Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Thanatophoric Dysplasia Type 1. Core disease mechanisms, molecular and cel...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 19
• Snippets retrieved: 20

Relevant Papers

[1] A Roadmap to Gene Discoveries and Novel Therapies in Monogenic Low and High Bone Mass Disorders

• Authors: M. Formosa, D. Bergen, C. Gregson, A. Maurizi, A. Kämpe et al.
• Year: 2021
• Venue: Frontiers in Endocrinology
• URL: https://www.semanticscholar.org/paper/be13ff3ea01dc5719f2c63b2cbf5d9f77bafd659
• DOI: 10.3389/fendo.2021.709711
• PMID: 34539568
• PMCID: 8444146
• Citations: 21
• Summary: The monogenic forms of rare low and high rare bone Mass disorders known to date are described, a roadmap to unravel the genetic determinants of monogenic rare bone mass disorders is provided, using proper phenotyping and genotyping methods are provided, and different genetic validation approaches paving the way for future treatments are described.
• Evidence snippets:
• Snippet 1 (score: 0.450) > Skeletal development is regulated by numerous genetic factors that guide the growth, modeling and remodeling of skeletal structures starting in early fetal development and continuing throughout life. These processes are crucial for attainment of normal height, skeletal patterning, bone shape, and mobility, but also for maintenance of normal bone mass and fracture resistance. Defects in the involved genes result in a large and heterogeneous group of disorders, collectively called skeletal dysplasias, in which the primary features are confined to the skeleton. More than 460 different forms of skeletal dysplasia, most of them monogenic, have been recognized (1). They are estimated to affect approximately 1/5,000 children (2,3), and can have distinct clinical manifestations and course. Clinical outcomes range in severity from neonatal lethality to only mild growth retardation, deformity or fracture risk. Diagnosis is based on growth pattern and other clinical characteristics, skeletal imaging, bone density testing, biochemical diagnostics, and genetic tests. Although the genetic basis has been described and mutations in the responsible genes identified in a significant proportion of these conditions, for several distinct skeletal dysplasia phenotypes the genetic cause is still not known (1). > Within this large group of genetic skeletal disorders, monogenic disorders affecting bone mass comprise an expanding subgroup (1,4). This includes disorders with low bone mass and skeletal fragility, and disorders leading to increased bone mass, both commonly associated with extraskeletal complications (5,6). Due to significant variability in severity, diagnosis can be challenging. Importantly, the underlying molecular genetic mechanisms for these disorders remain inadequately explored and, in several entities, the causative genetic defect, and underlying cellular and molecular pathophysiology are still uncharacterized. > The various skeletal dysplasia delineated to date have provided important information about the molecular pathways governing skeletal health both in these conditions and in the general population, underscoring the significance of new gene discoveries not only for the individuals affected by the monogenic rare bone mass disorder, but also more widely to the musculoskeletal research field (7). Indeed, the large wealth of data generated from monogenic and polygenic bone mass disorders, frailty and other musculoskeletal traits, have led

[2] EndoCompass Project: Research Roadmap for Calcium and Bone Endocrinology

• Authors: K. Jähn-Rickert, K. Z. Tomsic, A. Anastasilakis, Jean-Philippe Bertocchio, M. L. Brandi et al.
• Year: 2025
• Venue: Hormone Research in Pædiatrics
• URL: https://www.semanticscholar.org/paper/fccbdcae3a86c448632e05f9c38ad2563c14284d
• DOI: 10.1159/000549160
• PMID: 41296665
• PMCID: 12698132
• Summary: This framework identifies crucial investigation areas into metabolic bone disease pathophysiology, prevention, and treatment strategies, ultimately aimed at reducing the burden of these disorders on individuals and society.
• Evidence snippets:
• Snippet 1 (score: 0.446) > Skeletal dysplasias encompass a large spectrum of genetic disorders of the skeleton with abnormal bone growth, structure, or strength [85]. Individually, they are rare but, collectively, due to the large number of skeletal dysplasias (>700), they result in significant morbidity. The underlying pathology remains inadequately understood and the optimal therapy is often undefined, with precision drug treatment targeting the underlying molecular mechanism not available for most skeletal dysplasias. Gene discoveries have increased exponentially, demonstrating the value of advanced genetic tools and motivating further research into the complex pathogenesis of skeletal dysplasias. > However, further basic research is required to uncover the cellular pathology and implicated molecular pathways in various forms of skeletal dysplasia. Understanding the pathophysiology of skeletal dysplasias may also benefit a larger patient population. This is evidenced by anti-sclerostin treatment for osteoporosis [86] which, at present, is in clinical trials for osteogenesis imperfecta. Preclinical data show positive effects on bone mass and strength [87]. > The spectrum of disease manifestations of various skeletal dysplasias in different phases of life and health projections across the life course remain inadequately studied. Research on therapeutic approaches needs to focus not only on correcting the pathophysiology but also, more broadly, on surgical approaches, rehabilitation, functional/environmental adaptations, preventative measures, pain management, psychological support, and quality of life. Patient groups must be involved in identifying these research goals. International registries should be utilized to collect and analyse such data. > A multidisciplinary approach is of particular importance in genetic skeletal disorders, to enable cohesive care throughout the life course. The patients have a range of physical impairments due to their skeletal disorder, but also a disease-specific spectrum of extraskeletal manifestations requiring medical attention. These may include, for example, dental and oral health problems, immune deficiency, impaired hearing, and neurological or ophthalmologic manifestations.

[3] Mitochondrial Dysfunction in Diabetes: Shedding Light on a Widespread Oversight

• Authors: F. Iheagwam, A. J. Joseph, E. D. Adedoyin, Olawumi Toyin Iheagwam, Samuel Akpoyowvare Ejoh
• Year: 2025
• Venue: Pathophysiology
• URL: https://www.semanticscholar.org/paper/dbf8042761c1a5fc50f8cd894cc498505abac7cb
• DOI: 10.3390/pathophysiology32010009
• PMID: 39982365
• PMCID: 12077258
• Citations: 23
• Summary: This review aims to elucidate the complex link between mitochondrial dysfunction and diabetes, covering the spectrum of diabetes types, the role of mitochondria in insulin resistance, highlighting pathophysiological mechanisms, mitochondrial DNA damage, and altered mitochondrial biogenesis and dynamics.
• Evidence snippets:
• Snippet 1 (score: 0.436) > The landscape of DM research is continuously evolving, with emerging technologies and approaches offering new insights into the pathophysiology of the disease and potential therapeutic targets. Advancements in omics technologies, encompassing genomes, transcriptomics, proteomics, and metabolomics, have transformed the molecular mechanisms underlying DM [134]. High-throughput sequencing techniques enable comprehensive analysis of genetic variants, gene expression profiles, protein abundance, and metabolite levels associated with DM and its complications [135]. Single-cell omics approaches provide unprecedented resolution and granularity, allowing researchers to dissect cellular heterogeneity and identify novel cell types, subpopulations, and signalling pathways involved in DM pathogenesis. Integrating multi-omics data sets offers a systems-level perspective of DM, unravelling complex networks of molecular interactions and regulatory circuits underlying disease progression [136]. > In addition to omics technologies, advances in imaging modalities, such as MRI, PET, and optical imaging, enable non-invasive visualisation and quantification of metabolic, functional, and structural changes. Molecular imaging probes targeting specific biomarkers and metabolic pathways provide valuable insights into disease mechanisms and treatment responses in preclinical and clinical settings [85]. Despite significant progress in DM research, numerous unanswered questions and knowledge gaps persist, hindering the ability to develop effective prevention and treatment strategies. Key areas requiring further investigation include the role of epigenetics, environmental factors, and the microbiome in DM susceptibility and progression. Moreover, the interaction between environmental cues and genetic predisposition remains incompletely understood, highlighting the need for comprehensive multi-omics studies and large-scale epidemiological analyses to identify gene-environment interactions and modifiable risk factors for DM [137]. Furthermore, the heterogeneity of DM phenotypes and clinical outcomes poses a challenge for personalised medicine approaches, necessitating robust biomarkers and predictive models to stratify patients based on disease subtypes, prognosis, and treatment response [138].

