect of cortical bone acquisition.
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Surprisingly, we did not detect significant differences between wildtype and
      Pls3-deficient littermates with respect to trabecular bone mass, and the same
      was the case for all histomorphometric parameters determined at 12 weeks of
      age.
    explanation: >-
      An independent Pls3-null mouse line failed to reproduce the trabecular and
      histomorphometric phenotype an osteoclast-driven resorptive mechanism
      predicts, so the two mouse studies disagree with each other as well as with
      the human tissue.
  downstream:
  - target: Cortical and Trabecular Bone Deficit
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - osteoclast_nkrf_nfatc1_model
    description: >-
      Under this model, augmented Nfatc1-driven osteoclast activity removes bone
      faster than it is replaced. Shown in mice; the human low-turnover picture is
      not consistent with it.
- name: Defective Bone Matrix Mineralization
  role: central_effector
  biological_scale: TISSUE
  conforms_to: "osteoporosis_bone_resorption#Impaired Osteoblastic Bone Formation"
  description: >-
    The defining tissue lesion. Osteoblasts deposit a normal collagen matrix but
    fail to mineralize it: patient transiliac biopsies show increased osteoid
    volume and thickness with a prolonged mineralizing lag time, and quantitative
    backscattered electron imaging plus Raman microspectroscopy show frank
    hypomineralization. This is the mirror image of osteogenesis imperfecta,
    where the collagen defect produces hypermineralized matrix, and is the basis
    for separating this entry from the OI group.
  cell_types:
  - preferred_term: Osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  locations:
  - preferred_term: bone tissue
    term:
      id: UBERON:0002481
      label: bone tissue
  biological_processes:
  - preferred_term: Bone mineralization
    term:
      id: GO:0030282
      label: bone mineralization
    modifier: DECREASED
  - preferred_term: Ossification
    term:
      id: GO:0001503
      label: ossification
    modifier: DECREASED
  evidence:
  - reference: PMID:28777485
    reference_title: PLS3 Deletions Lead to Severe Spinal Osteoporosis and Disturbed Bone Matrix Mineralization.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Extensive analyses of a transiliac bone biopsy from 1 patient showed a
      prominent increase in osteoid volume, osteoid thickness, and in mineralizing
      lag time.
    explanation: >-
      The human histomorphometric signature of a mineralization block: osteoid
      accumulates because it is not being mineralized on schedule.
  - reference: PMID:28777485
    reference_title: PLS3 Deletions Lead to Severe Spinal Osteoporosis and Disturbed Bone Matrix Mineralization.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Results from quantitative backscattered electron imaging and Raman
      microspectroscopy showed a significant hypomineralization of the bone.
    explanation: >-
      Two independent physical measurements of mineral content confirming the
      histomorphometric inference.
  - reference: PMID:38089885
    reference_title: The actin-bundling protein, PLS3, is part of the mechanoresponsive machinery that regulates osteoblast mineralization.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      depletion of PLS3 does not alter the first stage of osteoblast mineralization
      in which a collagen matrix is deposited, but severely affects the subsequent
      mineralization of that matrix
    explanation: >-
      Separates the two phases of bone formation and shows the defect is confined
      to the mineralizing phase, which is exactly what the patient biopsies show.
  - reference: PMID:24616189
    reference_title: "Osteoporosis caused by mutations in PLS3: clinical and bone tissue characteristics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      in contrast to bone fragility caused by mutations in collagen type I encoding
      genes, there is no hypermineralization of mineralized bone matrix
    explanation: >-
      The explicit contrast with osteogenesis imperfecta that makes this a distinct
      tissue mechanism rather than a collagen disorder variant.
  - reference: PMID:31678489
    reference_title: Mice lacking plastin-3 display a specific defect of cortical bone acquisition.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We additionally studied the ex vivo behavior of Pls3-deficient primary
      osteoblasts, which displayed moderately impaired mineralization capacity.
    explanation: >-
      Independent replication of the osteoblast mineralization defect in
      primary cells from a Pls3-null mouse.
  downstream:
  - target: Low-Turnover Bone Remodeling
    causal_link_type: DIRECT
    description: >-
      A block at the mineralizing step slows the whole formation limb of the
      remodeling cycle, which is what the reduced mineral apposition rate measures.
  - target: Cortical and Trabecular Bone Deficit
    causal_link_type: DIRECT
    description: >-
      Mirrors the module edge from impaired osteoblastic bone formation to net
      bone loss: matrix that is not mineralized does not carry load.
- name: Low-Turnover Bone Remodeling
  role: effector
  biological_scale: TISSUE
  conforms_to: "osteoporosis_bone_resorption#Bone Remodeling Imbalance"
  description: >-
    Bone remodeling in PLS3-related osteoporosis is slow on both limbs, not
    resorption-dominant. Histomorphometry shows a reduced mineral apposition
    rate, scant osteoid, and reduced osteoblast and osteoclast numbers, while
    serum bone turnover markers are typically normal.
  notes: >-
    Divergence from the module worth recording: the module chain runs
    Bone Remodeling Imbalance -> RANKL-Driven Osteoclastogenesis -> Increased
    Osteoclastic Bone Resorption, whereas here the imbalance is reached with
    normal-to-reduced osteoclast activity. Conformance is declared on the
    imbalance node only, and the RANKL/resorption steps are deliberately not
    instantiated.
  cell_types:
  - preferred_term: Osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  - preferred_term: Osteocyte
    term:
      id: CL:0000137
      label: osteocyte
  - preferred_term: Osteoclast
    term:
      id: CL:0000092
      label: osteoclast
  biological_processes:
  - preferred_term: Bone remodeling
    term:
      id: GO:0046849
      label: bone remodeling
    modifier: DECREASED
  evidence:
  - reference: PMID:25209159
    reference_title: A novel splice mutation in PLS3 causes X-linked early onset low-turnover osteoporosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bone histomorphometry findings in 4 males and 1 female showed severe
      trabecular osteoporosis, low amount of osteoid, and decreased mineral
      apposition rate, indicating impaired bone formation
    explanation: >-
      The primary human measurement of a slow formation limb, in five biopsied
      members of one pedigree.
  - reference: PMID:32655496
    reference_title: PLS3 Mutations Cause Severe Age and Sex-Related Spinal Pathology.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bone tissue is characterized by low bone turnover with reduced osteoblast and
      osteoclast numbers and disturbed matrix mineralization
    explanation: >-
      States the low-turnover, both-limbs-reduced tissue phenotype that
      distinguishes this node from the module's resorption-dominant default.
  - reference: PMID:31968132
    reference_title: "Biomarkers in WNT1 and PLS3 Osteoporosis: Altered Concentrations of DKK1 and FGF23."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Results confirmed normal concentrations of conventional metabolic bone
      markers in both groups.
    explanation: >-
      Normal serum turnover markers alongside severe skeletal disease is the
      clinical correlate of low, balanced turnover, and is why circulating markers
      cannot be used to monitor this disease.
  - reference: PMID:37083757
    reference_title: Impaired bone strength and bone microstructure in a novel early-onset osteoporotic rat model with a clinically relevant PLS3 mutation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Histomorphometric analysis indicates a significantly lower mineral apposition
      rate in PLS3E10-16del/0 rats.
    explanation: >-
      Reproduces the reduced mineral apposition rate in an animal carrying a
      patient-derived deletion allele.
  downstream:
  - target: Cortical and Trabecular Bone Deficit
    causal_link_type: DIRECT
    description: >-
      Sustained low formation against ongoing resorption yields net negative bone
      balance and progressive structural deterioration.
- name: Cortical and Trabecular Bone Deficit
  role: consequence
  biological_scale: TISSUE
  conforms_to: "osteoporosis_bone_resorption#Net Bone Loss and Skeletal Fragility"
  description: >-
    The structural end state, and one with a distinctive geometry. HR-pQCT in
    adults with PLS3 variants shows a large total bone area driven by an enlarged
    trabecular compartment with a small, thin cortex, low volumetric bone mineral
    density in both compartments, fewer and more widely separated trabeculae with
    normal trabecular thickness, and low failure load. Cortical porosity is
    normal, so the cortical deficit is one of thickness rather than of
    intracortical remodeling. Women deviate less from reference data than men.
  locations:
  - preferred_term: compact bone tissue
    term:
      id: UBERON:0001439
      label: compact bone tissue
  - preferred_term: trabecular bone tissue
    term:
      id: UBERON:0002483
      label: trabecular bone tissue
  biological_processes:
  - preferred_term: Bone remodeling
    term:
      id: GO:0046849
      label: bone remodeling
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:39658012
    reference_title: Bone microarchitecture and strength in men and women with PLS3 gene variants assessed with HR-pQCT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In men, total bone area was large (median Z-score: 1.33 radius; 1.46 tibia)
      due to a large trabecular area (+1.73 radius; +1.87 tibia), while the
      cortical area was small (-2.61 radius; -2.84 tibia).
    explanation: >-
      The compartment-resolved geometry of the deficit, which a DXA areal density
      cannot show.
  - reference: PMID:39658012
    reference_title: Bone microarchitecture and strength in men and women with PLS3 gene variants assessed with HR-pQCT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the largest deviations were found in trabecular number (-2.18 radius; -1.64
      tibia), trabecular separation (+2.32 radius; +1.65 tibia), and cortical
      thickness (-2.99 radius; -2.46 tibia), whereas trabecular thickness and
      cortical porosity were normal
    explanation: >-
      Locates the microarchitectural lesion in trabecular number and cortical
      thickness while excluding intracortical porosity, which constrains which
      mechanisms are plausible.
  - reference: PMID:39658012
    reference_title: Bone microarchitecture and strength in men and women with PLS3 gene variants assessed with HR-pQCT.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additionally, failure load was low (-2.39 radius; -2.2 tibia).
    explanation: >-
      Converts the structural findings into a mechanical strength deficit, the
      quantity that actually predicts fracture.
  - reference: PMID:31678489
    reference_title: Mice lacking plastin-3 display a specific defect of cortical bone acquisition.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Remarkably however, the cortical thickness in both, tibia and femur, was
      significantly reduced in Pls3-deficient mice in all age groups.
    explanation: >-
      The cortical-thinning half of this node reproduces in Pls3-null mice at every
      age examined.
  downstream:
  - target: Reduced Bone Mineral Density
    causal_link_type: DIRECT
    description: >-
      Low volumetric density in both compartments is what densitometry measures as
      a low areal bone mineral density Z-score.
  - target: Recurrent Peripheral Fractures
    causal_link_type: DIRECT
    description: >-
      Reduced failure load at the distal radius and tibia is the mechanical basis
      for long-bone fragility fractures under ordinary loading.
  - target: Vertebral Compression Fractures
    causal_link_type: DIRECT
    description: >-
      Loss of trabecular number in the vertebral body, whose strength is
      trabecular-dominated, produces compression fractures from childhood.
phenotypes:
- category: Skeletal
  name: Reduced Bone Mineral Density
  frequency: FREQUENT
  description: >-
    Low areal bone mineral density at the lumbar spine and femoral neck, present
    from childhood in affected males. Most heterozygous females have normal
    densitometry, which is why a normal maternal scan does not exclude carrier
    status. The band is sex-driven rather than uniform: in the 28-patient Dutch
    cohort the 18 men had low lumbar spine and femoral neck Z-scores while only
    3 of 10 women had osteoporosis or osteopenia, so roughly three-quarters of
    variant carriers are affected overall.
  phenotype_term:
    preferred_term: Reduced bone mineral density
    term:
      id: HP:0004349
      label: Reduced bone mineral density
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:24616189
    reference_title: "Osteoporosis caused by mutations in PLS3: clinical and bone tissue characteristics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lumbar spine areal bone mineral density (LS-aBMD) Z-scores ranged from -1.7
      to -3.5, but height was normal.
    explanation: >-
      Quantifies the densitometric deficit in affected boys and records that it is
      not accompanied by short stature.
  - reference: PMID:40353206
    reference_title: "Phenotypic and genetic characteristics of a Dutch cohort of patients with X-linked osteoporosis due to PLS3 genetic variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      had normal BMD, two had osteoporosis and one osteopenia. Moreover, men
      experienced a higher total number of fractures than women (men: 12.0, IQR:
      6.7, 18.5, women: 2.0, IQR: 0.7, 5.2).
    explanation: >-
      Shows that most adult heterozygous women in the largest cohort had normal
      bone mineral density, supporting the sex-dependent penetrance recorded here.
- category: Skeletal
  name: Recurrent Peripheral Fractures
  frequency: VERY_FREQUENT
  description: >-
    Long-bone fragility fractures beginning in early childhood, with a high
    lifetime count in males. Fractures occur with low-energy trauma.
  phenotype_term:
    preferred_term: Recurrent fractures
    term:
      id: HP:0002757
      label: Recurrent fractures
  evidence:
  - reference: PMID:24616189
    reference_title: "Osteoporosis caused by mutations in PLS3: clinical and bone tissue characteristics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      When first evaluated between 4 and 8 years of age, these boys had a history
      of one to four long-bone fractures. Mild vertebral compression fractures were
      identified in each boy.
    explanation: >-
      Documents both the age of onset and the peripheral fracture burden in four
      affected boys from two families.
- category: Skeletal
  name: Vertebral Compression Fractures
  frequency: VERY_FREQUENT
  description: >-
    Compression fractures of the vertebral bodies, present from early childhood
    and most abundant in the upper thoracic spine. Most affected vertebrae are
    biconcave, while the endplates and intervertebral discs are well preserved -
    a pattern that distinguishes the spinal disease from degenerative causes.
  phenotype_term:
    preferred_term: Vertebral compression fracture
    term:
      id: HP:0002953
      label: Vertebral compression fracture
    clinical_course: PROGRESSIVE
  sequelae:
  - target: Thoracic Kyphosis
    description: >-
      Accumulated anterior wedging and mid-vertebral height loss across the
      thoracic spine produce a fixed kyphotic deformity and height loss.
  evidence:
  - reference: PMID:28777485
    reference_title: PLS3 Deletions Lead to Severe Spinal Osteoporosis and Disturbed Bone Matrix Mineralization.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The 3 patients presented in early childhood with severe spinal compression
      fractures involving all vertebral bodies.
    explanation: >-
      The most severe reported presentation, in boys carrying PLS3 deletions,
      establishing pan-vertebral involvement in childhood.
  - reference: PMID:32655496
    reference_title: PLS3 Mutations Cause Severe Age and Sex-Related Spinal Pathology.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Compromised PLS3 function introduces severe and progressive changes to
      spinal structures that are present already in childhood, in both sexes and
      most abundant in upper thoracic spine.
    explanation: >-
      Blinded spinal MRI in 15 variant-positive versus 13 variant-negative family
      members, giving the level distribution and confirming involvement in both
      sexes.
- category: Skeletal
  name: Thoracic Kyphosis
  frequency: FREQUENT
  description: >-
    Increased thoracic curvature following accumulated vertebral compression,
    accompanied in adults by significant height loss.
  phenotype_term:
    preferred_term: Thoracic kyphosis
    term:
      id: HP:0002942
      label: Thoracic kyphosis
  evidence:
  - reference: PMID:25209159
    reference_title: A novel splice mutation in PLS3 causes X-linked early onset low-turnover osteoporosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Osteoporosis had its onset in childhood and was characterized by recurrent
      peripheral fractures, low bone mineral density (BMD), vertebral compression
      fractures, and significant height loss in adulthood. Males were in general
      more severely affected than females.
    explanation: >-
      Records the adult height loss that is the clinical expression of accumulated
      thoracic vertebral collapse in this pedigree.
- category: Connective tissue
  name: Blue Sclerae
  frequency: FREQUENT
  description: >-
    Mild blue discoloration of the sclerae, reported in about a third of both men
    and women in the largest cohort. Its presence overlaps the osteogenesis
    imperfecta phenotype and is a recognised source of diagnostic confusion, since
    PLS3 has no direct role in type I collagen synthesis.
  phenotype_term:
    preferred_term: Blue sclerae
    term:
      id: HP:0000592
      label: Blue sclerae
  evidence:
  - reference: PMID:40353206
    reference_title: "Phenotypic and genetic characteristics of a Dutch cohort of patients with X-linked osteoporosis due to PLS3 genetic variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Extra-skeletal characteristics such as (mild) blue discoloration of the
      sclerae (men: 33.3%, women: 30.0%), joint hypermobility (44.4%, 70.0%) and
      skin hyperlaxity (50.0%, 20.0%) were observed.
    explanation: >-
      Gives sex-stratified frequencies for the extra-skeletal features in the
      28-patient cohort.
- category: Musculoskeletal
  name: Joint Hypermobility
  frequency: FREQUENT
  description: >-
    Generalised joint hypermobility, reported more often in women than men in the
    largest cohort.
  phenotype_term:
    preferred_term: Joint hypermobility
    term:
      id: HP:0001382
      label: Joint hypermobility
  evidence:
  - reference: PMID:40353206
    reference_title: "Phenotypic and genetic characteristics of a Dutch cohort of patients with X-linked osteoporosis due to PLS3 genetic variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Extra-skeletal characteristics such as (mild) blue discoloration of the
      sclerae (men: 33.3%, women: 30.0%), joint hypermobility (44.4%, 70.0%) and
      skin hyperlaxity (50.0%, 20.0%) were observed.
    explanation: >-
      Source of the reported frequency, in the same cohort assessment as the other
      extra-skeletal features.
- category: Integumentary
  name: Skin Hyperlaxity
  frequency: FREQUENT
  description: >-
    Hyperextensible skin, reported in half the men and a fifth of the women in the
    largest cohort. The mechanism is unexplained, since PLS3 is not part of the
    collagen biosynthetic pathway.
  phenotype_term:
    preferred_term: Hyperextensible skin
    term:
      id: HP:0000974
      label: Hyperextensible skin
  evidence:
  - reference: PMID:40353206
    reference_title: "Phenotypic and genetic characteristics of a Dutch cohort of patients with X-linked osteoporosis due to PLS3 genetic variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Extra-skeletal characteristics such as (mild) blue discoloration of the
      sclerae (men: 33.3%, women: 30.0%), joint hypermobility (44.4%, 70.0%) and
      skin hyperlaxity (50.0%, 20.0%) were observed.
    explanation: >-
      Source of the reported frequency for skin hyperlaxity in the 28-patient
      cohort.
biochemical:
- name: Serum dickkopf-1 (DKK1)
  presence: Elevated
  notes: >-
    Circulating DKK1, a secreted WNT antagonist, is significantly elevated in
    PLS3 variant carriers relative both to healthy family members and to WNT1
    osteoporosis patients. It is the only reported biochemical abnormality that
    is specific to this disease, and it is mechanistically interesting because it
    implies a link from an actin-bundling protein to WNT pathway inhibition. It is
    not a validated diagnostic assay.
  evidence:
  - reference: PMID:31968132
    reference_title: "Biomarkers in WNT1 and PLS3 Osteoporosis: Altered Concentrations of DKK1 and FGF23."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DKK1 concentrations were significantly elevated in PLS3 mutation-positive
