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Background: The aim of this research is to establish and validate a prognostic model for predicting prognosis in non-small cell lung cancer (NSCLC) patients with bone metastases. Methods: Overall, 176 NSCLC patients with bone metastases were retrospectively evaluated in the research. We employed the LASSO-Cox regression method to select the candidate indicators for predicting the prognosis among NSCLC patients complicated with bone metastases. We employed the receiver operating characteristic curve (ROC) and the concordance index (C-index) to assess the discriminative ability. Results: Based on the LASSO-Cox regression analysis, 9 candidate indicators were screened to build the prognostic model. The prognostic model had a higher C-index in the training cohort (0.738, 95% CI: 0.680-0.796) and the validation cohort (0.660, 95% CI: 0.566-0.754) than the advanced lung cancer inflammation index (ALI). Furthermore, the AUCs of the 1-, 2-, and 3-year OS predictions for the prognostic model were higher than ALI in both cohorts. Kaplan-Meier curves and the estimated restricted mean survival time (RMST) values showed that the patients in the low-risk subgroup had the lower probabilities of cancer-specific mortality than high-risk subgroup. Conclusions: The prognostic model could provide clinicians with precise information and facilitate individualized treatment for patients with bone metastases.
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Osteoarthritis (OA) is an age-related or post-traumatic degenerative whole joint disease characterized by the rupture of articular cartilage homeostasis, the regulatory mechanisms of which remain elusive. This study identifies the essential role of heterogeneous nuclear ribonucleoprotein K (hnRNPK) in maintaining articular cartilage homeostasis. Hnrnpk expression is markedly downregulated in human and mice OA cartilage. The deletion of Hnrnpk effectively accelerates the development of post-traumatic and age-dependent OA in mice. Mechanistically, the KH1 and KH2 domain of Hnrnpk bind and degrade the mRNA of WWC1. Hnrnpk deletion increases WWC1 expression, which in turn leads to the activation of Hippo signaling and ultimately aggravates OA. In particular, intra-articular injection of LPA and adeno-associated virus serotype 5 expressing WWC1 RNA interference ameliorates cartilage degeneration induced by Hnrnpk deletion, and intra-articular injection of adeno-associated virus serotype 5 expressing Hnrnpk protects against OA. Collectively, this study reveals the critical roles of Hnrnpk in inhibiting OA development through WWC1-dependent downregulation of Hippo signaling in chondrocytes and defines a potential target for the prevention and treatment of OA.
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Cartilagem Articular , Condrócitos , Ribonucleoproteínas Nucleares Heterogêneas Grupo K , Via de Sinalização Hippo , Osteoartrite , Proteínas Serina-Treonina Quinases , Transdução de Sinais , Animais , Humanos , Masculino , Camundongos , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Condrócitos/metabolismo , Dependovirus/genética , Modelos Animais de Doenças , Regulação da Expressão Gênica , Ribonucleoproteínas Nucleares Heterogêneas Grupo K/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas Grupo K/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Osteoartrite/metabolismo , Osteoartrite/genética , Osteoartrite/etiologia , Osteoartrite/patologia , Osteoartrite/terapia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
The intervertebral disc (IVD) acts as a fibrocartilaginous joint to anchor adjacent vertebrae. Although several studies have demonstrated the cellular heterogeneity of adult mature IVDs, a single-cell transcriptomic atlas mapping early IVD formation is still lacking. Here, the authors generate a spatiotemporal and single cell-based transcriptomic atlas of human IVD formation at the embryonic stage and a comparative mouse transcript landscape. They identify two novel human notochord (NC)/nucleus pulposus (NP) clusters, SRY-box transcription factor 10 (SOX10)+ and cathepsin K (CTSK)+ , that are distributed in the early and late stages of IVD formation and they are validated by lineage tracing experiments in mice. Matrisome NC/NP clusters, T-box transcription factor T (TBXT)+ and CTSK+ , are responsible for the extracellular matrix homeostasis. The IVD atlas suggests that a subcluster of the vertebral chondrocyte subcluster might give rise to an inner annulus fibrosus of chondrogenic origin, while the fibroblastic outer annulus fibrosus preferentially expresseds transgelin and fibromodulin . Through analyzing intercellular crosstalk, the authors further find that notochordal secreted phosphoprotein 1 (SPP1) is a novel cue in the IVD microenvironment, and it is associated with IVD development and degeneration. In conclusion, the single-cell transcriptomic atlas will be leveraged to develop preventative and regenerative strategies for IVD degeneration.