[4] High Fidelity of Mouse Models Mimicking Human Genetic Skeletal Disorders

• Authors: R. Brommage, C. Ohlsson
• Year: 2020
• Venue: Frontiers in Endocrinology
• URL: https://www.semanticscholar.org/paper/3b9e1d0da086028d9f89e99a06b7222353ab6b2d
• DOI: 10.3389/fendo.2019.00934
• PMID: 32117046
• PMCID: 7010808
• Citations: 25
• Influential citations: 1
• Summary: Data is organized for 441 human genetic bone disorders with regard to heredity, gene function, molecular pathways, and fidelity of relevant mouse models to mimic the human skeletal disorders to identify mutant genes responsible for human rare genetic skeletal disorders.
• Evidence snippets:
• Snippet 1 (score: 0.414) > Rare human genetic diseases cumulatively affect about 1 in 200 individuals and involve an estimated 7,000 genes. Major research efforts are underway to identify these mutant genes and characterize their disease phenotypes. Knowledge gained can guide therapies and provide hypotheses to develop future treatments. As recently summarized (1), "Genome sequencing has revolutionized the diagnosis of genetic diseases. Close collaborations between basic scientists and clinical genomicists are now needed to link genetic variants with disease causation. To facilitate such collaborations, we recommend prioritizing clinically relevant genes for functional studies, developing reference variant-phenotype databases, adopting phenotype description standards, and promoting data sharing." > Rare human genetic skeletal dysplasias affect about 1 in 5,000 individuals (2) and account for 5% of all birth defects (3). The International Skeletal Dysplasia Society (ISDS, https://www.isds. ch), promotes scientific progress in the field of skeletal dysplasias and dysostoses, meets every second year, and published skeletal nosology summaries during 2001 (4), 2006 (5), 2010 (6), 2015 (7), and 2019 (8). There are presently 441 skeletal nosology genes, with an average of 20 new genes identified yearly (Figure 1). The classification aims to (i) identify metabolic pathways active in cartilage and bone, and their regulatory mechanisms; (ii) identify cellular signaling networks and gene expression sequences implicated in skeletal development; (iii) identify candidate genes for genetic disorders; (iv) facilitate integration of data coming from spontaneous and genetically engineered mouse mutants; (v) help in developing diagnostic strategies; (vi) stimulate the design and exploration of new therapeutic possibilities; and (vii) provide a knowledge framework accessible to physicians as well as to basic scientists and thus to facilitate communication between clinical genetics and pediatrics and the basic sciences (4). > The objectives of the present review include further characterizations of these 441 skeletal nosology genes and evaluating the reliability of mutant mouse models to mimic these human skeletal disorders.

[5] Human Dermal Fibroblast: A Promising Cellular Model to Study Biological Mechanisms of Major Depression and Antidepressant Drug Response

• Authors: P. Mesdom, R. Colle, É. Lebigot, S. Trabado, Eric Deflesselle et al.
• Year: 2020
• Venue: Current Neuropharmacology
• URL: https://www.semanticscholar.org/paper/79368e365458486de96794333613c12a6063bf54
• DOI: 10.2174/1570159X17666191021141057
• PMID: 31631822
• PMCID: 7327943
• Citations: 12
• Summary: This review highlights the great and still underused potential of HDF, which stands out as a very promising tool in the understanding of MDD and AD mechanisms of action.
• Evidence snippets:
• Snippet 1 (score: 0.411) > Background: Human dermal fibroblasts (HDF) can be used as a cellular model relatively easily and without genetic engineering. Therefore, HDF represent an interesting tool to study several human diseases including psychiatric disorders. Despite major depressive disorder (MDD) being the second cause of disability in the world, the efficacy of antidepressant drug (AD) treatment is not sufficient and the underlying mechanisms of MDD and the mechanisms of action of AD are poorly understood. Objective The aim of this review is to highlight the potential of HDF in the study of cellular mechanisms involved in MDD pathophysiology and in the action of AD response. Methods The first part is a systematic review following PRISMA guidelines on the use of HDF in MDD research. The second part reports the mechanisms and molecules both present in HDF and relevant regarding MDD pathophysiology and AD mechanisms of action. Results HDFs from MDD patients have been investigated in a relatively small number of works and most of them focused on the adrenergic pathway and metabolism-related gene expression as compared to HDF from healthy controls. The second part listed an important number of papers demonstrating the presence of many molecular processes in HDF, involved in MDD and AD mechanisms of action. Conclusion The imbalance in the number of papers between the two parts highlights the great and still underused potential of HDF, which stands out as a very promising tool in our understanding of MDD and AD mechanisms of action

[6] A Comprehensive Study of De Novo Mutations on the Protein-Protein Interaction Interfaces Provides New Insights into Developmental Delay

• Authors: Dhruba Tara Maharjan, Weichen Song, Zhe Liu, Weidi Wang, Wenxiang Cai et al.
• Year: 2022
• Venue: Biomolecules
• URL: https://www.semanticscholar.org/paper/cf81638fe2c43e5a6dc5bf24e4523f0f192068db
• DOI: 10.3390/biom12111643
• PMID: 36358993
• PMCID: 9687726
• Summary: A comprehensive study indicated the significant role of PPI interface DNMs in developmental delay pathogenicity and identified 302 DD-related PsychiPPIs, defined as PPIs harboring a statistically significant number of DNM missenses at their interface, and 42 DD candidate genes from Psychi PPI.
• Evidence snippets:
• Snippet 1 (score: 0.409) > Several FGFR3 de novo mutations were identified in thanatophoric dysplasia (TD) patients.Some patients with these mutations have an intellectual disability and severe skeletal deformities, which correspond to the symptom of DD [95].Additionally, research has shown that ALOX5 is related to memory deficits and synaptic dysfunction in a mouse model of Alzheimer's disease [96].Despite the supportive evidence, our hypothesis is not entirely settled.Studies involved in cell or animal models are required to prove our findings. > This study showed a significant association between PPI interface DNMs and developmental delay, combined with our PsychiPPI-based disease-related genes searching framework.With the development of whole exome sequencing, researchers worldwide could identify thousands of DNM missenses in a large-scale study within a relevantly short time.We may contribute to discovering disease mechanisms and early diagnosis of developmental delay and other potential neuropsychiatric diseases.