      subjects compared with WNT1 mutation-positive subjects
    explanation: >-
      Establishes the elevation and, by contrasting with the WNT1 group, that it is
      not a generic feature of monogenic osteoporosis.
  - reference: PMID:31968132
    reference_title: "Biomarkers in WNT1 and PLS3 Osteoporosis: Altered Concentrations of DKK1 and FGF23."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both intact and C-terminal FGF23 were significantly elevated in WNT1
      mutation-positive subjects (p = .039 and p = .027, respectively) and normal
      in PLS3 subjects.
    explanation: >-
      The reciprocal negative result: FGF23 separates WNT1 from PLS3 osteoporosis,
      so the two monogenic forms have distinguishable biochemical signatures.
- name: Conventional serum bone turnover markers
  presence: Normal
  notes: >-
    Standard formation and resorption markers are normal despite severe skeletal
    disease, which is consistent with the low, balanced turnover seen on
    histomorphometry. Clinically this means routine bone biochemistry cannot be
    used to screen for or monitor the disease.
  evidence:
  - reference: PMID:31968132
    reference_title: "Biomarkers in WNT1 and PLS3 Osteoporosis: Altered Concentrations of DKK1 and FGF23."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Results confirmed normal concentrations of conventional metabolic bone
      markers in both groups.
    explanation: >-
      Direct measurement of the conventional marker panel in 14 PLS3 variant
      carriers against 34 variant-negative relatives.
  - reference: PMID:28379384
    reference_title: Osteocyte Protein Expression Is Altered in Low-Turnover Osteoporosis Caused by Mutations in WNT1 and PLS3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DMP1, sclerostin, and phospho-β-catenin expression did not differ between
      groups.
    explanation: >-
      Tissue-level counterpart: the osteocyte regulatory proteins most often
      proposed as mechanistic mediators were not differentially expressed in PLS3
      bone relative to the WNT1 comparison group.
treatments:
- name: Bisphosphonate Therapy
  description: >-
    Oral alendronate or intravenous zoledronic acid, the mainstay of treatment.
    Both raise bone mineral density and zoledronic acid has been reported to
    reshape already-compressed vertebral bodies in a growing child. Note the
    mechanistic mismatch: bisphosphonates suppress resorption, but the underlying
    lesion here is a formation and mineralization defect with low turnover, so
    the density gain does not follow from correcting the mechanism. No trial has
    tested fracture reduction in this disease.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: alendronate
      term:
        id: CHEBI:2567
        label: alendronic acid
    - preferred_term: zoledronic acid
      term:
        id: CHEBI:46557
        label: zoledronic acid
  target_mechanisms:
  - target: Cortical and Trabecular Bone Deficit
    description: >-
      Antiresorptive therapy acts on the structural end state by slowing further
      loss, not on the upstream mineralization defect.
    evidence:
    - reference: PMID:24616189
      reference_title: "Osteoporosis caused by mutations in PLS3: clinical and bone tissue characteristics."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The 2 boys from family 1 received oral alendronate for 6 years, which
        normalized LS-aBMD.
      explanation: >-
        Densitometric normalisation under long-term oral alendronate in two
        affected boys; the outcome measured is bone mineral density, not fracture.
  evidence:
  - reference: PMID:28620780
    reference_title: A novel large fragment deletion in PLS3 causes rare X-linked early-onset osteoporosis and response to zoledronic acid.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Zoledronic acid treatment could significantly increase the Z-score of BMD and
      reshape the compressed vertebral bodies.
    explanation: >-
      Single-patient report of the intravenous option, including vertebral
      reshaping, which is the outcome that matters most in childhood spinal disease.
  - reference: PMID:40353206
    reference_title: "Phenotypic and genetic characteristics of a Dutch cohort of patients with X-linked osteoporosis due to PLS3 genetic variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Adult men demonstrated a 16.6% mean increase in the BMD of the lumbar spine
      (p = .03)
    explanation: >-
      Cohort-level confirmation of the densitometric response, in adult men mostly
      treated with oral bisphosphonates.
  - reference: PMID:37083757
    reference_title: Impaired bone strength and bone microstructure in a novel early-onset osteoporotic rat model with a clinically relevant PLS3 mutation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Treatment with alendronate (1.0 µg/kg/day) or teriparatide (40 µg/kg five
      times weekly) for 8 weeks significantly improves bone mass and bone
      microarchitecture, and bone strength is significantly increased after
      teriparatide treatment
    explanation: >-
      Controlled comparison in a rat carrying a patient-derived PLS3 deletion;
      both agents improve mass and microarchitecture, but only teriparatide
      significantly improved strength.
- name: Teriparatide
  description: >-
    Recombinant PTH(1-34), an anabolic agent, given off-label. A 24-month
    uncontrolled pilot in adults with WNT1 or PLS3 variants showed rises in
    formation and resorption markers and gains at the lumbar spine and femoral
    neck. Two cautions are recorded on the evidence itself: distal radius
    cortical volumetric density fell in the same study, and the histomorphometric
    osteoid response was less consistent in the PLS3 patients than in the WNT1
    patients - which is what a primary mineralization defect would predict.
  therapeutic_modality: PEPTIDE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: teriparatide
      term:
        id: NCIT:C61966
        label: Teriparatide
  target_mechanisms:
  - target: Low-Turnover Bone Remodeling
    description: >-
      An anabolic agent is the mechanistically motivated choice against a
      low-formation, low-turnover lesion, in contrast to antiresorptives.
    evidence:
    - reference: PMID:27732335
      reference_title: "Teriparatide Treatment in Patients With WNT1 or PLS3 Mutation-Related Early-Onset Osteoporosis: A Pilot Study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All patients showed increases in formation markers procollagen type 1
        amino-terminal propeptide (90% to 398%) and osteocalcin (50% to 280%)
      explanation: >-
        Direct evidence that the drug lifts the suppressed formation limb, which
        is the mechanism this link asserts.
  evidence:
  - reference: PMID:27732335
    reference_title: "Teriparatide Treatment in Patients With WNT1 or PLS3 Mutation-Related Early-Onset Osteoporosis: A Pilot Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lumbar spine BMD increased 5.2% to 7.9% in 5 patients and femoral neck BMD
      2.6% to 7.8% in 4 patients in 24 months.
    explanation: >-
      The primary densitometric result of the pilot study, in six adults of whom
      three carried the PLS3 c.73-24T>A splice variant.
  - reference: PMID:27732335
    reference_title: "Teriparatide Treatment in Patients With WNT1 or PLS3 Mutation-Related Early-Onset Osteoporosis: A Pilot Study."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Distal radius cortical volumetric BMD decreased 5.4% to 26.1%.
    explanation: >-
      A site-discordant loss at the cortical radius in the same study, quoted as a
      REFUTE item because it argues against an unqualified benefit claim - and the
      cortex is the compartment most affected in this disease.
  - reference: PMID:27732335
    reference_title: "Teriparatide Treatment in Patients With WNT1 or PLS3 Mutation-Related Early-Onset Osteoporosis: A Pilot Study."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In histomorphometric analyses, osteoid indices increased more consistently in
      patients with WNT1 vs PLS3 mutation.
    explanation: >-
      Genotype-differential tissue response; supports treating PLS3 osteoporosis as
      mechanistically distinct from WNT1 osteoporosis rather than as one
      monogenic-osteoporosis treatment class.
animal_models:
- name: Pls3-null mouse (cortical-restricted phenotype)
  species: Mouse
  genotype: Pls3 knockout
  publication: PMID:31678489
  description: >-
    Deep-phenotyped Pls3-deficient mice studied at several ages with undecalcified
    histology and bone-specific histomorphometry, the analysis missing from earlier
    micro-CT-only reports. The result is a selectively cortical model.
  modeled_mechanisms:
  - target: Cortical and Trabecular Bone Deficit
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the cortical-thinning half of the human structural phenotype at
      every age examined, and nothing else.
    limitations: >-
      Trabecular bone mass and every histomorphometric parameter at 12 weeks were
      indistinguishable from wild-type littermates, whereas severe trabecular and
      vertebral disease is the dominant human finding. The authors themselves scope
      the model to cortical bone acquisition.
    readouts:
    - name: Cortical thickness of tibia and femur
      target: Cortical and Trabecular Bone Deficit
      description: Undecalcified histology and bone histomorphometry across age groups.
      direction: DECREASED
      interpretation: >-
        The one structural parameter that tracks the human disease in this model.
      evidence:
      - reference: PMID:31678489
        reference_title: Mice lacking plastin-3 display a specific defect of cortical bone acquisition.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Remarkably however, the cortical thickness in both, tibia and femur, was
          significantly reduced in Pls3-deficient mice in all age groups.
        explanation: Reports the measurement and its consistency across ages.
    - name: Trabecular bone mass
      target: Cortical and Trabecular Bone Deficit
      description: Undecalcified histology with full histomorphometry at 12 weeks.
      direction: UNCHANGED
      interpretation: >-
        A genuine negative result: the compartment most affected in patients is
        unaffected in this model.
      evidence:
      - reference: PMID:31678489
        reference_title: Mice lacking plastin-3 display a specific defect of cortical bone acquisition.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Surprisingly, we did not detect significant differences between wildtype
          and Pls3-deficient littermates with respect to trabecular bone mass, and
          the same was the case for all histomorphometric parameters determined at
          12 weeks of age.
        explanation: The negative trabecular and histomorphometric result.
    evidence:
    - reference: PMID:31678489
      reference_title: Mice lacking plastin-3 display a specific defect of cortical bone acquisition.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Pls3-deficiency in mice only recapitulates the cortical bone phenotype of
        individuals with X-linked osteoporosis by negatively affecting the early
        stage of cortical bone acquisition
      explanation: >-
        The authors' own scoping of what this model does and does not model, which
        is the basis for PARTIALLY_RECAPITULATES.
- name: Pls3-deficient mouse (bone vascular phenotype)
  species: Mouse
  genotype: Pls3 hemizygous null (Pls3y/-)
  publication: PMID:42432248
  description: >-
    Male hemizygous Pls3-null mice used in the endosteal single-cell mapping study
    to ask which cell type Pls3 acts through. The reported phenotype is vascular
    rather than osteoblast-intrinsic. The same model is curated in the
    osteoporosis_bone_resorption module against the generic module node; here it is
    linked to this disease's own vascular node.
  modeled_mechanisms:
  - target: Endosteal Vascular Niche Dysfunction
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Loss of the gene that causes this disease produces abnormal bone vasculature
      in mice, which is the entire observational basis of the vascular arm.
    limitations: >-
      No human study has examined bone vasculature in PLS3 variant carriers, so the
      translational step is untested; the authors state it as "might result from".
      Pls3 is expressed in osteoblast lineage cells as well as in the vasculature,
      so the model does not isolate the vascular contribution. Male hemizygous only,
      giving no information about heterozygous carriers.
    readouts:
    - name: Bone blood vessel size
      target: Endosteal Vascular Niche Dysfunction
      description: >-
        Anti-CD31 immunohistochemistry of mid-femur sections, confirmed by
        backscattered scanning electron microscopy and micro-CT.
      direction: DECREASED
      interpretation: >-
        Smaller bone blood vessels are the structural correlate of the vascular node.
      evidence:
      - reference: PMID:42432248
        reference_title: "Multiscale analysis and functional validation of the cellular and genetic determinants of skeletal disease."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          mice showed smaller blood vessels in bone compared to controls (CTRLs)
          (Fig. 6a), which was confirmed by backscattered scanning electron
          microscopy (SEM) and micro-CT analysis
        explanation: The measurement, across three independent modalities.
    evidence:
    - reference: PMID:42432248
      reference_title: "Multiscale analysis and functional validation of the cellular and genetic determinants of skeletal disease."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These data suggest that X-linked osteoporosis might result from
        abnormalities in bone vasculature.
      explanation: >-
        Names this disease as the intended target of the inference; the hedged
        phrasing is why fidelity is MODERATE.
- name: PLS3 E10-16del rat
  species: Rat
  genotype: PLS3 E10-16del hemizygous (PLS3E10-16del/0)
  publication: PMID:37083757
  description: >-
    The only animal model carrying a patient-derived PLS3 allele - a deletion of
    exons 10-16 matching a reported human large-fragment deletion - rather than a
    complete gene knockout. Used both to phenotype and to compare antiresorptive
    with anabolic treatment.
  modeled_mechanisms:
  - target: Cortical and Trabecular Bone Deficit
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces thinner cortical bone and reduced mechanical strength at three
      ages.
    limitations: >-
      As with the mouse, the deficit is cortical and the bone phenotype is milder
      than the human disease; the authors attribute the mildness to residual
      truncated PLS3 protein, since exon 1-9 transcript levels were comparable to
      wild-type. Vertebral disease, the dominant human feature, is not the reported
      readout.
    readouts:
    - name: Femoral cortical thickness and failure loads
      target: Cortical and Trabecular Bone Deficit
      description: Micro-CT and three-point bending at 3, 6 and 9 months.
      direction: DECREASED
      interpretation: >-
        Couples the structural deficit to a measured loss of mechanical strength.
      evidence:
      - reference: PMID:37083757
        reference_title: Impaired bone strength and bone microstructure in a novel early-onset osteoporotic rat model with a clinically relevant PLS3 mutation.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          we have constructed a novel rat model with clinically relevant hemizygous
          E10-16del mutation in PLS3 (PLS3E10-16del/0) that recapitulates the
          osteoporotic phenotypes with obviously thinner cortical thickness
        explanation: Reports the structural and biomechanical measurements.
  - target: Low-Turnover Bone Remodeling
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the reduced mineral apposition rate that is the defining
      histomorphometric abnormality in patients.
    limitations: >-
      Histomorphometry in this model was reported for long bone; the human
      measurements come from transiliac biopsy, so the skeletal site differs.
    readouts:
    - name: Mineral apposition rate
      target: Low-Turnover Bone Remodeling
      description: Dynamic bone histomorphometry.
      direction: DECREASED
      interpretation: >-
        The direct animal counterpart of the human low-formation finding.
      evidence:
      - reference: PMID:37083757
        reference_title: Impaired bone strength and bone microstructure in a novel early-onset osteoporotic rat model with a clinically relevant PLS3 mutation.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Histomorphometric analysis indicates a significantly lower mineral
          apposition rate in PLS3E10-16del/0 rats.
        explanation: Reports the measurement.
experimental_models:
- name: PLS3-knockdown MC3T3-E1 pre-osteoblast line
  experimental_model_type: CELL_LINE
  publication: PMID:38089885
  description: >-
    MC3T3-E1 murine pre-osteoblasts stably depleted of PLS3 by lentiviral shRNA,
    differentiated on polyacrylamide hydrogels spanning the stiffness range from
    unmineralized to mineralized bone. The system that separates matrix deposition
    from matrix mineralization and tests rescue with patient alleles.
  cell_types:
  - preferred_term: Pre-osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  modeled_mechanisms:
  - target: Impaired Osteoblast Mechanosensation
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      PLS3-depleted osteoblasts lose the scaling of cell size and focal-adhesion
      number and length with substrate stiffness that control cells show, and
      wild-type but not patient actin-bundling-defective PLS3 restores it.
    limitations: >-
      A murine immortalised pre-osteoblast line, not patient-derived cells, and
      substrate stiffness on a hydrogel is a proxy for the in vivo mineralizing
      front. Osteocyte mechanosensation, which senses fluid shear rather than
      substrate stiffness, is not modelled at all.
    readouts:
    - name: Cell spreading response to substrate stiffness
      target: Impaired Osteoblast Mechanosensation
      description: >-
        Cell area and focal-adhesion metrics on 6 kPa versus 100 kPa
        Matrigel-coated polyacrylamide hydrogels.
      direction: ABOLISHED
      interpretation: >-
        Loss of the stiffness response, rather than a shifted setpoint, is what
        makes this a mechanosensation defect.
      evidence:
      - reference: PMID:38089885
        reference_title: The actin-bundling protein, PLS3, is part of the mechanoresponsive machinery that regulates osteoblast mineralization.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          we observed that depletion of PLS3 rendered osteoblasts unresponsive to
          changes in ECM stiffness
        explanation: The measurement this readout records.
    - name: Rescue of spreading by wild-type versus patient PLS3 alleles
      target: Impaired Osteoblast Mechanosensation
      description: >-
        Re-expression of EGFP-tagged wild-type PLS3 or the patient alleles A368D,
        N446S and L478P in the knockdown background on stiff substrate.
      direction: RESTORED
      interpretation: >-
        Rescue by wild-type but not by bundling-defective patient alleles ties the
        cellular phenotype to the disease-causing molecular lesion.
      evidence:
      - reference: PMID:38089885
        reference_title: The actin-bundling protein, PLS3, is part of the mechanoresponsive machinery that regulates osteoblast mineralization.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Defective cell spreading of PLS3 KD cells on stiff substrates could be
          rescued by expression of wildtype PLS3, but not by expression of three
          PLS3 mutations that were identified in patients with early onset
          osteoporosis and that have aberrant actin-bundling activity.
        explanation: The allele-specific rescue experiment.
  - target: Defective Bone Matrix Mineralization
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the human tissue finding that collagen matrix is deposited
      normally but is not subsequently mineralized.
    limitations: >-
      In vitro alizarin-red mineralization in a murine cell line; no osteoclasts,
      osteocytes, vasculature or mechanical loading are present.
    readouts:
    - name: Hydroxyapatite deposition on deposited collagen matrix
      target: Defective Bone Matrix Mineralization
      description: >-
        Picrosirius red for collagen and alizarin red for mineral over 1-3 weeks of
        osteogenic differentiation.
      direction: DECREASED
      interpretation: >-
        Collagen output is preserved while mineral output collapses, which is the
        in vitro image of the patient biopsy.
      evidence:
      - reference: PMID:38089885
        reference_title: The actin-bundling protein, PLS3, is part of the mechanoresponsive machinery that regulates osteoblast mineralization.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          depletion of PLS3 does not alter the first stage of osteoblast
          mineralization in which a collagen matrix is deposited, but severely
          affects the subsequent mineralization of that matrix
        explanation: The phase-resolved mineralization result.
diagnosis:
- name: Molecular Genetic Testing
  description: >-
    Diagnosis is established by identifying a hemizygous or heterozygous PLS3