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Degeneração do Disco Intervertebral , Disco Intervertebral , Núcleo Pulposo , Humanos , Camundongos , Animais , Diferenciação Celular , Fatores de TranscriçãoRESUMO
The harmonious functioning of growth plate chondrocytes is crucial for skeletogenesis. These cells rely on an appropriate intensity of glycolysis to maintain survival and function in an avascular environment, but the underlying mechanism is poorly understood. Here we show that Hnrnpk orchestrates growth plate development by maintaining the appropriate intensity of glycolysis in chondrocytes. Ablating Hnrnpk causes the occurrence of dwarfism, exhibiting damaged survival and premature differentiation of growth plate chondrocytes. Furthermore, Hnrnpk deficiency results in enhanced transdifferentiation of hypertrophic chondrocytes and increased bone mass. In terms of mechanism, Hnrnpk binds to Hif1a mRNA and promotes its degradation. Deleting Hnrnpk upregulates the expression of Hif1α, leading to the increased expression of downstream glycolytic enzymes and then exorbitant glycolysis. Our study establishes an essential role of Hnrnpk in orchestrating the survival and differentiation of chondrocytes, regulating the Hif1α-glycolysis axis through a post-transcriptional mechanism during growth plate development.
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Condrócitos , Lâmina de Crescimento , Diferenciação Celular/genética , Condrócitos/metabolismo , Glicólise/genética , Lâmina de Crescimento/metabolismo , RNA Mensageiro/metabolismoRESUMO
Intervertebral disc degeneration (IDD) is the leading cause of low back pain (LBP). However, effective therapeutic drugs for IDD remain to be further explored. Inflammatory cytokines play a pivotal role in the onset and progression of IDD. Dihydroartemisinin (DHA) has been well reported to have powerful anti-inflammatory effects, but whether DHA could ameliorate the development of IDD remained unclear. In this study, the effects of DHA on extracellular matrix (ECM) metabolism and cellular senescence were firstly investigated in nucleus pulposus cells (NPCs) under tumor necrosis factor alpha (TNFα)-induced inflammation. Meanwhile, AKT agonist sc-79 was used to determine whether DHA exerted its actions through regulating PI3K/AKT and NF-κB signaling pathways. Next, the therapeutic effects of DHA were tested in a puncture-induced rat IDD model. Finally, we detected the activation of PI3K/AKT and NF-κB signaling pathways in clinical degenerative nucleus pulposus specimens. We demonstrated that DHA ameliorated the imbalance between anabolism and catabolism of extracellular matrix and alleviated NPCs senescence induced by TNFα in vitro. Further, we illustrated that DHA mitigated the IDD progression in a puncture-induced rat model. Mechanistically, DHA inhibited the activation of PI3K/AKT and NF-κB signaling pathways induced by TNFα, which was undermined by AKT agonist sc-79. Molecular docking predicted that DHA bound to the PI3K directly. Intriguingly, we also verified the activation of PI3K/AKT and NF-κB signaling pathways in clinical degenerative nucleus pulposus specimens, suggesting that DHA may qualify itself as a promising drug for mitigating IDD.