[7] Investigating the role of NPR1 in dilated cardiomyopathy and its potential as a therapeutic target for glucocorticoid therapy

• Authors: Yaomeng Huang, Tongxin Li, Shichao Gao, Shuyu Li, Xiaoran Zhu et al.
• Year: 2023
• Venue: Frontiers in Pharmacology
• URL: https://www.semanticscholar.org/paper/be229f6f2059faab4c97ec0a04bd055adab9dfe1
• DOI: 10.3389/fphar.2023.1290253
• PMID: 38026943
• PMCID: 10662320
• Citations: 3
• Summary: Natriuretic peptide receptor 1 (NPR1) was identified as a core gene associated with DCM through bioinformatics analysis and led to substantial improvements in cardiac and renal function, accompanied by an upregulation of NPR1 expression.
• Evidence snippets:
• Snippet 1 (score: 0.408) > Multiple pathways and molecules are involved in this process; however, the detailed underlying mechanisms remain unclear. In recent years, with the development of high-throughput sequencing and gene chip technologies, the use of bioinformatics technology to explore the occurrence, development, and prognosis of diseases has become a hot topic for scholars worldwide (Hwang et al., 2018;Nayor et al., 2019;Rinschen et al., 2019;Sturm et al., 2019;Montaner et al., 2020). > The present study aimed to use bioinformatics technology to screen for DCM-related genes and investigate their mechanisms, with the purpose of revealing the pathogenesis of DCM and seeking treatment methods. The GSE3586 dataset, containing expression profiles related to DCM, was selected from the Gene Expression Omnibus (GEO) database. This study aimed to predict the core genes that may play crucial roles in disease progression at the molecular level through the enrichment of relevant molecular pathways associated with DCM. Furthermore, the phenotype of the core genes was validated to further support the results of the bioinformatics analysis through basic and clinical experiments. Additionally, the role of glucocorticoids in DCM treatment is discussed in this article with the purpose of providing a theoretical and experimental basis for exploring the pathogenesis of DCM and elucidating therapeutic methods. This study also provides a theoretical reference for the interpretation, early diagnosis, and treatment of DCM.

[8] New therapeutic targets in rare genetic skeletal diseases

• Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
• Year: 2015
• Venue: Expert Opinion on Orphan Drugs
• URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
• DOI: 10.1517/21678707.2015.1083853
• PMID: 26635999
• PMCID: 4643203
• Citations: 37
• Influential citations: 1
• Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
• Evidence snippets:
• Snippet 1 (score: 0.404) > proteins of the cartilage ECM such as type II collagen [50]. However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e. chondrocyte) to the abnormal extracellular environment is also important for disease progression as illustrated by several GSDs discussed in this review. > It is important that 'omics'-based approaches and technologies are systematically applied to the study of rare GSDs so that definitive reference profiles and disease signatures are generated for each phenotype. These can then be used in a Systems Biology approach to identify both common and dissimilar pathological signatures and disease mechanisms. This approach is entirely dependent upon relevant in vitro and in vivo models (and also novel 'disease-mechanism phenocopies' [107]) for testing new diagnostic and prognostic tools and for determining the molecular mechanisms that underpin the pathophysiology so that effective therapeutic treatments can be developed and validated. This approach will eventually lead to personalized treatments and care strategies centred on shared disease mechanisms with the use of relevant biomarkers to monitor the efficacy of treatment and disease progression. > It is vital that all relevant stakeholders are involved from the outset in defining the appropriate outcomes of any potential therapeutic regime. The perceptions of a successful therapy can differ widely between the clinical academic community and the relevant patient-support groups and it is vital that there is engagement on all these issues. > In summary, the identification of causative genes and mutations for GSDs over the last 20 years, coupled with the generation and in-depth analysis of a plethora of relevant cell and mouse models, has derived new knowledge on disease mechanisms and suggested potential therapeutic targets. The fast-evolving hypothesis that clinically disparate diseases can share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
• Snippet 2 (score: 0.386) > The extensive clinical variability and genetic heterogeneity of GSDs, coupled with complex disease mechanisms, renders this extensive group of rare diseases a bench to bedside challenge. Indeed, this large number of different and highly complex phenotypes makes the identification, validation and development of potential therapies almost impossible for anything other than the most common GSDs. As an alternative approach, we might consider identifying genotype-and/or phenotype-independent 'core disease mechanisms' that are shared amongst families of clinically unrelated GSDs. This approach would allow the focusing of resources into several areas of concerted investigation that have the potential to identify and validate therapeutic targets with a broad application to GSDs, inherited connective tissues as a whole and rare genetic disease in general. Indeed, Jürgen Spranger first suggested the idea of 'bone dysplasia families' in 1985 [124] and proposed that phenotypes with a similar clinical and radiographic phenotype would likely have a similar disease mechanism. Thirty years later, we can now expand upon this pioneering concept and propose that common disease mechanisms can also be shared amongst clinically different phenotypes ('common amongst the rare'). > In this context, ER stress has been associated with a diverse range of genetic diseases and chronic conditions such as skeletal dysplasia (as discussed in this review), myopathy [125], cerebro-vascular [42], kidney [126], ischaemia and cardiovascular diseases [127]. Moreover, ER stress is emerging as a very attractive target that is being successfully exploited in a broad range of diseases including neuropathy, juvenile-onset openangle glaucoma, obesity, diabetes, asthma and epidermolysis bullosa, to name but a few. Historically many GSDs were considered diseases of the ECM and proposed therapeutic interventions involved the removal and/or correction of the relevant mutated gene or abnormal gene product. This was particularly the case with dominant-negative mutations in the large structural proteins of the cartilage ECM such as type II collagen [50]. However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e.

[9] Nasopharyngeal Carcinoma Signaling Pathway: An Update on Molecular Biomarkers

• Authors: W. Tulalamba, T. Janvilisri
• Year: 2012
• Venue: International Journal of Cell Biology
• URL: https://www.semanticscholar.org/paper/307cb9186444d9dad6e2e3b53763be0de76de186
• DOI: 10.1155/2012/594681
• PMID: 22500174
• PMCID: 3303613
• Citations: 93
• Influential citations: 5
• Summary: The molecular signaling pathways in the NPC are discussed for the holistic view of NPC development and progression and the important insights toward NPC pathogenesis may offer strategies for identification of novel biomarkers for diagnosis and prognosis.
• Evidence snippets:
• Snippet 1 (score: 0.402) > In the pregenomic eras, highly integrated and complex circuitry of molecular signaling in NPC pathogenesis was only partially understood. Over the past decade, the knowledge of the molecular mechanisms in NPC carcinogenesis has been rapidly accumulated. Dysregulation and abnormal protein expression of molecules in certain signaling pathways involved in cellular functions including proliferation, adhesion, survival, and apoptosis has been demonstrated in the NPC cells. Detailed information on the complex network in signaling pathway leading to a coordinated pattern of gene expression and regulation in NPC will undoubtedly provide important clues to develop novel prognostic and therapeutic strategies for this cancer. Refining molecular markers into clinically relevant assays may assist in the detection of NPC in asymptomatic patients, as well as stage classification and monitoring disease progression and treatments. Furthermore, selective regulation of particular proteins targeting cancer cell proliferation, invasion, and apoptosis is a hopeful prospect for future anticancer therapy that slow disease progression and improve survival.