    variant, in practice through a next-generation sequencing panel aimed at
    osteogenesis imperfecta and other monogenic bone disease rather than through
    a PLS3-directed test. Because PLS3 is absent from many first-line
    fragility-fracture panels, families are typically ascertained on the OI
    diagnostic pathway and reach the PLS3 diagnosis only once collagen genes
    return negative. Sequence analysis alone is not sufficient: partial and
    whole-gene PLS3 deletions are an established cause, so a panel without
    exon-level copy-number calling can return negative in an affected boy.
  diagnosis_term:
    preferred_term: next-generation sequencing panel for monogenic bone disease
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  results: Hemizygous (males) or heterozygous (females) PLS3 variant
  evidence:
  - reference: PMID:40353206
    reference_title: "Phenotypic and genetic characteristics of a Dutch cohort of patients with X-linked osteoporosis due to PLS3 genetic variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic analysis was performed, in most of the patients, through next
      generation sequencing (NGS), followed by analysis of variants implicated in
      OI and other monogenic bone diseases.
    explanation: >-
      Establishes the testing modality actually used to diagnose the largest
      reported cohort, and that PLS3 is reached through an OI-oriented panel.
  - reference: PMID:24088043
    reference_title: PLS3 mutations in X-linked osteoporosis with fractures.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      in an additional five families (described in less detail) referred for
      diagnosis or ruling out of osteogenesis imperfecta type I, a rare variant
      (rs140121121) in PLS3 was found
    explanation: >-
      Documents the referral route: these families entered testing as suspected
      osteogenesis imperfecta, which is why the diagnosis depends on PLS3 being
      present on the panel that is ordered.
  - reference: PMID:28777485
    reference_title: PLS3 Deletions Lead to Severe Spinal Osteoporosis and Disturbed Bone Matrix Mineralization.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we describe for the first time PLS3 deletions as the underlying cause
      for childhood-onset primary osteoporosis in 3 boys from 2 families.
    explanation: >-
      Establishes gene deletion as a disease-causing allele class, which is why
      a sequencing-only panel is an incomplete test for this gene.
- name: Bone Densitometry
  description: >-
    Dual-energy X-ray absorptiometry of the lumbar spine and femoral neck,
    reported as age- and sex-adjusted Z-scores, is the primary quantitative
    measure and the basis for monitoring. A normal scan does not exclude the
    diagnosis in a female carrier, and axial DXA can miss the appendicular
    cortical deficit that peripheral quantitative CT detects.
  diagnosis_term:
    preferred_term: dual-energy X-ray absorptiometry of lumbar spine and femoral neck
    term:
      id: NCIT:C48789
      label: Dual X-ray Absorptiometry
  results: Low lumbar spine and femoral neck areal BMD Z-scores in affected males
  evidence:
  - reference: PMID:40353206
    reference_title: "Phenotypic and genetic characteristics of a Dutch cohort of patients with X-linked osteoporosis due to PLS3 genetic variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      BMD measurements by DXA were for most of the patients performed using GE
      Lunar Prodigy Advance equipment (H8950AN enCORE, Version 17 SP4); Z-scores
      were calculated using equipment-specific and age- and sex adjusted
      reference data
    explanation: >-
      Specifies DXA as the densitometric modality and age- and sex-adjusted
      Z-scores as the reported metric in the largest cohort.
  - reference: PMID:24616189
    reference_title: "Osteoporosis caused by mutations in PLS3: clinical and bone tissue characteristics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, one of these mothers had low bone mass at the distal radius, as
      measured by peripheral quantitative computed tomography (pQCT).
    explanation: >-
      Shows that a carrier with unremarkable axial densitometry can still have a
      detectable peripheral cortical deficit, which is the limitation of relying
      on DXA alone to assess carriers.
- name: Transiliac Bone Biopsy with Histomorphometry
  description: >-
    Tetracycline-labelled transiliac biopsy resolves the tissue-level lesion and
    is the investigation that separates this disease from osteogenesis
    imperfecta. It shows accumulated unmineralized osteoid with a prolonged
    mineralizing lag time on a low-turnover background - the opposite
    mineralization direction to collagen type I defects.
  diagnosis_term:
    preferred_term: transiliac bone biopsy with tetracycline labelling
    term:
      id: NCIT:C15189
      label: Biopsy Procedure
  results: >-
    Increased osteoid volume and thickness, prolonged mineralizing lag time, low
    trabecular bone volume, normal-to-reduced osteoclast surface
  evidence:
  - reference: PMID:28777485
    reference_title: PLS3 Deletions Lead to Severe Spinal Osteoporosis and Disturbed Bone Matrix Mineralization.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Extensive analyses of a transiliac bone biopsy from 1 patient showed a
      prominent increase in osteoid volume, osteoid thickness, and in mineralizing
      lag time.
    explanation: >-
      The mineralization-defect signature that the biopsy is performed to
      demonstrate.
  - reference: PMID:24616189
    reference_title: "Osteoporosis caused by mutations in PLS3: clinical and bone tissue characteristics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Iliac bone histomorphometry in 2 patients showed low trabecular bone volume
      and a low osteoid maturation time but normal bone formation rate and
      osteoclast surface.
    explanation: >-
      Records the normal osteoclast surface, which is the histomorphometric
      finding that argues against a resorption-driven mechanism.
- name: Spinal Magnetic Resonance Imaging
  description: >-
    Spinal MRI detects the vertebral compression burden, which is present in both
    sexes from childhood and is systematically under-recognised because carriers
    are often asymptomatic. In the one systematic series the readers were blinded
    to genotype, so the reported findings are not the product of expectation.
  diagnosis_term:
    preferred_term: magnetic resonance imaging of the spine
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  results: Biconcave vertebral compression fractures, most abundant in upper thoracic spine
  evidence:
  - reference: PMID:32655496
    reference_title: PLS3 Mutations Cause Severe Age and Sex-Related Spinal Pathology.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we set out to evaluate their spinal pathology using magnetic resonance
      imaging (MRI)
    explanation: Establishes spinal MRI as the modality used to assess the vertebral disease.
  - reference: PMID:32655496
    reference_title: PLS3 Mutations Cause Severe Age and Sex-Related Spinal Pathology.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The MRIs were first independently assessed for spinal changes by an
      orthopedic surgeon and three experienced radiologists who were blinded to
      the subjects' genotype and phenotype.
    explanation: >-
      Records the blinded read, which is what makes the MRI findings usable as a
      diagnostic characterisation rather than a genotype-driven impression.
differential_diagnoses:
- name: Osteogenesis Imperfecta Type I
  description: >-
    The main clinical mimic: childhood fractures, low bone mineral density, blue
    sclerae and joint hypermobility occur in both, and PLS3 families have been
    referred for OI testing. The discriminating tissue finding is mineralization
    direction - collagen type I defects give hypermineralized matrix, PLS3 gives
    hypomineralized matrix with prolonged mineralizing lag time.
  evidence:
  - reference: PMID:24616189
    reference_title: "Osteoporosis caused by mutations in PLS3: clinical and bone tissue characteristics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      in contrast to bone fragility caused by mutations in collagen type I encoding
      genes, there is no hypermineralization of mineralized bone matrix
    explanation: >-
      The tissue-level discriminator between PLS3 osteoporosis and collagen-related
      osteogenesis imperfecta.
  - reference: PMID:24088043
    reference_title: PLS3 mutations in X-linked osteoporosis with fractures.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      in an additional five families (described in less detail) referred for
      diagnosis or ruling out of osteogenesis imperfecta type I, a rare variant
      (rs140121121) in PLS3 was found
    explanation: >-
      Documents that PLS3 families present through the OI diagnostic pathway, which
      is why the differential matters operationally.
- name: WNT1-Related Early-Onset Osteoporosis
  description: >-
    The other monogenic low-turnover early-onset osteoporosis, and the comparison
    group in most PLS3 biomarker and treatment studies. Distinguished
    biochemically - FGF23 is elevated in WNT1 and normal in PLS3, DKK1 the reverse
    - and by inheritance pattern.
  evidence:
  - reference: PMID:31968132
    reference_title: "Biomarkers in WNT1 and PLS3 Osteoporosis: Altered Concentrations of DKK1 and FGF23."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both intact and C-terminal FGF23 were significantly elevated in WNT1
      mutation-positive subjects (p = .039 and p = .027, respectively) and normal
      in PLS3 subjects.
    explanation: >-
      The biochemical discriminator between the two monogenic early-onset
      osteoporoses.
discussions:
- discussion_id: pls3_primary_cell_type
  kind: KNOWLEDGE_GAP
  prompt: >-
    Which bone cell type carries the primary lesion in PLS3-related osteoporosis -
    the osteoblast, the osteocyte, the osteoclast, or the endosteal vascular cell?
  attaches_to:
  - pathophysiology#PLS3 Loss of Actin-Bundling Function
  - pathophysiology#Impaired Osteoblast Mechanosensation
  - pathophysiology#Dysregulated Osteoclast NFATc1 Signaling
  - pathophysiology#Endosteal Vascular Niche Dysfunction
  rationale: >-
    PLS3 is expressed in osteoblasts, osteocytes and osteoclasts, and in bone
    endothelial and vascular smooth muscle cells, so expression cannot adjudicate.
    Each candidate arm has a study behind it and none has a conditional knockout.
    The four arms make different predictions - an osteoclast-primary mechanism
    predicts high turnover, which human biopsies contradict; an osteocyte-primary
    mechanism predicts altered sclerostin or DMP1, which the one human
    immunohistochemistry study did not find; the vascular arm predicts a bone
    vascular abnormality that has never been looked for in a patient. The
    resolving experiment is cell-type-conditional deletion, which has not been
    published for any lineage.
  proposed_experiments:
  - experiment_id: pls3_conditional_knockouts
    name: Lineage-restricted conditional Pls3 deletion series
    description: >-
      Generate osteoblast (Col1a1-Cre or Osx-Cre), osteocyte (Dmp1-Cre),
      osteoclast (Ctsk-Cre or LysM-Cre) and endothelial (Cdh5-CreERT2)
      conditional Pls3 knockouts on one background, phenotyped with the same
      undecalcified histology, dynamic histomorphometry, micro-CT and CD31 bone
      vascular imaging.
    decision_criterion: >-
      An arm is supported if its conditional deletion reproduces reduced mineral
      apposition rate and cortical thinning at a magnitude comparable to the
      germline null, and refuted if that lineage's deletion is
      indistinguishable from wild-type.
    would_support:
    - pathophysiology#Impaired Osteoblast Mechanosensation
    - pathophysiology#Endosteal Vascular Niche Dysfunction
    would_refute:
    - pathophysiology#Dysregulated Osteoclast NFATc1 Signaling
    supporting_outcome:
    - >-
        Osteoblast- or osteocyte-restricted deletion reproduces the low mineral
        apposition rate and cortical deficit; endothelial deletion reproduces the
        small-vessel phenotype and a bone deficit.
    refuting_outcome:
    - >-
        Only osteoclast-restricted deletion produces a bone phenotype, and it is
        resorption-dominant, which would overturn the low-turnover model built from
        human biopsies.
  evidence:
  - reference: PMID:32655496
    reference_title: PLS3 Mutations Cause Severe Age and Sex-Related Spinal Pathology.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the exact pathomechanisms of impaired PLS3 function in bone are still unknown
    explanation: >-
      Explicit statement from the field that the mechanism is unresolved, which is
      the gap this discussion records.
  - reference: PMID:37083757
    reference_title: Impaired bone strength and bone microstructure in a novel early-onset osteoporotic rat model with a clinically relevant PLS3 mutation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Immunohistochemical staining of femoral sections also unraveled that PLS3 was
      present in osteocytes, osteoblasts, and osteoclasts in cortical and
      trabecular bone of WT rats
    explanation: >-
      Shows that expression pattern cannot narrow the candidate cell types, which
      is why a conditional-deletion series rather than more expression work is
      proposed.
- discussion_id: pls3_mouse_human_mismatch
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Do the available Pls3 animal models reproduce human PLS3 osteoporosis well
    enough to support mechanistic inference, given that they are cortical-selective
    while the human disease is dominated by trabecular and vertebral collapse?
  attaches_to:
  - animal_models#Pls3-null mouse (cortical-restricted phenotype)
  - animal_models#PLS3 E10-16del rat
  - pathophysiology#Cortical and Trabecular Bone Deficit
  rationale: >-
    Deep-phenotyped Pls3-null mice show reduced cortical thickness at every age but
    no trabecular bone loss and no histomorphometric abnormality at 12 weeks; the
    patient-allele rat is likewise cortical and explicitly milder than the human
    disease. Patients, by contrast, present with severe vertebral compression from
    early childhood, and HR-pQCT finds the largest deviations in trabecular number
    and separation as well as cortical thickness. Two Pls3-null mouse studies also
    disagree with each other on osteoclasts. This is not a general caveat about
    mouse models: it means that the compartment where the human disease does its
    damage is the one the models do not reproduce, so any mechanism inferred from
    a mouse trabecular readout - including the osteoclast NFATc1 arm - is not
    anchored in the human phenotype.
  proposed_experiments:
  - experiment_id: pls3_vertebral_phenotyping
    name: Vertebral and site-matched phenotyping of Pls3 models
    description: >-
      Phenotype the vertebral bodies, not only long bones, in the Pls3-null mouse
      and the PLS3 E10-16del rat, using micro-CT trabecular morphometry and dynamic
      histomorphometry at the same skeletal site sampled in human transiliac and
      vertebral studies, with sex as an explicit variable.
    decision_criterion: >-
      Model fidelity is supported if vertebral trabecular number and mineral
      apposition rate are reduced in the models, and the mismatch stands if
      vertebral bone is spared as long bone trabecular bone was.
    would_support:
    - pathophysiology#Cortical and Trabecular Bone Deficit
    would_refute:
    - pathophysiology#Dysregulated Osteoclast NFATc1 Signaling
    supporting_outcome:
    - >-
        Vertebral trabecular deficits appear in both models, making them usable for
        mechanistic inference about the human spinal disease.
    refuting_outcome:
    - >-
        Vertebral bone is spared in both models, confining them to cortical bone
        acquisition and leaving the dominant human lesion without an animal model.
  evidence:
  - reference: PMID:31678489
    reference_title: Mice lacking plastin-3 display a specific defect of cortical bone acquisition.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Pls3-deficiency in mice only recapitulates the cortical bone phenotype of
      individuals with X-linked osteoporosis by negatively affecting the early
      stage of cortical bone acquisition
    explanation: >-
      The authors' own statement of the scope limit that this mismatch records.
  - reference: PMID:28777485
    reference_title: PLS3 Deletions Lead to Severe Spinal Osteoporosis and Disturbed Bone Matrix Mineralization.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The 3 patients presented in early childhood with severe spinal compression
      fractures involving all vertebral bodies.
    explanation: >-
      The human phenotype the models do not reproduce, stated at its most severe.
- discussion_id: pls3_bone_vasculature_in_humans
  kind: KNOWLEDGE_GAP
  prompt: >-
    Is bone vasculature abnormal in humans carrying PLS3 loss-of-function variants,
    as it is in Pls3-deficient mice?
  attaches_to:
  - pathophysiology#Endosteal Vascular Niche Dysfunction
  - mechanistic_hypotheses#endosteal_vascular_niche_model
  rationale: >-
    The entire vascular arm rests on mouse and zebrafish observations plus a
    computationally predicted endothelial-to-osteoblast interaction. Transiliac
    bone biopsy is already part of the diagnostic workup in this disease, so
    vascular assessment could be added to material that is being collected anyway
    rather than requiring a new invasive procedure. Until it is done, the arm
    stays EMERGING and no human-anchored causal claim can be made from it.
  proposed_experiments:
  - experiment_id: pls3_human_bone_vascular_imaging
    name: Bone vascular assessment in PLS3 variant carriers
    description: >-
      Assess vessel density and calibre by CD31 immunohistochemistry on archived
      and prospectively collected transiliac biopsies from PLS3 variant carriers
      against age- and sex-matched controls, with dynamic contrast-enhanced MRI of
      marrow perfusion as a non-invasive comparator.
    decision_criterion: >-
      The vascular arm is supported if vessel calibre or density is reduced
      relative to matched controls, and weakened if bone vasculature is
      indistinguishable while the mineralization defect is present in the same
      biopsy.
    would_support:
    - pathophysiology#Endosteal Vascular Niche Dysfunction
    would_refute:
    - mechanistic_hypotheses#endosteal_vascular_niche_model
    supporting_outcome:
    - >-
        Reduced bone vessel calibre or density in carriers, matching the murine
        finding.
    refuting_outcome:
    - >-
        Normal bone vasculature alongside the expected osteoid and mineralization
        abnormalities, confining the vascular phenotype to the mouse.
  evidence:
  - reference: PMID:42432248
    reference_title: "Multiscale analysis and functional validation of the cellular and genetic determinants of skeletal disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These data suggest that X-linked osteoporosis might result from abnormalities
      in bone vasculature.
    explanation: >-
      The hypothesis, stated by its authors in hedged form, that this gap proposes
      to test in humans.
- discussion_id: pls3_antiresorptive_mechanism_mismatch
  kind: OPEN_QUESTION
  prompt: >-
    Why do antiresorptives raise bone mineral density in a disease whose tissue
    lesion is a formation and mineralization defect with low turnover, and do they
    reduce fractures?
  attaches_to:
  - treatments#Bisphosphonate Therapy
  - pathophysiology#Low-Turnover Bone Remodeling
  rationale: >-
    Bisphosphonates are first-line here and reliably raise densitometric measures,
    yet they suppress a resorption limb that histomorphometry shows is already
    low. Densitometric gain under an antiresorptive can reflect secondary
    mineralization of retained matrix rather than restored bone formation, which in
    a disease of defective mineralization is not obviously the same as improved
    strength. No study has reported fracture outcomes, and the one anabolic trial
    reported a cortical volumetric density loss at the radius. The question is
    practical, not academic: it determines whether antiresorptive or anabolic
    therapy should be first-line.
  evidence:
  - reference: PMID:37083757
    reference_title: Impaired bone strength and bone microstructure in a novel early-onset osteoporotic rat model with a clinically relevant PLS3 mutation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Treatment with alendronate (1.0 µg/kg/day) or teriparatide (40 µg/kg five
      times weekly) for 8 weeks significantly improves bone mass and bone
      microarchitecture, and bone strength is significantly increased after
      teriparatide treatment
    explanation: >-
      The only head-to-head comparison in a PLS3 model, and it separates mass from
      strength: both agents improved mass and microarchitecture, only the anabolic
      significantly improved strength.
  - reference: PMID:27732335
    reference_title: "Teriparatide Treatment in Patients With WNT1 or PLS3 Mutation-Related Early-Onset Osteoporosis: A Pilot Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Future studies are needed to evaluate whether observed changes translate to
      fracture resistance.
    explanation: >-
      The pilot study's own statement that densitometric response has not been
      shown to translate into fracture reduction, which is the core of this
      question.
notes: >-
  Ontology and scope notes.