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Artemisininas , Degeneração do Disco Intervertebral , Animais , Anti-Inflamatórios/farmacologia , Artemisininas/farmacologia , Citocinas/metabolismo , Degeneração do Disco Intervertebral/patologia , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Transdução de Sinais , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
Abnormal mechanical load is a main risk factor of intervertebral disc degeneration (IDD), and cellular senescence is a pathological change in IDD. In addition, extracellular matrix (ECM) stiffness promotes human nucleus pulposus cells (hNPCs) senescence. However, the molecular mechanism underlying mechano-induced cellular senescence and IDD progression is not yet fully elucidated. First, we demonstrated that mechano-stress promoted hNPCs senescence via NF-κB signaling. Subsequently, we identified periostin as the main mechano-responsive molecule in hNPCs through unbiased sequencing, which was transcriptionally upregulated by NF-κB p65; moreover, secreted periostin by senescent hNPCs further promoted senescence and upregulated the catabolic process in hNPCs through activating NF-κB, forming a positive loop. Both Postn (encoding periostin) knockdown via siRNA and periostin inactivation via neutralizing antibodies alleviated IDD and NPCs senescence. Furthermore, we found that mechano-stress initiated the positive feedback of NF-κB and periostin via PIEZO1. PIEZO1 activation by Yoda1 induced severe IDD in rat tails without compression, and Postn knockdown alleviated the Yoda1-induced IDD in vivo. Here, we reported for the first time that self-amplifying loop of NF-κB and periostin initiated via PIEZO1 under mechano-stress accelerated NPCs senescence, leading to IDD. Furthermore, periostin neutralizing antibodies, which may serve as potential therapeutic agents for IDD, interrupted this loop.
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Degeneração do Disco Intervertebral , Núcleo Pulposo , Animais , Anticorpos Neutralizantes/metabolismo , Moléculas de Adesão Celular , Senescência Celular/genética , Humanos , Degeneração do Disco Intervertebral/genética , Degeneração do Disco Intervertebral/metabolismo , Canais Iônicos/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Núcleo Pulposo/metabolismo , Núcleo Pulposo/patologia , RNA Interferente Pequeno/metabolismo , RatosRESUMO
PURPOSE: Although there are many researches that focus on the relationship between the vertebral artery and uncinate process (UP), there were no publications concerning difference in the dimensions of the UP between the normal spine and degenerative spine, especially in Chinese patient. The purpose of this study is to determine the anatomic parameters that can be used as a guide for the procedure in intervertebral foramen decompression and for analysis of the morphometric change in the UP of the cervical spondylosis patients. METHODS: Forty patients from January 2016 to January 2019 were enrolled in this study. Three-dimensional computed tomography scans of the cervical spine were performed. The patients were subdivided into two groups which were nondegenerative cervical spine group (20 cases) and degenerative cervical spine group (20 cases). Six parameters concerning the height, width and angle of the UP were measured. RESULTS: In nondegenerative group, the average pedicle width was 3.63 mm-5.91 mm from C3 to C7. The average width of safe UP resection will be 3.06 mm at C3, 3.12 mm at C4, 3.28 mm at C5, 2.74 mm at C6 and 2.01 mm at C7. The average safe depth will be 6.04 mm at C3, 6.52 mm at C4, 7.61 mm at C5, 6.07 mm at C6 and 5.09 mm at C7. There are statistic difference between degenerative group and nondegenerative group, especially in the parameter minimum height of UP, maximum height of UP, medial border's distance of UP and later border's distance of UP. CONCLUSION: In this retrospective study, our results suggest that for the Chinese patients who suffered from cervical spondylosis could be performed intervertebral foraminotomy decompression by resecting part of the UP. The safe range within the spinal canal was up to 6.73 mm of width between inferior vertebral endplate and superior vertebral endplate in the intervertebral space and up to 5.09 mm of depth from medial border of the UP to the lateral side atC3 to C7 without interfering the spinal nerve root and vertebral artery. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: Our study found the safe margin to perform intervertebral foramen decompression to the UP for the cervical spondylosis patients. This may help to improve safeness of the surgical procedure and provide data for future robotic surgery.