[10] Signaling Pathways in Bone Development and Their Related Skeletal Dysplasia

• Authors: Alessandra Guasto, V. Cormier-Daire
• Year: 2021
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/c5466b45e1a7e5aa8e7ad05c7d9287a9e84e9262
• DOI: 10.3390/ijms22094321
• PMID: 33919228
• PMCID: 8122623
• Citations: 51
• Summary: The principal signaling pathways involved in bone development and their associated skeletal dysplasia are reviewed and genotype–phenotype correlations have helped to elucidate their role in skeletogenesis.
• Evidence snippets:
• Snippet 1 (score: 0.400) > In this review, we discussed the main signaling pathways involved in bone development and how mutations in their components have been associated with SD. It is important to highlight that even if the signaling pathways have been discussed independently, there is a complex cross-talk among them at multiple levels. This, in association with the evidence that the mutation consequences depend on the specificity of the mutations and on their temporal and spatial mode of action, makes more difficult the understanding of the physiopathological mechanisms of these diseases. Moreover, these signaling pathways can be secondarily affected by alterations in other cellular processes, such as extracellular matrix regulation or metabolic processing. Indeed, several skeletal dysplasia, that we decided to omit in this review, have been associated with mutations in these processes. Fortunately, in the last decade, the development of new technologies, like whole exome and genome sequencing has accelerated the identification of skeletal dysplasia-causing mutations. On the other hand, the development of CRISPR-Cas9 technology and of several mouse models is helping the deciphering of the physiopathological mechanisms. Advanced genetic testing is also helping the diagnosis of skeletal dysplasia. The diagnosis and management of these pathologies have long been based on clinical feature and skeletal imaging. Today, these key techniques are increasingly combined with the genetic testing in order to obtain a more accurate and early diagnosis of SD. It also aids in prognosis and in counselling families regarding genetic recurrence risk and preconceptional reproductive planning [212][213][214]. These continuous discoveries will help to expand the genotype-phenotype correlation of SD and to develop new therapeutic strategies. Nowadays, few treatments are available for SD, but several clinical trials are ongoing to validate new drugs targeting specifically these pathways in achondroplasia or FOP for example, and highlighting the importance of multidisciplinary cross talks (from bed to bench side) [215].

[11] Changes in Serum Proteomic Profiles at Different Stages of Pregnancy Toxemia in Goats

• Authors: M. Uzti̇mür, C. N. Ünal, Gurler Akpinar
• Year: 2025
• Venue: Journal of Veterinary Internal Medicine
• URL: https://www.semanticscholar.org/paper/4b9c488b5dbd65d7b26fd2ad9aed70e8c4b59942
• DOI: 10.1111/jvim.70139
• PMID: 40492724
• PMCID: 12150350
• Summary: Understanding the serum proteome profiles of goats with pregnancy toxemia might help identify the proteomes and pathways responsible for the development of this disease and improve diagnosis and treatment.
• Evidence snippets:
• Snippet 1 (score: 0.400) > The pathophysiology and progression of this disease are not fully understood. > Traditional biomedical research has focused on the analysis of single genes, proteins, metabolites, or metabolic pathways in diseases. This molecular reductionist approach is based on the assumption that identifying genetic variations and molecular components will lead to new treatments for diseases [13][14][15][16]. However, many diseases are complex and multifactorial, and in order to determine the phenotype of such diseases, it is necessary to understand the changes that occur in more than one gene, pathway, protein, or metabolite at the cellular, tissue, and organismal levels [17][18][19]. Therefore, in recent years, proteomics, as one field of multi-omics technologies, has helped in evaluating the complex pathogenetic mechanisms of different diseases from a broad perspective and has made substantial contributions [20,21]. In veterinary medicine, proteomic analysis of metabolic diseases such as ketosis [16], hypocalcemia [22], and fatty liver [23] in dairy cows has contributed valuable insights for the definition of new pathophysiological pathways and new diagnosis and treatment protocols for these diseases. The proteomic approach can contribute importantly to a broad and detailed understanding of the changes that occur at the organismal level associated with the increase in BHBA concentration in goats with pregnancy toxemia. Our aim was to evaluate the serum protein profiles of goats with SPT or CPT using proteomic techniques to determine the proteomic profiles of these animals and to identify the relevant pathophysiological mechanisms.

[12] Induction of a Massive Endoplasmic Reticulum and Perinuclear Space Expansion by Expression of Lamin B Receptor Mutants and the Related Sterol Reductases TM7SF2 and DHCR7

• Authors: Monika Zwerger, Thorsten Kolb, Karsten Richter, I. Karakesisoglou, H. Herrmann
• Year: 2010
• Venue: Molecular Biology of the Cell
• URL: https://www.semanticscholar.org/paper/61372770eb4e88e4e59ad4713d36b140c007ecf4
• DOI: 10.1091/mbc.E09-08-0739
• PMID: 19940018
• PMCID: 2808238
• Citations: 53
• Influential citations: 3
• Summary: Study of disease-related lamin B receptor mutant proteins and of the related sterol reductases TM7SF2 and DHCR7 in human cultured cells revealed that some of the tested protein variants massively interfered with regular organization of the endoplasmic reticulum, the nuclear envelope, and the nucleus.
• Evidence snippets:
• Snippet 1 (score: 0.398) > These mutations can lead to Pelger-Hue ¨t anomaly (PHA) or to Greenberg skeletal dysplasia. PHA in the heterozygous state is a mild condition in which the granulocytes of affected individuals display hypolobulated nuclei. Immunoblot analysis of lymphoblastoid cells from heterozygous patients displayed approximately half of the wild-type LBR amount compared with control cells, whereas no mutated protein was detected. Apart from the abnormal nuclear morphology, no other clinical symptoms have been described in the heterozygous state. In one case of diagnosed PHA homozygosity with a splice site mutation, no mutant protein was detected but only trace amounts of normally spliced ("wild-type") LBR. This homozygous patient presented with mental retardation and disproportionate body stature, and his neutrophils had round, nonsegmented nuclei (Hoffmann et al., 2002). > Greenberg skeletal dysplasia is an autosomal recessive, severe chondrodystrophy characterized by fetal hydrops, abnormal chondro-osseous calcification and lethality of the fetuses (Oosterwijk et al., 2003;Waterham et al., 2003). Although elevated levels of an abnormal cholesterol precursor were detected in skin fibroblasts of an affected fetus, it was suggested that this disease represents an envelopathy rather than a defect in the cholesterol biosynthesis pathway (Waterham et al., 2003;Wassif et al., 2007). > Hardly anything is known about the molecular mechanisms leading to these diseases, and tissue material of Greenberg skeletal dysplasia affected fetuses is rare. Furthermore, because LBR is a dual-function protein, mutations might interfere with different cellular processes, such as cholesterol biosynthesis, NE function, and chromatin structure. > The purpose of our study was to investigate the cellular effects that are associated with the expression of human LBR disease mutants. We demonstrate that mutations in LBR can strongly affect the organization of NE components and the nuclear structure of cultured cells.