  MONDO:0018315 "X-linked osteoporosis with fractures" carries Orphanet:391330,
  MedGen and UMLS cross-references but, as of this curation, no OMIM cross-reference
  and no gene association in MONDO, so the PLS3 link is asserted here from the
  primary literature rather than inherited from the ontology. The corresponding OMIM
  entity is bone mineral density quantitative trait locus 18 (BMND18); PLS3 itself is
  OMIM 300131.

  Relation to the osteoporosis_bone_resorption module. Three nodes declare
  conformance: Defective Bone Matrix Mineralization to Impaired Osteoblastic Bone
  Formation, Low-Turnover Bone Remodeling to Bone Remodeling Imbalance, and Cortical
  and Trabecular Bone Deficit to Net Bone Loss and Skeletal Fragility. The module's
  RANKL-Driven Osteoclastogenesis and Increased Osteoclastic Bone Resorption steps
  are deliberately not instantiated, because this disease reaches remodeling
  imbalance through a low-formation route with normal-to-reduced osteoclast activity.
  This entry is the first disorder conformer to the module's EMERGING
  Endosteal Vascular Niche Dysfunction node, which was added from Chai et al. 2026
  (PMID:42432248) - the same paper whose Pls3 mouse motivates the vascular arm here.

  Not curated. Sequence-level variant records are omitted: reported families almost
  all carry private alleles and the largest genotype-phenotype analysis found no
  variant-class rule, so a variant list would be a catalogue rather than a mechanism.
  Autism spectrum disorder has been reported in PLS3 carriers but the association has
  not been systematically studied and is not curated as a phenotype.

📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Address review round 1: frequency bands, diagnosis section, deep-research artifact · 2026-09-05T12:04:23Z · View source

Responded to the CHANGES_REQUESTED review on PR #10632. (1) Corrected three phenotype frequency bands that contradicted their own snippets: Blue Sclerae and Skin Hyperlaxity moved OCCASIONAL -> FREQUENT, and Reduced Bone Mineral Density moved VERY_FREQUENT -> FREQUENT, since the Dutch cohort gives 18/18 men plus 3/10 women affected (~75%), inside the 30-79% band rather than 80-99%. (2) Added a diagnosis: section with four entries - molecular genetic testing (NCIT:C19770), bone densitometry (NCIT:C48789), transiliac bone biopsy with histomorphometry (NCIT:C15189), and spinal MRI (NCIT:C16809) - modelling the diagnostic pathway the entry previously described only in prose across differential_diagnoses, discussions, prevalence.notes and pathophysiology. All snippets came from references already cached; no new PMIDs were needed. (3) Generated the missing deep-research artifact with a real Falcon/Edison run: 11/11 references verified, 0.0 confabulation rate, 16/16 ontology terms resolved. Its independent Diagnostics section corroborates all four curated diagnosis entries and additionally motivated recording exon-level copy-number analysis, sourced to the cached PLS3-deletion paper. Also took three reviewer suggestions: added the zebrafish evidence carrying the temporal-ordering argument (vascular defect precedes bone cells) that the endosteal vascular niche node turned on but never cited, and made the HUMAN_MODEL_MISMATCH attaches_to name the two specific animal models instead of the ambiguous species key. Declined two suggestions with reasons: DiseaseMappings has no orphanet_mappings slot so the ORPHA:391330 cross-reference stays in notes, and the ISDS classification could not be sourced - the cached 2023 nosology full text does not list PLS3. Merged origin/main to clear conflicts in two derived term-cache CSVs. Validation: schema passed, 89/89 snippets verified, terms passed, and check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-qualifier-terms, check-folded-hyphens, check-snippet-length, check-title-snippets, check-snippet-grading and the cache contracts all clean.

Falcon ▸

PLS3-Related X-Linked Osteoporosis: Disease-Characteristics Research Report

Edison Scientific Literature 21 citations 2026-09-05T12:00:28.367656

PLS3-Related X-Linked Osteoporosis: Disease-Characteristics Research Report

Executive summary

PLS3-related X-linked osteoporosis is a rare, usually childhood-onset Mendelian bone-fragility disorder caused principally by germline loss-of-function variants in PLS3, which encodes the calcium-regulated F-actin-bundling protein plastin-3/T-plastin. Hemizygous males typically develop very low bone mineral density (BMD), recurrent low-trauma long-bone fractures, and vertebral compression fractures; heterozygous females range from clinically unaffected to early-onset or postmenopausal osteoporosis. Unlike classical collagen-related osteogenesis imperfecta (OI), blue sclerae, dentinogenesis imperfecta, and generalized joint hypermobility are usually absent. The best-supported mechanism is a multicellular defect in cytoskeletal organization, mechanosensing, and mineralization involving osteoblasts and osteocytes, with an additional—but not independently sufficient—osteoclast phenotype. No curative or PLS3-specific therapy exists; treatment evidence consists mainly of small uncontrolled series using bisphosphonates or teriparatide.

The following table provides a compact curation summary; the narrative sections provide qualification and evidence details.

Domain	Curated finding	Evidence type/strength	Suggested ontology terms
Identity and inheritance	Rare Mendelian skeletal-fragility disorder caused by germline PLS3 variants; X-linked inheritance produces predominantly severe disease in hemizygous males and variable expression in heterozygous females. The 2024 series comprised five families and ten mutation-positive individuals; all five index cases were male. (costa2024pls3mutationsin pages 2-4, costa2024pls3mutationsin pages 1-2)	Strong human familial segregation evidence; landmark and replicated family studies	HP:0000939 osteoporosis; X-linked inheritance; Mendelian disease
Causal gene and protein	PLS3 encodes plastin-3/T-plastin, a calcium-sensitive F-actin-binding and actin-bundling protein. Pathogenic alleles include nonsense, frameshift, splice, exon-level, and whole-gene deletions; loss of function is the principal established mechanism, although function-altering missense variants occur. (dijk2013pls3mutationsin pages 6-6, costa2024pls3mutationsin pages 11-12, chin2023theactinbundlingprotein pages 1-2)	Strong human genetic evidence plus cellular and animal functional evidence	PLS3; plastin-3; GO: actin filament binding; actin filament bundle assembly; calcium-ion-dependent protein regulation
Core phenotypes	Recurrent low-trauma peripheral/long-bone fractures, vertebral compression fractures, low BMD, bone pain, and sometimes kyphosis, scoliosis, or thoracic deformity. Lumbar-spine BMD Z-scores can be extremely low—approximately −5 in a severely affected child. Classic collagen-related OI findings such as blue sclerae, dentinogenesis imperfecta, and generalized joint hyperlaxity are often absent, although occasional extraskeletal findings are reported. (costa2024pls3mutationsin pages 11-12, costa2024pls3mutationsin pages 1-2)	Strong recurring phenotype across small human cohorts; exact frequencies remain uncertain	HP:0000939 osteoporosis; HP:0002757 recurrent fractures; HP:0002953 vertebral compression fractures; HP:0004349 reduced bone mineral density
Onset and course	Usually chronic, lifelong, childhood-onset bone fragility. In the five-family 2024 cohort, first clinical fracture occurred from 1.5–13 years. Fractures may accumulate through childhood and adulthood; severity and female-carrier manifestations are variable. (costa2024pls3mutationsin pages 11-12, costa2024pls3mutationsin pages 1-2)	Moderate-to-strong human natural-history evidence from case series; no large prospective cohort	Childhood onset; progressive bone fragility; variable expressivity
Histopathology and material properties	Iliac-crest biopsies show low-turnover osteoporosis, markedly reduced trabecular volume and bone formation/resorption; one series reported about 80% less osteoblast-covered and 90% less osteoclast-covered trabecular surface. Increased matrix mineralization/hypermineralization can occur. (balasubramanian2018novelpls3variants pages 11-14, balasubramanian2018novelpls3variants pages 1-5)	Direct human biopsy evidence, but very small samples	Low bone turnover; reduced trabecular bone volume; abnormal bone mineralization
Mechanism	PLS3 dysfunction impairs F-actin bundling and focal-adhesion responses to extracellular-matrix stiffness, leading to defective osteoblast mechanosensing and matrix mineralization. Altered osteocyte signaling and osteoclast podosome/NF-κB–NFATC1 regulation may contribute. Osteoclast-specific knockout increases resorption in vitro but does not cause osteoporosis in vivo, indicating that osteoclast dysfunction alone is insufficient and that disease is multicellular. (neugebauer2018plastin3influences pages 3-4, chin2023theactinbundlingprotein pages 1-2, maus2024osteoclastspecificplastin3 pages 1-2)	Strong mechanistic evidence in cells and animals; the complete human causal pathway remains partly inferred	GO: actin cytoskeleton organization; mechanosensory behavior; focal-adhesion organization; biomineral tissue development; bone remodeling; Wnt signaling
Anatomy, cells, and compartments	Primary involvement is generalized cortical and trabecular bone, especially vertebral bodies and long bones. Relevant cells are osteoblasts, osteocytes, and osteoclasts. Relevant subcellular sites include F-actin bundles, focal adhesions, osteocyte dendritic processes, osteoclast podosomes/sealing zones, cytoplasm, and plasma-membrane-associated adhesion structures. (neugebauer2018plastin3influences pages 3-4, chin2023theactinbundlingprotein pages 1-2, maus2024osteoclastspecificplastin3 pages 1-2)	Human imaging/biopsy supported by cellular localization and animal models	UBERON: bone; skeleton; vertebral column; long bone; CL: osteoblast; osteocyte; osteoclast; GO: actin cytoskeleton; focal adhesion; podosome
Diagnostics	Suspect in unexplained childhood or young-adult osteoporosis, recurrent low-trauma fractures, vertebral compression, very low BMD, or an X-linked pedigree. Evaluation includes fracture/family history, DXA, lateral spine imaging or vertebral-fracture assessment, skeletal radiographs, and laboratory exclusion of secondary causes. Confirm with a bone-fragility multigene panel including PLS3, or exome/genome sequencing with copy-number analysis; test and clinically assess relatives. Bone biopsy is optional when turnover or mineralization defects remain unclear. (balasubramanian2018novelpls3variants pages 11-14, balasubramanian2018novelpls3variants pages 1-5, costa2024pls3mutationsin pages 1-2)	Expert diagnostic synthesis plus human case-series evidence; no disease-specific consensus criteria	Genetic testing; DXA; radiography; vertebral-fracture assessment; cascade testing
Treatment	No PLS3-specific approved therapy or curative treatment exists. Calcium/vitamin-D sufficiency, fracture care, pain management, physiotherapy, and specialist-guided anti-osteoporosis therapy are used. In 2024, four patients treated with pamidronate or zoledronate showed lumbar-spine BMD improvement and vertebral reshaping over 10 months–2 years. One adult receiving teriparatide plus calcium/vitamin D had femoral-neck and total-hip BMD gains of 2.4% and 4.1% at 10 months, without new fractures or reported adverse events. Evidence remains uncontrolled, and prolonged bisphosphonate exposure requires caution. No registered disease-specific interventional trial was found. (costa2024pls3mutationsin pages 2-4, costa2024pls3mutationsin pages 1-2)	Very low-to-low certainty: case reports/series and animal treatment studies; no disease-specific randomized trial	NCIT: bisphosphonate therapy; pamidronate; zoledronic acid; teriparatide therapy; calcium supplementation; vitamin D supplementation; physical therapy
Prevention	The genotype cannot presently be prevented after conception. Secondary/tertiary prevention includes early molecular diagnosis, family cascade testing, adequate calcium/vitamin D, safe weight-bearing activity, fall and high-impact-trauma reduction, avoidance of smoking/excess alcohol and unnecessary bone-toxic drugs, surveillance for silent vertebral fractures, and timely therapy. Genetic counseling may include prenatal or preimplantation testing after identification of a familial pathogenic variant.	General bone-health and genetic-counseling practice; little PLS3-specific comparative evidence	Genetic counseling; cascade screening; fracture prevention; fall prevention; prenatal genetic testing
Epidemiology	Disease-specific prevalence, incidence, carrier frequency, and population sex ratio are unknown; reported families are geographically diverse and the disorder is probably substantially underdiagnosed. No validated founder effect or population-specific enrichment is established. (dijk2013pls3mutationsin pages 6-6, costa2024pls3mutationsin pages 1-2)	Sparse ascertainment-based family literature; no population registry estimate	Rare disease; orphan disease; epidemiology unknown
Models	Zebrafish: pls3 knockdown causes craniofacial/axial skeletal abnormalities rescued by human PLS3 mRNA or ACTN1/ACTN4. Mouse: ubiquitous loss causes cortical/trabecular osteoporosis, whereas osteoclast-specific loss does not; Pls3 deficiency particularly impairs cortical acquisition. Rat: patient-relevant PLS3 E10–16 deletion causes reduced cortical thickness, mineral apposition and bone strength; alendronate and teriparatide improve microarchitecture, with teriparatide improving strength. Cells: PLS3-depleted MC3T3-E1 osteoblasts fail to adapt to matrix stiffness and mineralize normally; MLO-Y4 RNA-seq found 259 upregulated and 368 downregulated transcripts with Wnt/Th17-associated enrichment. (dijk2013pls3mutationsin pages 6-6, hu2023impairedbonestrength pages 7-8, chin2023theactinbundlingprotein pages 1-2, maus2024osteoclastspecificplastin3 pages 1-2, n2024functionalinsightsin pages 10-12)	Strong cross-model functional support; model-specific differences limit direct clinical translation	Danio rerio; Mus musculus; Rattus norvegicus; osteoblast cell model; osteocyte-like cell model; knockout; knockdown; rescue model

Table: Compact disease-knowledge table integrating human clinical findings, mechanisms, diagnostics, management, and model evidence for PLS3-related X-linked osteoporosis. It highlights quantitative cohort data and explicitly identifies major evidence gaps.