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PURPOSE: Preaxial polydactyly (PPD) is a common congenital hand malformation classified into four subtypes (PPD I-IV). Variants in the zone of polarizing activity regulatory sequence (ZRS) within intron 5 of the LMBR1 gene are linked to most PPD types. However, the genes responsible for PPD I and the underlying mechanisms are unknown. METHODS: A rare large four-generation family with isolated PPD I was subjected to genome-wide genotyping and sequence analysis. In vitro and in vivo functional studies were performed in Caco-2 cells, 293T cells, and a knockin transgenic mouse model. RESULTS: A novel g.101779T>A (reference sequence: NG_009240.2; position 446 of the ZRS) variant segregates with all PPD I-affected individuals. The knockin mouse with this ZRS variant exhibited PPD I phenotype accompanying ectopic and excess expression of Shh. We confirmed that HnRNP K can bind the ZRS and SHH promoters. The ZRS mutant enhanced the binding affinity for HnRNP K and upregulated SHH expression. CONCLUSION: Our results identify the first PPD I disease-causing variant. The variant leading to PPD I may be associated with enhancing SHH expression mediated by HnRNP K. This study adds to the ZRS-associated syndromes classification system for PPD and clarifies the underlying molecular mechanisms.
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Proteínas Hedgehog/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo K/metabolismo , Botões de Extremidades/crescimento & desenvolvimento , Proteínas de Membrana/genética , Polidactilia/genética , Polimorfismo de Nucleotídeo Único , Polegar/anormalidades , Regulação para Cima , Animais , Células CACO-2 , Modelos Animais de Doenças , Feminino , Técnicas de Introdução de Genes , Células HEK293 , Humanos , Íntrons , Botões de Extremidades/metabolismo , Botões de Extremidades/patologia , Masculino , Camundongos , Camundongos Transgênicos , Linhagem , Polidactilia/metabolismoRESUMO
Chordoma is an extremely rare malignant bone tumor with a high rate of relapse. While cancer stem cells (CSCs) are closely associated with tumor recurrence, which depend on its capacity to self-renew and induce chemo-/radioresistance, whether and how CSCs participate in chordoma recurrence remains unclear. The current study found that tumor cells in recurrent chordoma displayed more dedifferentiated CSC-like properties than those in corresponding primary tumor tissues. Meanwhile, MTNR1B deletion along with melatonin receptor 1B (MTNR1B) down-regulation was observed in recurrent chordoma. Further investigation revealed that activation of Gαi2 by MTNR1B upon melatonin stimulation could inhibit SRC kinase activity via recruiting CSK and SRC, increasing SRC Y530 phosphorylation, and decreasing SRC Y419 phosphorylation. This subsequently suppressed ß-catenin signaling and stemness via decreasing ß-catenin p-Y86/Y333/Y654. However, MTNR1B loss in chordoma mediated increased CSC properties, chemoresistance, and tumor progression by releasing melatonin's repression of ß-catenin signaling. Clinically, MTNR1B deletion was found to correlate with patients' survival. Together, our study establishes a novel convergence between melatonin and ß-catenin signaling pathways and reveals the significance of this cross talk in chordoma recurrence. Besides, we propose that MTNR1B is a potential biomarker for prediction of chordoma prognosis and selection of treatment options, and chordoma patients might benefit from targeting MTNR1B/Gαi2/SRC/ß-catenin axis.
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Biomarcadores Tumorais/deficiência , Neoplasias Ósseas/metabolismo , Condroma/metabolismo , Melatonina/farmacologia , Proteínas de Neoplasias/metabolismo , Recidiva Local de Neoplasia/metabolismo , Receptor MT2 de Melatonina/deficiência , Transdução de Sinais/efeitos dos fármacos , beta Catenina/metabolismo , Animais , Biomarcadores Tumorais/genética , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Condroma/tratamento farmacológico , Condroma/genética , Condroma/patologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas de Neoplasias/genética , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Receptor MT2 de Melatonina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , beta Catenina/genéticaRESUMO
Arthrogryposis is a group of phenotypically and genetically heterogeneous disorders characterized by congenital contractures of two or more parts of the body; the pathogenesis and the causative genes of arthrogryposis remain undetermined. We examined a four-generation arthrogryposis pedigree characterized by camptodactyly, limited forearm supination, and loss of myofibers in the forearms and hands. By using whole-exome sequencing, we confirmed MET p.Y1234C mutation to be responsible for arthrogryposis in this pedigree. MET p.Y1234C mutation caused the failure of activation of MET tyrosine kinase. A Met p.Y1232C mutant mouse model was established. The phenotypes of homozygous mice included embryonic lethality and complete loss of muscles that originated from migratory precursors. Heterozygous mice were born alive and showed reduction of the number of myofibers in both appendicular and axial muscles. Defective migration of muscle progenitor cells and impaired proliferation of secondary myoblasts were proven to be responsible for the skeletal muscle dysplasia of mutant mice. Overall, our study shows MET to be a causative gene of arthrogryposis and MET mutation could cause skeletal muscle dysplasia in human beings.