[13] National survey of prevalence and prognosis of thanatophoric dysplasia in Japan

• Authors: H. Sawai, Kaname Oka, Mariko Ushioda, G. Nishimura, T. Omori et al.
• Year: 2019
• Venue: Pediatrics International
• URL: https://www.semanticscholar.org/paper/e23e5206d3c38544903bccbd18b15535dfbbbf7c
• DOI: 10.1111/ped.13927
• PMID: 31247124
• PMCID: 6852317
• Citations: 11
• Influential citations: 1
• Summary: Investigation of the prevalence and prognosis of Thanatophoric dysplasia in Japan finds that the disease is a rare congenital disease of the skeletal system and the prognosis is poor.
• Evidence snippets:
• Snippet 1 (score: 0.395) > National survey of prevalence and prognosis of thanatophoric dysplasia in Japan

[14] Multi‐gene panel sequencing in highly consanguineous families and patients with congenital forms of skeletal dysplasias

• Authors: Naseebullah Kakar, F. Rehman, Ramandeep Kaur, G. Bhavani, M. Goyal et al.
• Year: 2024
• Venue: Clinical Genetics
• URL: https://www.semanticscholar.org/paper/08f6a00a89b10f2208d3e03fb37a980a49142dfc
• DOI: 10.1111/cge.14509
• PMID: 38378010
• Citations: 2
• Summary: Panel sequencing proved to be a highly effective way to decipher the genetic basis of SKDs in highly consanguineous families as well as sporadic and or familial cases from South Asia, and expand the allelic spectrum of skeletal dysplasias.
• Evidence snippets:
• Snippet 1 (score: 0.391) > Inherited skeletal dysplasias (SKDs) are a heterogeneous group of developmental disorders of the skeleton, also known as osteochondrodysplasias, characterized by abnormal growth of bone and cartilage.The abnormal shape and size of the skeleton lead to disproportional long bones which can result in different types of SKDs. 1 Based on radiographic and molecular features SKDs are classified into distinct groups, including proportionate and disproportionate short stature, increased bone fragility, and skeletal deformities.SKDs show remarkable clinical and genetic heterogeneity that comprises more than 750 types. 2 Each type of SKD is rare, with the overall birth incidence rate worldwide estimated to be $1 of 3300 live births. 3Relatively common SKDs include osteogenesis imperfecta (OI) also known as brittle bone disease, osteopetrosis, achondroplasia, hypochondroplasia, campomelic dysplasia, and thanatophoric dysplasia. 4inically, SKDs can present with short stature, rhizomelic or mesomelic or acromelic limb shortening, bony deformities, or spine involvement.Genetic studies of inherited SKDs offer the opportunity to identify corresponding disease genes, thus providing significant clues in understanding the pathophysiology of these disorders. 5,6This can possibly contribute to the medical and surgical treatment options of the individuals affected with SKD in order to improve their quality of life and lifespan, as exemplified in the case of some genetic types of OI. > Over the past decade, next-generation sequencing (NGS) has enhanced the identification of variants in genes associated with rare diseases, including inherited skeletal dysplasia. 5,7,8Until recently the diagnosis of SKDs usually depended on the opinions of experienced clinicians or radiologists.However, multigene panel sequencing approaches now enable the identification of the underlying genetic cause of SKDs when pathogenic variants are identified, irrespective of the clinical diagnosis.

[15] Modelling Mitochondrial Disease in Human Pluripotent Stem Cells: What Have We Learned?

• Authors: Cameron L. McKnight, Y. C. Low, D. Elliott, D. Thorburn, Ann E. Frazier
• Year: 2021
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/bf41f9d980522896fcd2284bd630fbb418e55941
• DOI: 10.3390/ijms22147730
• PMID: 34299348
• PMCID: 8306397
• Citations: 20
• Summary: Mitochondrial diseases disrupt cellular energy production and are among the most complex group of inherited genetic disorders. Affecting approximately 1 in 5000 live births, they are both clinically and genetically heterogeneous, and can be highly tissue specific, but most often affect cell types with high energy demands in the brain, heart, and kidneys. There are currently no clinically validated treatment options available, despite several agents showing therapeutic promise. However, modell...
• Evidence snippets:
• Snippet 1 (score: 0.389) > Mitochondrial disease hPSC models provide a system to study disease gene-or mutation-related pathomechanisms in tissues relevant to the clinical phenotype. Ultimately, the long-term goal of these models would be to identify a phenotype in a clinically relevant cell type that could be used to validate efficacy of targeted treatments, or for use in highthroughput treatment trials [94][95][96] (Figure 2). > There are now a wide range of endpoints that have been validated in terminally differentiated cell types to investigate the underlying cellular mechanisms of disease and efficiently identify targetable pathways. Many of these approaches can also be adapted to suit different cell types and even organoids at scale. The tissue specific nature of mitochondrial diseases means that mitochondrial function post-differentiation can be distinct to that from the undifferentiated stem cells or original fibroblast line, often greatly exaggerating any underlying defects [97]. Additionally, detailed transcriptomic and proteomic analyses can elucidate cellular compensation mechanisms and potential target pathways to inform downstream treatment studies [98,99]. Other approaches include microscopic visualization of key cellular features to determine a mutation's impact on cell structure or function [100]. For cardiomyocytes and neurons, electrophysiology can provide highly sensitive data to identify even subtle functional changes [101]. Calcium imaging can be particularly informative in the context of mitochondrial diseases, since calcium handling is a key role of mitochondria [102,103].

[16] Targeting Hepatic Stellate Cells for the Prevention and Treatment of Liver Cirrhosis and Hepatocellular Carcinoma: Strategies and Clinical Translation

• Authors: Hao Xiong, Jinsheng Guo
• Year: 2025
• Venue: Pharmaceuticals
• URL: https://www.semanticscholar.org/paper/76e92127053136900f7e3f10e2c9278251ced5d2
• DOI: 10.3390/ph18040507
• PMID: 40283943
• PMCID: 12030350
• Citations: 7
• Summary: HSC-targeted approaches using specific surface markers and receptors may enable the selective delivery of drugs, oligonucleotides, and therapeutic peptides that exert optimized anti-fibrotic and anti-HCC effects.
• Evidence snippets:
• Snippet 1 (score: 0.387) > Significant progress has been made in elucidating the cellular and molecular mechanisms of liver fibrosis; however, only a few findings have been successfully translated into clinical applications. Firstly, the high cost of drug development and target validation necessitates prolonged timelines and substantial financial investment. Secondly, as regulatory requirements become more stringent, there is an increasing demand for drugs with well-defined clinical efficacy and safety profiles. Moreover, the efficacy observed in animal models often fails to fully translate to clinical settings due to differences in pharmacokinetics, extracellular matrix (ECM) cross-linking, and disease pathophysiology. Despite advancements in anti-fibrotic drug development, accurately identifying ideal noninvasive biomarkers for fibrotic activity and establishing consensus on optimal clinical endpoints remain significant challenges [113,114]. > Currently, addressing the underlying cause remains the only proven strategy to halt or reverse liver fibrosis progression, while the development of effective anti-fibrotic therapies continues to pose a major challenge in liver disease management. Over the past few decades, substantial progress has been made in elucidating the cellular and molecular mechanisms underlying liver fibrosis. Liver fibrosis is a complex pathological change involving multiple cells, factors, and pathways, and the study of the cellular and molecular mechanisms of its occurrence and development provides an important theoretical basis and therapeutic target for clinical drug development. It is anticipated that improved animal models and well-designed clinical trials will facilitate the successful translation of anti-fibrotic research into effective clinical treatments in the near future.