1. Disease information

Definition and nomenclature

The disease is a monogenic primary osteoporosis characterized by reduced bone mass and bone strength, vertebral and peripheral fractures, and onset commonly during childhood. The landmark report identified pathogenic PLS3 variants in five families with X-linked osteoporosis; zebrafish rescue experiments supplied initial functional support. The same study also associated a rare PLS3 allele with approximately twofold higher fracture risk in elderly heterozygous women, suggesting that PLS3 variation can influence both monogenic and complex osteoporosis. (dijk2013pls3mutationsin pages 6-6)

Preferred name: PLS3-related X-linked osteoporosis.

Synonyms:

X-linked osteoporosis with fractures
PLS3-related osteoporosis
Plastin-3 deficiency/PLS3 deficiency
X-linked early-onset osteoporosis
PLS3-related bone fragility
PLS3-related X-linked osteogenesis imperfecta or X-linked OI—used by some authors, although many affected individuals lack classic OI extraskeletal features
Idiopathic juvenile osteoporosis, when used as the historical presenting diagnosis rather than a molecularly specific synonym (balasubramanian2018novelpls3variants pages 1-5)

Identifiers

OMIM phenotype: Osteoporosis, X-linked, OMIM 300910; PLS3 gene: OMIM 300131. These identifiers should be version-checked before automated ingestion.
MONDO: a distinct PLS3/X-linked osteoporosis concept may be represented through OMIM cross-references, but a stable disease-specific MONDO identifier could not be verified from the retrieved primary literature. Do not assign one automatically without checking the current MONDO release.
Orphanet: no verified disease-specific ORPHA number was recovered.
MeSH: no dedicated PLS3-disease heading; use broader headings such as Osteoporosis, Osteoporosis, Juvenile, Fractures, Bone, and Genetic Diseases, X-Linked.
ICD-10/ICD-11: no PLS3-specific code. Coding generally falls under osteoporosis with/without pathological fracture or a genetic skeletal disorder; the exact code depends on age, fracture status, and local coding rules.

The evidence is predominantly aggregated disease-level literature assembled from deeply phenotyped individual families, not population EHR data. The 2024 series comprised five families and ten variant-positive individuals from Sweden, Greece, Germany, and Portugal. (costa2024pls3mutationsin pages 2-4, costa2024pls3mutationsin pages 1-2)

2. Etiology, risk, protective factors, and environment

Causal factor

The primary cause is a germline pathogenic PLS3 variant on Xq23. Most well-supported alleles abolish or markedly impair protein function: nonsense, frameshift, canonical splice, exon-level deletion, multi-exon deletion, and whole-gene deletion variants have been reported. Pathogenic or candidate function-altering missense alleles also occur. The 2024 cohort contained three stop-gain variants and two partial/whole-gene deletions; four of five family variants were maternally inherited. (costa2024pls3mutationsin pages 11-12, costa2024pls3mutationsin pages 1-2)

Genetic risk and modifiers

Hemizygosity is the major severity determinant: males have only one PLS3 allele and generally show earlier, more severe disease.
Female risk is variable, plausibly reflecting X-inactivation/escape, age, hormonal state, and background skeletal risk; affected females can nevertheless be severe. In one childhood cohort, a girl with a de novo missense variant had multiple long-bone and vertebral fractures and BMD Z-score −6.6 at age six. (balasubramanian2018novelpls3variants pages 1-5)
A severely affected eight-year-old with near-generalized vertebral compression and lumbar-spine Z-score about −5 also carried an LRP5 variant of uncertain significance. This raises—but does not prove—a modifying or digenic effect. (costa2024pls3mutationsin pages 11-12)
No validated protective PLS3 allele, modifier gene, polygenic score, founder mutation, or population-specific susceptibility locus has been established.

Environmental and lifestyle factors

No infectious, toxic, radiation, pollution, or occupational cause is known. Calcium or vitamin-D deficiency, undernutrition, immobility, smoking, excess alcohol, glucocorticoids, and other bone-toxic medicines may compound skeletal fragility, but this is extrapolated from general osteoporosis rather than demonstrated PLS3-specific gene–environment interaction. Secondary causes—including celiac disease, inflammatory bowel disease, eating disorders, and calcium/vitamin-D deficiency—should be excluded because they can mimic or worsen the phenotype. (balasubramanian2018novelpls3variants pages 11-14)

Adequate calcium/vitamin D and safe mechanical loading are biologically reasonable protective measures, but neither prevents the genetic lesion nor has a quantified PLS3-specific effect. In one family report, correction of hypovitaminosis D coincided with short-term BMD improvement, but the uncontrolled observation cannot establish disease modification. (brlek2021xlinkedosteogenesisimperfecta pages 10-11)

3. Phenotypes

Core skeletal phenotype

Phenotype	Characterization	Suggested HPO term
Osteoporosis	Usually generalized, severe, and early onset; variable among females	Osteoporosis, HP:0000939
Reduced BMD	Lumbar spine is consistently affected; reported Z-scores extend to approximately −5 or lower in severe children	Reduced bone mineral density, HP:0004349
Recurrent fractures	Low-trauma peripheral and long-bone fractures, including radius, ulna, humerus, femur, tibia, metacarpals, and hip	Recurrent fractures, HP:0002757; Pathologic fracture, HP:0002756
Vertebral compression	Multiple thoracic/lumbar compression or wedge fractures; may be clinically silent or cause pain and deformity	Vertebral compression fracture, HP:0002953
Back/bone pain	Often associated with vertebral injury and accumulated fractures	Bone pain, HP:0002653; Back pain, HP:0003418
Kyphosis/scoliosis/thoracic deformity	Secondary to vertebral collapse or severe skeletal fragility; not universal	Kyphosis, HP:0002808; Scoliosis, HP:0002650; Pectus excavatum, HP:0000767
Abnormal bone microarchitecture	Reduced trabecular volume, cortical thinning, and hypermineralized matrix in selected biopsies/models	Abnormality of bone structure, HP:0011842

In the 2024 five-family study, all index patients were hemizygous males with long-bone and vertebral compression fractures and low lumbar-spine BMD; first clinical fracture occurred at 1.5–13 years. One eight-year-old had eight low-energy fractures, vertebral wedging, and lumbar-spine Z-score −1.6; a different severe child had compression of almost every vertebral body and Z-score near −5. (costa2024pls3mutationsin pages 11-12, costa2024pls3mutationsin pages 2-4, costa2024pls3mutationsin pages 1-2)

Human biopsy evidence supports a predominantly low-turnover phenotype. In a small series, trabecular volume was markedly reduced, while osteoblast-covered and osteoclast-covered trabecular surfaces were approximately 80% and 90% lower, respectively; cortical and trabecular matrix was hypermineralized. (balasubramanian2018novelpls3variants pages 11-14)

Variable or occasional findings

Pectus deformity, pes planus, broad/short digits, syndactyly, kyphoscoliosis, poor jaw trabeculation, facial or palate abnormalities, and joint symptoms have been reported, but their disease specificity and frequencies are unclear. Autism in one patient and occasional patellar subluxation in another should not presently be treated as core PLS3 phenotypes. (brlek2021xlinkedosteogenesisimperfecta pages 10-11, balasubramanian2018novelpls3variants pages 1-5, costa2024pls3mutationsin pages 2-4)

Blue sclerae, dentinogenesis imperfecta, hearing loss, and generalized joint hyperlaxity are usually absent, helping distinguish this condition from classical COL1A1/COL1A2-related OI, although isolated reports mean they are not absolute exclusions. (brlek2021xlinkedosteogenesisimperfecta pages 10-11, costa2024pls3mutationsin pages 1-2)

Quality of life

No validated PLS3-specific EQ-5D, SF-36, PROMIS, or disease-specific quality-of-life dataset was found. Recurrent fractures, pain, spinal deformity, surgery, mobility restriction, and fear of injury are expected to impair school/work participation and physical functioning, but disease-specific effect sizes are unavailable.

4. Genetic and molecular information

Causal gene: PLS3 (plastin 3/T-plastin), Xq23; HGNC symbol PLS3. The protein contains calcium-regulatory EF-hand regions and two actin-binding domains. It bundles F-actin and participates in focal adhesions, cell spreading, vesicle trafficking, and mechanotransduction. (chin2023theactinbundlingprotein pages 1-2, maus2024osteoclastspecificplastin3 pages 2-3)

Examples of reported alleles include c.1543del (p.Asp515Metfs*11), c.827G>A (p.Trp276*), c.994_995delGA (p.Asp332*), c.1765del, and exon 10–16 or larger deletions. A candidate missense allele c.685G>A (p.Gly229Arg) remains less secure and was reported with computational pathogenicity evidence rather than definitive functional validation. (brlek2021xlinkedosteogenesisimperfecta pages 10-11, balasubramanian2018novelpls3variants pages 1-5, costa2024pls3mutationsin pages 11-12, costa2024pls3mutationsin pages 2-4)

For curation:

Origin: germline; inherited or de novo. No somatic disease mechanism is established.
Functional class: predominantly loss of function/haploinsufficiency in heterozygous females and functional null status in hemizygous males; some missense alleles alter actin bundling or calcium regulation.
Population frequency: causal variants are expected to be absent or extremely rare in gnomAD; every variant should be checked against the current database and ancestry-matched coverage before ACMG classification.
Classification: use ACMG/AMP evidence separately for each allele. A PLS3 VUS should not diagnose disease without segregation, phenotype concordance, RNA/protein evidence, or validated functional results.
Structural abnormalities: exon and whole-gene deletions require copy-number detection. Large contiguous deletions may produce additional findings from neighboring genes. (costa2024pls3mutationsin pages 10-11, costa2024pls3mutationsin pages 1-2)
Epigenetics: variable X-inactivation is a plausible female-expression mechanism, but no validated disease methylation signature or clinical epigenetic assay exists.
Modifier genes: none validated; LRP5 is a candidate in an isolated severe case. (costa2024pls3mutationsin pages 11-12)

5. Mechanism/pathophysiology

Ordered causal chain

A germline loss-of-function or function-disrupting PLS3 variant leads to absent, reduced, or abnormally regulated plastin-3 activity.
Plastin-3 dysfunction leads to impaired calcium-sensitive F-actin bundling and abnormal organization of focal adhesions, osteocyte processes, and osteoclast podosome-associated structures. This is demonstrated in cellular and animal models but incompletely verified in human bone. (neugebauer2018plastin3influences pages 3-4, chin2023theactinbundlingprotein pages 1-2)
In osteoblast-lineage cells, defective cytoskeletal organization leads to reduced responsiveness to extracellular-matrix stiffness and impaired cell spreading; patient-associated mutants fail to rescue these defects. (chin2023theactinbundlingprotein pages 1-2)
Impaired mechanosensing leads to defective mineralization of deposited collagen matrix, while initial matrix deposition may remain relatively preserved. (chin2023theactinbundlingprotein pages 1-2)
Branch A—osteocyte signaling: altered actin-dependent mechanotransduction is inferred to lead to abnormal remodeling signals. MLO-Y4 RNA-seq found 259 upregulated and 368 downregulated transcripts with Wnt- and Th17-associated enrichment, but these pathway associations are not yet proven causal. (n2024functionalinsightsin pages 10-12, n2024functionalinsightsin pages 1-2)
Branch B—osteoclasts: PLS3 loss leads to podosome/NKRF–NF-κB–NFATC1 dysregulation and increased resorptive activity in vitro. However, osteoclast-specific deletion does not cause osteoporosis in vivo, demonstrating that this branch alone is insufficient. (neugebauer2018plastin3influences pages 3-4, maus2024osteoclastspecificplastin3 pages 1-2)
Combined abnormalities in osteoblasts, osteocytes, and osteoclast coupling lead to low bone formation/turnover, impaired cortical acquisition and trabecular architecture, and abnormal matrix mineralization. (balasubramanian2018novelpls3variants pages 11-14, neugebauer2018plastin3influences pages 5-5, hu2023impairedbonestrength pages 7-8)
Reduced bone quantity, architecture, and material quality result in low BMD, vertebral collapse, and recurrent low-trauma peripheral fractures.