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Artrogripose/genética , Displasia Fibromuscular/genética , Músculo Esquelético/metabolismo , Mutação/genética , Exoma/genética , Humanos , Imunoprecipitação , Hibridização In Situ , Microscopia Eletrônica de Transmissão , Linhagem , Sequenciamento do ExomaRESUMO
This study aimed to verify the effects of estrogen on the onset and development of adolescent idiopathic scoliosis and the mechanisms associated with these effects by constructing a pubescent bipedal rat model. Experiments were conducted to investigate whether scoliosis progression was prevented by a Triptorelin treatment. One hundred twenty bipedal rats were divided into female, OVX (ovariectomy), OVX + E2, Triptorelin, sham, and male groups. According to a spinal radiographic analysis, the scoliosis rates and curve severity of the female and OVX + E2 groups were higher than those in the OVX, Triptorelin, and male groups. The measurements obtained from the sagittal plane of thoracic vertebrae CT confirmed a relatively slower growth of the anterior elements and a faster growth of the posterior elements between T11 and T13 in the female and OVX + E2 groups than in the OVX and Triptorelin groups. Histomorphometry and immunohistochemistry revealed a significantly longer hypertrophic zone of the vertebral cartilage growth plates that expressed more type X collagen and less type II collagen in the OVX and Triptorelin groups than in the female and OVX + E2 groups. Ki67 immunostaining confirmed an increase in the proliferation of vertebral growth plate chondrocytes in the OVX group compared with the female and OVX + E2 groups. In conclusion, estrogen obviously increased the incidence of scoliosis and curve severity in pubescent bipedal rats. The underlying mechanism may be a loss of coupling of the endochondral ossification between the anterior and posterior columns. Triptorelin decreased the incidence of scoliosis and curve magnitudes in bipedal female rats.
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Estrogênios/metabolismo , Osteogênese , Escoliose/metabolismo , Animais , Condrócitos/metabolismo , Feminino , Masculino , Ratos , Ratos Sprague-Dawley , Escoliose/prevenção & controle , Coluna Vertebral/metabolismo , Coluna Vertebral/patologia , Pamoato de Triptorrelina/uso terapêuticoRESUMO
BACKGROUND/AIMS: Three rare MAPK7 variants that predispose individuals to adolescent idiopathic scoliosis have previously been identified. However, the mechanism underlying the effects of the mutations remain unknown. METHODS: Human mesenchymal stem cells (hMSCs) were isolated from both patients and healthy volunteer donors, and MAPK7 expression was detected by western blotting and real-time quantitative PCR (RT-qPCR). Zebrafish embryos were injected with mapk7 morpholinos or co-injected with morpholinos and wild-type (WT) MAPK7 messenger RNA (mRNA) at the one-cell stage, followed by calcein staining to evaluate bone formation. hMSCs were transfected with MAPK7 small interfering RNAs and osteogenesis was induced for 14 days. Alizarin red staining was performed and osteoblast markers were detected by western blotting and RT-qPCR. Since RPS6KA3 is a downstream target of MAPK7 and plays an important role in the osteogenesis, zebrafish embryos were then injected with rps6ka3 morpholinos, or co-injected with rps6ka3 or mapk7 morpholinos and WT RPS6KA3 mRNA at the one-cell stage. RESULTS: MAPK7 expression in the patient group was much lower than in the control group. Morpholino-induced mapk7 knockdown in zebrafish embryos led to body curvature, which was significantly reversed by WT MAPK7 mRNA. Calcein staining revealed that mapk7-knockdown delayed the ossification of the vertebrae. MAPK7 silencing in hMSCs impaired osteogenesis and downregulated osteoblast marker expression. Morpholino-induced rps6ka3-knockdown in zebrafish embryos led to body curvature, which was reversed by WT RPS6KA3 mRNA. Interestingly, RPS6KA3 mRNA also partially reversed the phenotype induced by mapk7 morpholinos. CONCLUSION: Impaired osteogenesis is linked to mutant MAPK7-induced idiopathic scoliosis , and RPS6KA3 may play an important role in this process.