[17] WNT Signaling and Bone: Lessons From Skeletal Dysplasias and Disorders

• Authors: Yentl Huybrechts, G. Mortier, E. Boudin, W. Van Hul
• Year: 2020
• Venue: Frontiers in Endocrinology
• URL: https://www.semanticscholar.org/paper/00fd0aa090f258a34c6590bc3dee4b211ecb0929
• DOI: 10.3389/fendo.2020.00165
• PMID: 32328030
• PMCID: 7160326
• Citations: 95
• Summary: This review discusses the skeletal disorders that are included in the latest nosology of skeletal disorders and that are caused by genetic defects involving the Wingless and int-1 (WNT) signaling pathway.
• Evidence snippets:
• Snippet 1 (score: 0.386) > The identification of novel disease-causing genes for rare skeletal dysplasias accelerated significantly in the last decades, initially by positional cloning efforts and more recently by the availability of next-generation sequencing technology. This resulted in the identification of the disease-causing gene for 92% of the skeletal disorders (6). The increased knowledge on monogenic diseases resulted in a better understanding of the pathological mechanisms and highlighted which pathways regulate specific cellular processes. This information is also relevant for understanding more common multifactorial diseases. Furthermore, it has been shown that therapeutic targets which are based on genetic evidence from Mendelian traits as well as genome-wide association studies (GWASs) are more likely to be successful in clinical studies for multifactorial diseases (150). Here, we focused on skeletal dysplasias caused by mutations in genes that encode proteins that are directly involved in one of the WNT signaling pathways. As shown in Table 1, mutations in these genes can result in a variety of skeletal dysplasias, each with specific clinical features. The broad spectrum of clinical observations reflect the cellular and spatial functions of WNT signaling, some of them associated with embryonal development, others with bone mass and homeostasis in adult life. For example, the clinical features of RS and OMOD are similar which led to the hypothesis that all causative genes are involved in the WNT/PCP pathway which is previously shown to be important during limb development (Figure 2) (102). On the other hand, the influence of canonical WNT signaling on bone mass was highlighted by unraveling the underlying pathogenic mechanisms of disorders with a progressively increasing bone mass such as sclerosteosis, Van Buchem disease, and high bone mass phenotypes (osteosclerosis) (51,53,57,107,113). The genes causing these disorders, SOST, LRP4, LRP5, and LRP6, are all involved in the canonical WNT signaling pathway (Figure 3), and all mutations reported result in an increased canonical WNT signaling (Table 1).

[18] Clinical metabolomics in type 2 diabetes mellitus: from pathogenesis to biomarkers

• Authors: Chuanxin Liu, Hetao Chen, Yujin Ma, Lei Zhang, Lulu Chen et al.
• Year: 2025
• Venue: Frontiers in Endocrinology
• URL: https://www.semanticscholar.org/paper/36f8d26a208b7b96763df2e9aa3211e440031c0e
• DOI: 10.3389/fendo.2025.1501305
• PMID: 40070584
• PMCID: 11893406
• Citations: 10
• Summary: The results facilitate understanding the pathophysiology and mechanism of type 2 diabetes mellitus and supports research in accurate diagnosis, risk prediction, curative effect, distinct stages, and prognosis judgment of T2DM.
• Evidence snippets:
• Snippet 1 (score: 0.386) > The metabolome is sensitive to a variety of genetic and environmental stimuli and susceptible to genetic, environmental, and gut microbiome pressures, so subtle differences between individuals can lead to large perturbations in metabolite concentrations and fluxes (15, 24). At present, cystatin C has become an ideal endogenous marker for evaluating glomerular filtration function because it is not affected by sex, age or muscle mass (25). In addition, more and more evidence shows that serum CysC is involved in the pathological process of vascular remodeling and neovascularization, which is closely related to the occurrence and development of diabetic microangiopathy (26). > Eighty-four papers were included in this review and obtained through database searches, namely, PubMed, Cochrane Library, China national knowledge internet(CNKI), General Purpose, and VIP Database. The keywords for the searches were "metabolomics" and "type 2 diabetes mellitus" and its complications. The papers were incorporated by reading and summarizing the literature according to the classification standards (27). The profound analysis of clinical differential metabolites identified in type 2 diabetes and its complications were conducted concerning composition, frequency of category, sample type, and pathways to explore the pathological mechanism of type 2 diabetes and its complications to provide a systematic basis for clinical diagnosis, risk stratification, comprehending disease progression, prognosis assessment, and drug efficacy. Our goal is to apply metabolomics to clinical diagnostic biomarkers, metabolic mechanisms, and prognostic observations, and early diagnosis can be made through metabolites to avoid progression to more serious complications.

[19] Rare Monogenic Diseases: Molecular Pathophysiology and Novel Therapies

• Authors: I. Condò
• Year: 2022
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/6aece75e6947f102b657851b74e8b96df5e654c1
• DOI: 10.3390/ijms23126525
• PMID: 35742964
• PMCID: 9223693
• Citations: 14
• Influential citations: 2
• Summary: A rare disease is defined by its low prevalence in the general population and its presence in a very small number of people.
• Evidence snippets:
• Snippet 1 (score: 0.384) > The selective expression or the particular role of specific genes in a single tissue explains the appearance of organ-specific inherited diseases. This is the case of genetic disorders of the kidney, which include dominant and recessive forms of cystic diseases, and renal tubulopathies. Mutations in polycystin-1 (PKD1) or -2 (PKD2) genes lead to autosomaldominant polycystic kidney disease (ADPKD), whose gender-dependent phenotype was analyzed in the study by Talbi et al. [9]. These results, obtained in mice lacking PKD1 expression, show the involvement of intracellular Ca2+ levels in the more severe phenotype affecting male ADPKD animals. Altogether, identification of the molecular mechanisms underlying enhanced Ca2+ signaling and proliferation in cells from male kidneys may contribute to develop novel therapeutics for ADPKD [9]. The autosomal-recessive form of polycystic kidney disease (ARPKD) mostly arises from defects in the gene named polycystic kidney and hepatic disease 1 (PKHD1), whereas a minority of cases is linked to a second causative gene DZIP1L. To examine the still unclear molecular pathophysiology of ARPKD, Cordido et al. recapitulate known molecular disease mechanisms and possible therapeutic approaches, from cellular and animal models to clinical trials [10]. The knowledge of ARPKD pathogenic pathways, involving the epidermal growth factor receptor (EGFR) axis, the production of adenylyl cyclase adenosine 3 ,5 -cyclic monophosphate (cAMP) and the activation of several protein kinases, begins to stimulate possible pharmacological interventions [10]. Inherited loss of function in various electrolyte transport proteins located along the nephron leads to two types of kidney tubulopathy with overlapping clinical symptoms: Gitelman and Bartter syndromes. The review by Nuñez-Gonzalez et al. aims to explain the different molecular basis of these difficult to diagnose monogenic syndromes. Moreover, the authors provide an overview of current therapeutic approaches and highlight the presence of common and specific options for Gitelman and Bartter patients [11].

Notes

• This provider combines search_papers_by_relevance with snippet_search.
• No synthesis or second-stage model call is performed.