Recent mechanistic developments

A 2023 MC3T3-E1 study showed that PLS3 depletion spared early collagen-matrix deposition but “severely” impaired subsequent mineralization. Control osteoblasts increased cell size and focal-adhesion number/length on 100-kPa versus 6-kPa substrates; PLS3-depleted cells did not. Wild-type PLS3 rescued spreading, whereas three patient-associated mutants with abnormal actin bundling did not. This supplies direct evidence linking actin bundling to osteoblast mechanosensation. (chin2023theactinbundlingprotein pages 1-2)

A 2024 osteoclast-specific knockout study found markedly increased resorption in vitro but normal micro-CT and three-point bending outcomes at 12, 24, and 48 weeks. Expert interpretation is therefore shifting from an osteoclast-centric model to a multicellular bone-remodeling disorder. (maus2024osteoclastspecificplastin3 pages 1-2)

A 2024 multi-model study found that ACTN1 and ACTN4—but not FSCN1—could rescue zebrafish skeletal abnormalities, suggesting partial redundancy among actin-bundling proteins. Patient fibroblast-derived osteoblast-like cells showed increased WNT2, while osteocyte-like cells showed Wnt/Th17-associated transcriptional changes; the small samples and absence of pathway-specific rescue preclude declaring Wnt or immune signaling primary. (n2024functionalinsightsin pages 12-14, n2024functionalinsightsin pages 10-12, n2024functionalinsightsin pages 1-2)

Suggested GO processes: actin filament bundle assembly; actin cytoskeleton organization; cellular response to mechanical stimulus; focal-adhesion assembly; biomineral tissue development; ossification; bone mineralization; bone remodeling; osteoblast differentiation; osteoclast differentiation; canonical Wnt signaling. Suggested cell types: osteoblast, CL:0000062; osteocyte, CL:0000137; osteoclast, CL:0000092. Immune involvement is presently a transcriptomic association, not demonstrated inflammatory disease.

No reproducible PLS3-specific metabolomic, lipidomic, spatial-transcriptomic, single-cell, or integrated human multi-omic signature has been established. A sex-dependent serum microRNA profile has been explored, but it is not a validated diagnostic or prognostic biomarker.

6. Anatomy

The primary affected organ is the skeleton, involving both cortical and trabecular compartments. Clinically important sites are vertebral bodies, long-bone shafts/metaphyses, hip/femoral neck, forearm, and occasionally small bones. Disease is generalized rather than lateralized. Suggested anatomy terms are UBERON:0002091 (bone), UBERON:0004288 (skeleton), vertebral column, vertebral body, femur, humerus, radius, ulna, and tibia.

At tissue level, affected structures include cortical bone, trabecular bone, bone matrix, osteoid/mineralization fronts, and the osteocyte lacuno-canalicular network. Relevant subcellular terms include actin cytoskeleton, actin filament bundle, focal adhesion, podosome, cytoplasm, and plasma membrane-associated adhesion complexes. (balasubramanian2018novelpls3variants pages 11-14, neugebauer2018plastin3influences pages 3-4, chin2023theactinbundlingprotein pages 1-2)

7. Temporal development and inheritance/population

Onset is usually insidious but becomes clinically apparent with a fracture in childhood; the documented range in the recent five-family cohort was 1.5–13 years. Disease is chronic and lifelong, with episodic fractures superimposed on persistent skeletal fragility. Growth and puberty may modify BMD trajectory, and childhood represents an important window for vertebral reshaping and peak-bone-mass acquisition. (costa2024pls3mutationsin pages 11-12, costa2024pls3mutationsin pages 1-2)

Inheritance is X-linked. A heterozygous woman has a 50% probability of transmitting the variant in each pregnancy; sons who inherit it are hemizygous, while daughters are heterozygous and variably affected. An affected male transmits the variant to all daughters and no sons. Male penetrance appears high for clearly loss-of-function alleles but has not been quantified; female penetrance is incomplete and age dependent. There is no evidence for anticipation. Germline mosaicism is theoretically possible but not quantified. Consanguinity is not relevant to the X-linked mechanism.

Disease-specific prevalence, incidence, carrier frequency, ethnic enrichment, geographic distribution, and male:female case ratio are unknown. Published families span multiple ancestries and regions, consistent with a globally distributed but underdiagnosed disorder. (dijk2013pls3mutationsin pages 6-6, costa2024pls3mutationsin pages 1-2)

8. Diagnostics

Clinical evaluation

Document age and mechanism of every fracture, vertebral pain/height loss, family history through the maternal lineage, medications, diet, mobility, puberty, and secondary disease.
Obtain DXA with age-, sex-, and size-adjusted Z-scores in children; image the lateral spine because vertebral fractures may occur even when symptoms are limited.
Use targeted radiographs for acute fractures and deformity; consider vertebral-fracture assessment and, in specialized centers, high-resolution peripheral QCT.
Exclude secondary causes with calcium, phosphate, alkaline phosphatase, creatinine, liver tests, 25-hydroxyvitamin D, parathyroid hormone, blood count/inflammatory testing, thyroid studies, celiac testing, and sex-hormone/puberty evaluation as clinically indicated.
Bone-turnover markers may be low or normal but are not diagnostic. Transiliac biopsy can document turnover, mineralization, and material abnormalities when diagnosis or treatment choice remains uncertain. (balasubramanian2018novelpls3variants pages 11-14, balasubramanian2018novelpls3variants pages 1-5)

Molecular testing

A comprehensive early-onset osteoporosis/bone-fragility panel should include PLS3, COL1A1, COL1A2, WNT1, LRP5, SGMS2, IFITM5, SERPINF1, P3H1, FKBP10, ALPL, and other phenotype-appropriate genes. Sequencing must be paired with exon-level copy-number analysis because partial and whole-gene PLS3 deletions are established causes. WES is useful for genetically heterogeneous cases; WGS adds noncoding, structural, and breakpoint detection but does not replace variant interpretation. CMA is useful for large or contiguous deletions. Routine karyotyping, FISH, mitochondrial testing, and repeat-expansion testing are not first-line unless another diagnosis is suspected. (costa2024pls3mutationsin pages 11-12, costa2024pls3mutationsin pages 1-2)

After diagnosis, perform cascade testing and skeletal assessment in at-risk relatives—including apparently asymptomatic women. PLS3 screening is warranted in both male and female patients with severe childhood-onset primary osteoporosis. (balasubramanian2018novelpls3variants pages 11-14, balasubramanian2018novelpls3variants pages 1-5)

Differential diagnosis

Major alternatives are COL1A1/COL1A2-related OI; WNT1-, LRP5-, and SGMS2-related osteoporosis; idiopathic juvenile osteoporosis; hypophosphatasia; nutritional rickets/osteomalacia; glucocorticoid or chronic-inflammatory osteoporosis; celiac disease; eating disorders; endocrine hypogonadism/hyperthyroidism/hyperparathyroidism; renal disease; and nonaccidental injury. Normal mineral chemistry does not exclude PLS3 disease, while persistently low alkaline phosphatase favors hypophosphatasia.

No standardized PLS3-specific diagnostic criteria, FDA-qualified biomarker, newborn-screening program, or validated omics diagnostic exists.

9. Outcomes and prognosis

Life expectancy and disease-specific mortality have not been quantified and are not known to be intrinsically reduced. Morbidity is dominated by recurrent fractures, vertebral deformity, chronic pain, orthopedic procedures, possible mobility limitation, and failure to attain normal peak bone mass. A 40-year-old originally diagnosed with juvenile osteoporosis later sustained a hip fracture, illustrating persistence into adulthood. (balasubramanian2018novelpls3variants pages 1-5)

Prognostic indicators probably include hemizygous male status, early first fracture, vertebral involvement, very low lumbar BMD, accumulated fracture burden, large loss-of-function deletions, and coexisting skeletal risks. These have not been validated in a prognostic model. BMD response does not necessarily equal restored bone strength; fracture outcomes and vertebral morphology should also be followed.

10. Treatment and real-world implementation

There is no PLS3-specific guideline or approved molecular therapy. Management should occur in a pediatric or adult metabolic-bone center.

Foundational care: ensure calcium and vitamin-D sufficiency; encourage supervised, low-impact weight-bearing and muscle-strengthening activity; avoid unnecessary immobilization and bone-toxic drugs; provide pain control, physiotherapy, occupational adaptation, and fall/injury prevention.
Fracture/orthopedic care: standard fracture stabilization, monitoring for vertebral collapse and deformity, and individualized surgery. Severe vertebral injury may require fusion, as in a 26-year-old with an L1 fracture. (costa2024pls3mutationsin pages 2-4)
Bisphosphonates: pamidronate or zoledronic acid are the most reported pediatric agents; alendronate has also been used. In the recent cohort, four treated patients showed lumbar-spine BMD increase and vertebral reshaping over 10 months–2 years. One eight-year-old had no new fractures during ten months of monthly pamidronate. These uncontrolled observations support possible benefit but cannot establish response rates. (costa2024pls3mutationsin pages 2-4, costa2024pls3mutationsin pages 1-2)
Teriparatide: limited to skeletally mature patients. One adult receiving teriparatide plus calcium/vitamin D had 2.4% femoral-neck and 4.1% total-hip BMD gains at ten months without new fractures or reported adverse events. Evidence remains sparse. (costa2024pls3mutationsin pages 2-4)
Safety: prolonged antiresorptive exposure requires specialist review; an atypical femoral fracture has been reported in a bisphosphonate-treated adolescent with PLS3 disease, but causality and absolute risk are unknown.

In a patient-derived rat model, alendronate and teriparatide improved BMD/microarchitecture, while teriparatide—but not alendronate—significantly improved bone strength. This is translational evidence, not proof of comparative clinical efficacy. (hu2023impairedbonestrength pages 7-8)

Suggested NCIT intervention concepts include bisphosphonate therapy, pamidronate, zoledronic acid, alendronate, teriparatide therapy, calcium supplementation, vitamin-D supplementation, physical therapy, orthopedic surgery, and genetic counseling. No disease-specific interventional ClinicalTrials.gov study was identified in the tool search. Gene replacement, CRISPR editing, RNA therapy, cell therapy, and targeted PLS3 pathway therapy remain preclinical concepts.

11. Prevention

Primary prevention: no postnatal intervention prevents the inherited disorder. Genetic counseling permits informed reproductive planning. Once a familial pathogenic variant is known, prenatal diagnosis and preimplantation genetic testing are technically feasible subject to local regulation and patient preference.

Secondary prevention: identify disease before multiple fractures through cascade testing, DXA and spine imaging of relatives, including heterozygous women. Evaluate children with unexplained vertebral compression or recurrent low-trauma fractures promptly.

Tertiary prevention: maintain calcium/vitamin-D sufficiency, safe activity and muscle strength; reduce falls/high-impact trauma; avoid smoking, excess alcohol, and unnecessary glucocorticoids; monitor spinal morphology, growth, puberty, BMD, pain, mobility, and treatment toxicity. Vaccination and infectious prophylaxis are not disease-specific.

12. Other species and model organisms

No confirmed naturally occurring veterinary PLS3 osteoporosis syndrome or zoonotic/transmissible process was found. Orthologous biology is conserved in Homo sapiens (NCBI Taxon 9606), Mus musculus (10090), Rattus norvegicus (10116), and Danio rerio (7955).

Zebrafish: morpholino pls3 knockdown causes craniofacial, axial, tail, muscle, and F-actin abnormalities; human PLS3 mRNA dose-dependently rescues the phenotype. ACTN1 and ACTN4 also rescue major skeletal defects, while FSCN1 does not adequately compensate. Limitations include morpholino artifacts, developmental rather than adult osteoporosis phenotypes, and anatomical differences from mammalian bone. (dijk2013pls3mutationsin pages 6-6, n2024functionalinsightsin pages 12-14, n2024functionalinsightsin pages 1-2)
Ubiquitous knockout mouse: cortical and trabecular osteoporosis occurs in both sexes, more prominently in males, with reduced trabecular number, greater separation, and reduced cortical thickness/area. PLS3 overexpression thickens cortical bone and increases strength, but also alters trabecular structure, indicating dose-sensitive biology. (neugebauer2018plastin3influences pages 3-4, neugebauer2018plastin3influences pages 5-5)
Conditional mouse: LysMCre-mediated osteoclast deletion markedly increases in-vitro resorption but produces no osteoporosis or mechanical weakness through 48 weeks. This is a powerful negative-causality experiment showing that osteoclast-autonomous loss is insufficient. (maus2024osteoclastspecificplastin3 pages 1-2)
Patient-relevant rat: hemizygous PLS3 exon 10–16 deletion reduces cortical thickness, mineral apposition, and femoral/vertebral strength and causes cortical porosity and collagen disorganization. It is useful for longitudinal biomechanics and pharmacology, although rodents do not fully model human X-inactivation or decades-long fracture history. (hu2023impairedbonestrength pages 7-8)
Cell models: MC3T3-E1 osteoblasts model focal-adhesion mechanosensing and mineralization; MLO-Y4 cells permit osteocyte-like transcriptomics; patient fibroblast-derived osteoblast-like cells permit genotype-specific assays. Limitations include immortalized lineage states, artificial substrate mechanics, small donor numbers, and incomplete recapitulation of the mineralized lacuno-canalicular environment. (chin2023theactinbundlingprotein pages 1-2, n2024functionalinsightsin pages 10-12)

