| 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. (pqac-00000009, pqac-00000010) | 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. (pqac-00000005, pqac-00000008, pqac-00000014) | 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. (pqac-00000008, pqac-00000010) | 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. (pqac-00000008, pqac-00000010) | 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. (pqac-00000001, pqac-00000002) | 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. (pqac-00000003, pqac-00000014, pqac-00000017) | 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. (pqac-00000003, pqac-00000014, pqac-00000017) | 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. (pqac-00000001, pqac-00000002, pqac-00000010) | 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. (pqac-00000009, pqac-00000010) | 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. (pqac-00000005, pqac-00000010) | 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. (pqac-00000005, pqac-00000007, pqac-00000014, pqac-00000017, pqac-00000019) | 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.*