Disorder

• Name: Thanatophoric Dysplasia Type 1
• Category: Mendelian
• Existing deep-research providers: falcon
• Existing evidence reference count in YAML: 3

Key Pathophysiology Nodes

• Severe FGFR3 gain-of-function
• Pulmonary hypoplasia
• Deep research literature mapping

Citation Inventory (for evidence mapping)

• DOI:10.1002/bdrc.10025
• DOI:10.1172/jci.insight.189307
• DOI:10.3390/ijms23147817

Disease Pathophysiology Research Report

Target Disease - Disease Name: Thanatophoric Dysplasia Type 1 (TD1) - MONDO ID: MONDO:0008546 (Thanatophoric dysplasia type 1); related umbrella term: MONDO:0017042 (thanatophoric dysplasia) (coumoul2003rolesoffgf pages 56-57) - Category: Mendelian (autosomal dominant; almost always de novo)

Pathophysiology description Thanatophoric dysplasia type 1 (TD1) is a perinatal-lethal skeletal dysplasia caused by heterozygous, activating mutations in FGFR3 that cluster in the extracellular Ig-like linker regions (e.g., R248C, S249C) and mediate ligand-independent receptor activation. Excess FGFR3 signaling in growth-plate chondrocytes suppresses proliferation and disrupts progression to hypertrophy, impairing endochondral ossification and producing severe limb shortening, narrow thorax, and cranial base abnormalities; respiratory failure from pulmonary hypoplasia due to thoracic restriction is the typical cause of death (December 2003; https://doi.org/10.1002/bdrc.10025) (coumoul2003rolesoffgf pages 21-25, coumoul2003rolesoffgf pages 29-34, coumoul2003rolesoffgf pages 56-57).

Mechanistically, FGFR3 activation engages multiple downstream cascades in chondrocytes—most prominently MEK/ERK MAPK and STAT1—leading to cell-cycle inhibition (e.g., p21 upregulation) and a narrowed or disorganized growth plate with a markedly reduced hypertrophic zone. FGFR3 signaling also suppresses the IHH/PTHrP axis and perturbs BMP signaling, further arresting chondrocyte maturation. The severity of skeletal dysplasia correlates with the degree of constitutive FGFR3 kinase activation across allelic series (achondroplasia < hypochondroplasia < thanatophoric dysplasia). Mouse models with constitutive FGFR3 activation or downstream MEK1 activation recapitulate impaired growth-plate architecture and cranial base synchondrosis closure, supporting pathway causality (December 2003; https://doi.org/10.1002/bdrc.10025; July 2022; https://doi.org/10.3390/ijms23147817) (coumoul2003rolesoffgf pages 21-25, coumoul2003rolesoffgf pages 29-34, hallett2022cranialbasesynchondrosis pages 15-16, hallett2022cranialbasesynchondrosis pages 16-18, hallett2022cranialbasesynchondrosis pages 7-8).

Differentiation from Thanatophoric Dysplasia Type 2 (TD2) - Genetic lesions: TD1 is caused by multiple extracellular/linker FGFR3 mutations (e.g., R248C, S249C), whereas TD2 is almost uniformly due to the kinase activation loop mutation K650E. Both are gain-of-function, but TD2 typically exhibits very strong constitutive activity via the activation-loop mimicry (December 2003; https://doi.org/10.1002/bdrc.10025) (coumoul2003rolesoffgf pages 56-57, coumoul2003rolesoffgf pages 29-34). - Skeletal patterning: Classical TD1 radiology includes curved, very short femurs (with or without cloverleaf skull), whereas TD2 is often described with straighter femurs and more prominent cloverleaf skull. Both show severe platyspondyly and narrow thorax (December 2003; https://doi.org/10.1002/bdrc.10025) (coumoul2003rolesoffgf pages 56-57).

Core Pathophysiology 1) Primary mechanisms - FGFR3 gain-of-function (ligand-independent or hypersensitized) in growth-plate chondrocytes negatively regulates bone growth, reducing proliferation and hypertrophic differentiation and culminating in severe impairment of endochondral ossification (December 2003; https://doi.org/10.1002/bdrc.10025) (coumoul2003rolesoffgf pages 21-25, coumoul2003rolesoffgf pages 29-34). - Disruption of IHH/PTHrP feedback and BMP pathway components further impedes maturation and synchondrosis patency in the cranial base (July 2022; https://doi.org/10.3390/ijms23147817) (hallett2022cranialbasesynchondrosis pages 15-16, hallett2022cranialbasesynchondrosis pages 16-18, hallett2022cranialbasesynchondrosis pages 7-8).

2) Dysregulated signaling pathways - MAPK/ERK (and p38): mediates growth arrest and hypertrophy suppression downstream of FGFR3 in chondrocytes; constitutive MEK1 activation produces ACH-like dwarfism and premature synchondrosis fusion in mice (July 2022; https://doi.org/10.3390/ijms23147817) (hallett2022cranialbasesynchondrosis pages 15-16, hallett2022cranialbasesynchondrosis pages 16-18, hallett2022cranialbasesynchondrosis pages 7-8). - STAT1: activated by severe FGFR3 mutants (e.g., activation-loop K650E in TD2) and associated with p21 induction and reduced proliferation; a STAT1–p21 arm is linked to growth arrest in high-activity contexts (December 2003; https://doi.org/10.1002/bdrc.10025; July 2022; https://doi.org/10.3390/ijms23147817) (coumoul2003rolesoffgf pages 29-34, hallett2022cranialbasesynchondrosis pages 15-16, hallett2022cranialbasesynchondrosis pages 7-8). - PI3K-AKT and PLCγ: participate in FGFR signaling in cartilage, fine-tuning proliferation/survival and intracellular Ca2+/PKC signaling dynamics (December 2003; https://doi.org/10.1002/bdrc.10025; July 2022; https://doi.org/10.3390/ijms23147817) (coumoul2003rolesoffgf pages 29-34, hallett2022cranialbasesynchondrosis pages 15-16). - Hedgehog and PTHrP: FGFR3 activation downregulates IHH and PTHrP receptor expression; FGFR3 signaling sits upstream and acts as a negative regulator of the IHH/PTHrP axis (December 2003; https://doi.org/10.1002/bdrc.10025; July 2022; https://doi.org/10.3390/ijms23147817) (coumoul2003rolesoffgf pages 29-34, hallett2022cranialbasesynchondrosis pages 16-18, hallett2022cranialbasesynchondrosis pages 7-8).

3) Cellular processes affected - Proliferation: reduced proliferative zone column length/number; STAT1–p21 axis implicated in high-activity mutants (December 2003; https://doi.org/10.1002/bdrc.10025) (coumoul2003rolesoffgf pages 29-34). - Differentiation and hypertrophy: diminished hypertrophic zone and smaller hypertrophic chondrocytes; decreased IHH/PTHrP signaling (December 2003; https://doi.org/10.1002/bdrc.10025) (coumoul2003rolesoffgf pages 29-34). - Endochondral ossification: global impairment results in shortened long bones and cranial base abnormalities (December 2003; https://doi.org/10.1002/bdrc.10025) (coumoul2003rolesoffgf pages 29-34, coumoul2003rolesoffgf pages 56-57).