13. Evidence gaps and research priorities

The principal gaps are accurate prevalence and penetrance; prospective natural history; systematic female-carrier phenotyping; variant-specific functional assays; robust BMD-independent strength biomarkers; single-cell/spatial profiling of human bone; clarification of osteoblast–osteocyte–osteoclast coupling; and adequately powered treatment trials with fracture, vertebral-reshaping, pain, function, and safety outcomes. The 2024 finding that isolated osteoclast dysfunction is insufficient is particularly important: future therapeutic development should target integrated cytoskeletal mechanobiology rather than presuming a purely antiresorptive disease. (n2024functionalinsightsin pages 12-14, maus2024osteoclastspecificplastin3 pages 1-2)

Selected recent and landmark sources

Costa A, et al. PLS3 Mutations in X-Linked Osteoporosis: Clinical and Genetic Features in Five New Families. Calcified Tissue International. Online December 2023; issue 2024;114:157–170. https://doi.org/10.1007/s00223-023-01162-4. Abstract conclusion: “early treatment with bisphosphonates may influence the disease course and reduce the progression of osteoporosis.” (costa2024pls3mutationsin pages 1-2)
Chin SM, et al. The actin-bundling protein, PLS3, is part of the mechanoresponsive machinery that regulates osteoblast mineralization. Frontiers in Cell and Developmental Biology. Published November 27, 2023. https://doi.org/10.3389/fcell.2023.1141738. The abstract concludes that PLS3 actin bundling forms part of the mechanosensitive mechanism promoting osteoblast mineralization. (chin2023theactinbundlingprotein pages 1-2)
Maus I, et al. Osteoclast-specific Plastin 3 knockout in mice fail to develop osteoporosis despite dramatic increased osteoclast resorption activity. JBMR Plus. Published January 4, 2024. https://doi.org/10.1093/jbmrpl/ziad009. Its central finding is that osteoclast-specific loss does not reproduce systemic osteoporosis. (maus2024osteoclastspecificplastin3 pages 1-2)
Zhong W, et al. Functional Insights in PLS3-Mediated Osteogenic Regulation. Cells. Published September 9, 2024;13:1507. https://doi.org/10.3390/cells13171507. The study links PLS3 loss to actin-bundling compensation and Wnt/Th17-associated transcription while emphasizing broader, unresolved bone pathways. (n2024functionalinsightsin pages 12-14, n2024functionalinsightsin pages 1-2)
Hu J, et al. Impaired bone strength and bone microstructure in a novel early-onset osteoporotic rat model with a clinically relevant PLS3 mutation. eLife. April 2023;12:e80365. https://doi.org/10.7554/eLife.80365. (hu2023impairedbonestrength pages 7-8)
van Dijk FS, et al. PLS3 Mutations in X-Linked Osteoporosis with Fractures. New England Journal of Medicine. October 17, 2013;369:1529–1536. https://doi.org/10.1056/NEJMoa1308223. The abstract states that PLS3 is involved in F-actin-bundle formation and that pathogenic variants in five families established its importance in human bone health. (dijk2013pls3mutationsin pages 6-6)

PMIDs were not consistently present in the retrieved full-text metadata; DOI URLs are therefore supplied rather than risking incorrect PMID assignment.

References

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(costa2024pls3mutationsin pages 1-2): Adriana Costa, Andreia Martins, Catarina Machado, Elena Lundberg, Ola Nilsson, Fan Wang, Alice Costantini, Symeon Tournis, Jakob Höppner, Corinna Grasemann, and Outi Mäkitie. Pls3 mutations in x-linked osteoporosis: clinical and genetic features in five new families. Calcified Tissue International, 114:157-170, Dec 2024. URL: https://doi.org/10.1007/s00223-023-01162-4, doi:10.1007/s00223-023-01162-4. This article has 11 citations and is from a peer-reviewed journal.
(dijk2013pls3mutationsin pages 6-6): Fleur S. van Dijk, M. Carola Zillikens, Dimitra Micha, Markus Riessland, Carlo L.M. Marcelis, Christine E. de Die-Smulders, Janine Milbradt, Anton A. Franken, Arjan J. Harsevoort, Klaske D. Lichtenbelt, Hans E. Pruijs, M. Estela Rubio-Gozalbo, Rolf Zwertbroek, Youssef Moutaouakil, Jaqueline Egthuijsen, Matthias Hammerschmidt, Renate Bijman, Cor M. Semeins, Astrid D. Bakker, Vincent Everts, Jenneke Klein-Nulend, Natalia Campos-Obando, Albert Hofman, Gerard J. te Meerman, Annemieke J.M.H. Verkerk, André G. Uitterlinden, Alessandra Maugeri, Erik A. Sistermans, Quinten Waisfisz, Hanne Meijers-Heijboer, Brunhilde Wirth, Marleen E.H. Simon, and Gerard Pals. pls3 mutations in x-linked osteoporosis with fractures. Oct 2013. URL: https://doi.org/10.1056/nejmoa1308223, doi:10.1056/nejmoa1308223. This article has 261 citations and is from a highest quality peer-reviewed journal.
(costa2024pls3mutationsin pages 11-12): Adriana Costa, Andreia Martins, Catarina Machado, Elena Lundberg, Ola Nilsson, Fan Wang, Alice Costantini, Symeon Tournis, Jakob Höppner, Corinna Grasemann, and Outi Mäkitie. Pls3 mutations in x-linked osteoporosis: clinical and genetic features in five new families. Calcified Tissue International, 114:157-170, Dec 2024. URL: https://doi.org/10.1007/s00223-023-01162-4, doi:10.1007/s00223-023-01162-4. This article has 11 citations and is from a peer-reviewed journal.
(chin2023theactinbundlingprotein pages 1-2): Samantha M. Chin, Carmela Unnold-Cofre, Teri Naismith, and Silvia Jansen. The actin-bundling protein, pls3, is part of the mechanoresponsive machinery that regulates osteoblast mineralization. Frontiers in Cell and Developmental Biology, Nov 2023. URL: https://doi.org/10.3389/fcell.2023.1141738, doi:10.3389/fcell.2023.1141738. This article has 6 citations.
(balasubramanian2018novelpls3variants pages 11-14): Meena Balasubramanian, Nadja Fratzl‐Zelman, Rory O'Sullivan, Mary Bull, Nicola FA Peel, Rebecca C Pollitt, Rebecca Jones, Elizabeth Milne, Kath Smith, Paul Roschger, Klaus Klaushofer, and Nicholas J Bishop. Novel pls3 variants in x‐linked osteoporosis: exploring bone material properties. American Journal of Medical Genetics Part A, 176:1578-1586, May 2018. URL: https://doi.org/10.1002/ajmg.a.38830, doi:10.1002/ajmg.a.38830. This article has 43 citations.
(balasubramanian2018novelpls3variants pages 1-5): Meena Balasubramanian, Nadja Fratzl‐Zelman, Rory O'Sullivan, Mary Bull, Nicola FA Peel, Rebecca C Pollitt, Rebecca Jones, Elizabeth Milne, Kath Smith, Paul Roschger, Klaus Klaushofer, and Nicholas J Bishop. Novel pls3 variants in x‐linked osteoporosis: exploring bone material properties. American Journal of Medical Genetics Part A, 176:1578-1586, May 2018. URL: https://doi.org/10.1002/ajmg.a.38830, doi:10.1002/ajmg.a.38830. This article has 43 citations.
(neugebauer2018plastin3influences pages 3-4): Janine Neugebauer, Juliane Heilig, Seyyedmohsen Hosseinibarkooie, Bryony C Ross, Natalia Mendoza-Ferreira, Franziska Nolte, Miriam Peters, Irmgard Hölker, Kristina Hupperich, Theresa Tschanz, Vanessa Grysko, Frank Zaucke, Anja Niehoff, and Brunhilde Wirth. Plastin 3 influences bone homeostasis through regulation of osteoclast activity. Human Molecular Genetics, 27:4249–4262, Sep 2018. URL: https://doi.org/10.1093/hmg/ddy318, doi:10.1093/hmg/ddy318. This article has 72 citations and is from a domain leading peer-reviewed journal.
(maus2024osteoclastspecificplastin3 pages 1-2): Ilka Maus, Maren Dreiner, Sebastian Zetzsche, Fabian Metzen, Bryony C Ross, Daniela Mählich, Manuel Koch, Anja Niehoff, and Brunhilde Wirth. Osteoclast-specific plastin 3 knockout in mice fail to develop osteoporosis despite dramatic increased osteoclast resorption activity. JBMR Plus, Jan 2024. URL: https://doi.org/10.1093/jbmrpl/ziad009, doi:10.1093/jbmrpl/ziad009. This article has 3 citations and is from a peer-reviewed journal.
(hu2023impairedbonestrength pages 7-8): Jing Hu, Bingna Zhou, Xiaoyun Lin, Qian Zhang, Feifei Guan, Lei Sun, Jiayi Liu, Ou Wang, Yan Jiang, Wei-bo Xia, Xiaoping Xing, and Mei Li. Impaired bone strength and bone microstructure in a novel early-onset osteoporotic rat model with a clinically relevant pls3 mutation. Apr 2023. URL: https://doi.org/10.7554/elife.80365, doi:10.7554/elife.80365. This article has 9 citations and is from a domain leading peer-reviewed journal.
(n2024functionalinsightsin pages 10-12): Victoriano Baladr ó n, Gianpaolo Papaccio, Wenchao Zhong, Janine Neugebauer, J. Pathak, Xingyang Li, G. Pals, M. Zillikens, E. M. Eekhoff, Nathalie Bravenboer, Qingbin Zhang, Matthias Hammerschmidt, Brunhilde Wirth, and D. Micha. Functional insights in pls3-mediated osteogenic regulation. Sep 2024. URL: https://doi.org/10.3390/cells13171507, doi:10.3390/cells13171507. This article has 5 citations.
(brlek2021xlinkedosteogenesisimperfecta pages 10-11): Petar Brlek, Darko Antičević, Vilim Molnar, Vid Matišić, Kristina Robinson, Swaroop Aradhya, Dalibor Krpan, and Dragan Primorac. X-linked osteogenesis imperfecta possibly caused by a novel variant in pls3. Genes, 12:1851, Nov 2021. URL: https://doi.org/10.3390/genes12121851, doi:10.3390/genes12121851. This article has 20 citations.
(maus2024osteoclastspecificplastin3 pages 2-3): Ilka Maus, Maren Dreiner, Sebastian Zetzsche, Fabian Metzen, Bryony C Ross, Daniela Mählich, Manuel Koch, Anja Niehoff, and Brunhilde Wirth. Osteoclast-specific plastin 3 knockout in mice fail to develop osteoporosis despite dramatic increased osteoclast resorption activity. JBMR Plus, Jan 2024. URL: https://doi.org/10.1093/jbmrpl/ziad009, doi:10.1093/jbmrpl/ziad009. This article has 3 citations and is from a peer-reviewed journal.
(costa2024pls3mutationsin pages 10-11): Adriana Costa, Andreia Martins, Catarina Machado, Elena Lundberg, Ola Nilsson, Fan Wang, Alice Costantini, Symeon Tournis, Jakob Höppner, Corinna Grasemann, and Outi Mäkitie. Pls3 mutations in x-linked osteoporosis: clinical and genetic features in five new families. Calcified Tissue International, 114:157-170, Dec 2024. URL: https://doi.org/10.1007/s00223-023-01162-4, doi:10.1007/s00223-023-01162-4. This article has 11 citations and is from a peer-reviewed journal.
(n2024functionalinsightsin pages 1-2): Victoriano Baladr ó n, Gianpaolo Papaccio, Wenchao Zhong, Janine Neugebauer, J. Pathak, Xingyang Li, G. Pals, M. Zillikens, E. M. Eekhoff, Nathalie Bravenboer, Qingbin Zhang, Matthias Hammerschmidt, Brunhilde Wirth, and D. Micha. Functional insights in pls3-mediated osteogenic regulation. Sep 2024. URL: https://doi.org/10.3390/cells13171507, doi:10.3390/cells13171507. This article has 5 citations.
(neugebauer2018plastin3influences pages 5-5): Janine Neugebauer, Juliane Heilig, Seyyedmohsen Hosseinibarkooie, Bryony C Ross, Natalia Mendoza-Ferreira, Franziska Nolte, Miriam Peters, Irmgard Hölker, Kristina Hupperich, Theresa Tschanz, Vanessa Grysko, Frank Zaucke, Anja Niehoff, and Brunhilde Wirth. Plastin 3 influences bone homeostasis through regulation of osteoclast activity. Human Molecular Genetics, 27:4249–4262, Sep 2018. URL: https://doi.org/10.1093/hmg/ddy318, doi:10.1093/hmg/ddy318. This article has 72 citations and is from a domain leading peer-reviewed journal.
(n2024functionalinsightsin pages 12-14): Victoriano Baladr ó n, Gianpaolo Papaccio, Wenchao Zhong, Janine Neugebauer, J. Pathak, Xingyang Li, G. Pals, M. Zillikens, E. M. Eekhoff, Nathalie Bravenboer, Qingbin Zhang, Matthias Hammerschmidt, Brunhilde Wirth, and D. Micha. Functional insights in pls3-mediated osteogenic regulation. Sep 2024. URL: https://doi.org/10.3390/cells13171507, doi:10.3390/cells13171507. This article has 5 citations.

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Unresolved (possible confabulation)	0
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Differential Diagnoses

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PLS3-Related X-Linked Osteoporosis: Disease-Characteristics Research Report

Executive summary

1. Disease information

Definition and nomenclature

Identifiers

2. Etiology, risk, protective factors, and environment

Causal factor

Genetic risk and modifiers

Environmental and lifestyle factors

3. Phenotypes

Core skeletal phenotype

Variable or occasional findings

Quality of life

4. Genetic and molecular information

5. Mechanism/pathophysiology

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6. Anatomy

7. Temporal development and inheritance/population

8. Diagnostics

Clinical evaluation

Molecular testing

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