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Proteína Quinase 7 Ativada por Mitógeno/genética , Osteogênese , Escoliose/patologia , Animais , Células da Medula Óssea/citologia , Diferenciação Celular , Células Cultivadas , Regulação para Baixo , Embrião não Mamífero/metabolismo , Fluoresceínas/metabolismo , Humanos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Proteína Quinase 7 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 7 Ativada por Mitógeno/metabolismo , Morfolinos/metabolismo , Osteoblastos/citologia , Osteoblastos/metabolismo , Polimorfismo de Nucleotídeo Único , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Escoliose/metabolismo , Curvaturas da Coluna Vertebral/diagnóstico por imagem , Curvaturas da Coluna Vertebral/patologia , Peixe-Zebra/crescimento & desenvolvimentoRESUMO
BACKGROUND: Multiple epiphyseal dysplasia (MED) is a heterogeneous genetic condition characterized by variable phenotypes, such as short stature (mild to moderate), joint deformities, abnormal gait, scoliosis, and brachydactyly. Recessive mutations in the SLC26A2 gene cause a phenotype of multiple epiphyseal dysplasia-4 (MED-4). In the present study, we identified novel compound heterozygous mutations in the SLC26A2 gene in a Chinese family with two affected sibs with MED-4. CASE PRESENTATION: Radiographs revealed hip dysplasia, brachydactyly and scoliosis in patient 1. Radiological examinations in patient 2 also showed hip dysplasia recently. Both of them were diagnosed with MED-4. SLC26A2 c.824 T > C and SLC26A2 c.1198C > T were identified in two siblings in this family, which were inherited from both parents, one mutation from each. CONCLUSIONS: This is the first Chinese MED-4 family attributed to SLC26A2 mutations, and these results show that these novel compound heterozygous mutations in SLC26A2 contribute to MED-4.
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Mutação , Osteocondrodisplasias/genética , Patela/anormalidades , Análise de Sequência de DNA/métodos , Transportadores de Sulfato/genética , Criança , China , Feminino , Predisposição Genética para Doença , Heterozigoto , Humanos , Masculino , Osteocondrodisplasias/diagnóstico por imagem , Patela/diagnóstico por imagem , Linhagem , IrmãosRESUMO
Adolescent idiopathic scoliosis (AIS) is a complex genetic disorder characterized by three-dimensional spinal curvatures, affecting 2%-3% of school age children, yet the causes underlying AIS are not well understood. Here, we first conducted a whole-exome sequencing and linkage analysis on a three-generation Chinese family with autosomal-dominant (AD) AIS, and then performed targeted sequencing in a discovery cohort comprising 20 AD AIS families and 86 simplex patients, and finally identified three disease-associated missense variants (c.886G> A, c.1943C> T, and c.1760C> T) in the MAPK7 gene (encoding mitogen-activated protein kinase 7). Genotyping of the three rare variants in a Chinese replication cohort comprising 1,038 simplex patients and 1,841 controls showed that their combined allele frequency was significantly over-represented in patients as compared with controls (2.0% [41/2,076] vs. 0.7% [27/3,682]; odds ratio = 2.7; P = 2.8 × 10-5 ). In vitro, we demonstrated that the three MAPK7 mutants disrupted nuclear translocation in cellular models, which is necessary for the normal function of MAPK7. In vivo, we also conducted CRISPR/Cas9-mediated deletion of mapk7 in zebrafish recapitulating the characteristic phenotype of idiopathic scoliosis. Taken together, our findings suggest that rare coding variants in MAPK7 predispose to AIS, providing clues to understanding the mechanisms of AIS.