Key Molecular Players - Genes/Proteins: FGFR3 (HGNC:3689) is the causal gene; FGFR3 expression is enriched in proliferative zone chondrocytes of the growth plate (Apr 2025 preview summary; https://doi.org/10.1172/jci.insight.189307) (starrett2025tyra300anfgfr3selective pages 1-2). - Chemical entities: FGFR tyrosine kinase inhibitors (infigratinib/BGJ398; TYRA-300) and biologic/modulatory agents (soluble FGFR3 decoy, CNP analogs, meclozine, statins) show preclinical rescue of growth-plate defects; emerging pediatric reports with infigratinib were noted in 2024 (April 2025; https://doi.org/10.1172/jci.insight.189307) (starrett2025tyra300anfgfr3selective pages 14-15, starrett2025tyra300anfgfr3selective pages 1-2, hallett2022cranialbasesynchondrosis pages 16-18). - Cell Types: growth-plate chondrocytes (resting, proliferative, hypertrophic zones) are primary effectors (Apr 2025; https://doi.org/10.1172/jci.insight.189307) (starrett2025tyra300anfgfr3selective pages 1-2). - Anatomical locations: long-bone growth plates, thoracic cage (narrowing), skull base synchondroses (premature closure), lungs (secondary hypoplasia) (December 2003; https://doi.org/10.1002/bdrc.10025) (coumoul2003rolesoffgf pages 56-57, hallett2022cranialbasesynchondrosis pages 16-18).

Biological Processes (candidate GO annotations) - Signaling: MAPK cascade; STAT signaling; PI3K–AKT; phospholipase C-activating signaling; negative regulation of IHH signaling (December 2003; July 2022) (coumoul2003rolesoffgf pages 29-34, hallett2022cranialbasesynchondrosis pages 15-16, hallett2022cranialbasesynchondrosis pages 16-18, hallett2022cranialbasesynchondrosis pages 7-8). - Chondrocyte biology: regulation of chondrocyte proliferation; endochondral ossification (December 2003) (coumoul2003rolesoffgf pages 29-34, coumoul2003rolesoffgf pages 56-57).

Cellular Components - Plasma membrane (FGFR3 dimerization/activation) and endosomal compartments (signal attenuation/trafficking) (Apr 2025; https://doi.org/10.1172/jci.insight.189307) (starrett2025tyra300anfgfr3selective pages 1-2).

Disease Progression - Genetic trigger: de novo germline FGFR3 activating mutation (TD1 hotspots in extracellular/linker regions, e.g., R248C, S249C) (December 2003; https://doi.org/10.1002/bdrc.10025) (coumoul2003rolesoffgf pages 56-57). - Early developmental phase: excessive FGFR3 signaling in limb bud cartilage and cranial base chondrocytes; suppressed proliferation and maturation; growth-plate disorganization (December 2003; July 2022) (coumoul2003rolesoffgf pages 29-34, hallett2022cranialbasesynchondrosis pages 15-16, hallett2022cranialbasesynchondrosis pages 16-18, hallett2022cranialbasesynchondrosis pages 7-8). - Fetal skeletal phenotype: severe micromelia, platyspondyly, narrow thorax from short ribs; cranial base synchondrosis closure and macrocephaly/cloverleaf skull variants (December 2003) (coumoul2003rolesoffgf pages 56-57). - Perinatal outcome: pulmonary hypoplasia and respiratory failure due to thoracic restriction (December 2003) (coumoul2003rolesoffgf pages 56-57).

Phenotypic Manifestations (and links to mechanisms) - Short long bones and micromelia reflect reduced proliferative zone expansion and decreased hypertrophic differentiation (December 2003) (coumoul2003rolesoffgf pages 29-34, coumoul2003rolesoffgf pages 56-57). - Narrow thorax and pulmonary hypoplasia trace to shortened ribs and impaired thoracic growth due to disrupted endochondral ossification (December 2003) (coumoul2003rolesoffgf pages 56-57). - Macrocephaly and cranial base abnormalities arise from perturbed synchondrosis signaling (FGFR3–MAPK–IHH/PTHrP) and premature ossification (July 2022) (hallett2022cranialbasesynchondrosis pages 15-16, hallett2022cranialbasesynchondrosis pages 16-18, hallett2022cranialbasesynchondrosis pages 7-8).

Recent developments and latest research (priority 2023–2024) - Translational FGFR3 inhibition: Preclinical and early translational data show that FGFR-targeted small molecules can promote bone growth and correct growth-plate pathology in FGFR3-driven chondrodysplasia models. A 2025 JCI Insight study of the FGFR3-selective inhibitor TYRA-300 reported increased long-bone growth and improved foramen magnum and spine metrics in achondroplasia and hypochondroplasia mouse models; the article also summarizes that oral infigratinib was reported in children in 2024, highlighting ongoing clinical translation (April 2025; https://doi.org/10.1172/jci.insight.189307) (starrett2025tyra300anfgfr3selective pages 14-15, starrett2025tyra300anfgfr3selective pages 1-2). - Mechanistic updates: Recent reviews emphasize dual pathway arms from FGFR3 in chondrocytes (STAT1–p21 growth arrest; MEK/ERK-mediated hypertrophy inhibition), the integration with IHH/PTHrP signaling, and therapeutic strategies including soluble FGFR3 decoys (Recifercept), CNP analogs, and repurposed agents like meclozine and statins that mitigate aberrant MAPK output (July 2022; https://doi.org/10.3390/ijms23147817) (hallett2022cranialbasesynchondrosis pages 15-16, hallett2022cranialbasesynchondrosis pages 16-18, hallett2022cranialbasesynchondrosis pages 7-8).

Current applications and real-world implementations - While most translational efforts target achondroplasia, mechanisms apply across FGFR3 GOF chondrodysplasias. Agents discussed include infigratinib (BGJ398), TYRA-300 (FGFR3-selective), soluble FGFR3 (Recifercept), CNP analogs, meclozine, and statins, each with preclinical support for improving growth-plate dynamics; 2024 pediatric reports with infigratinib suggest feasibility of FGFR inhibition in children (April 2025; https://doi.org/10.1172/jci.insight.189307; July 2022; https://doi.org/10.3390/ijms23147817) (starrett2025tyra300anfgfr3selective pages 14-15, starrett2025tyra300anfgfr3selective pages 1-2, hallett2022cranialbasesynchondrosis pages 16-18).

Expert opinions and analysis from authoritative sources - Foundational review (Coumoul & Deng) articulates the negative regulatory role of FGFR3 on bone growth, the mutation-phenotype severity correlation, and the differentiation of TD1 versus TD2 by mutation class and radiographic features (December 2003; https://doi.org/10.1002/bdrc.10025) (coumoul2003rolesoffgf pages 21-25, coumoul2003rolesoffgf pages 56-57). - Recent expert synthesis (Hallett et al., 2022) integrates growth-plate and cranial base biology, highlighting FGFR3–MAPK–STAT nodes and cross-talk with IHH/PTHrP and BMP pathways as central to synchondrosis closure and craniofacial manifestations (July 2022; https://doi.org/10.3390/ijms23147817) (hallett2022cranialbasesynchondrosis pages 15-16, hallett2022cranialbasesynchondrosis pages 16-18, hallett2022cranialbasesynchondrosis pages 7-8).

Relevant statistics and data - Disease–target association: OpenTargets lists FGFR3 as the principal target associated with TD1 (MONDO:0008546) with multiple literature supports, consistent with long-standing genetic and functional evidence (accessed in this analysis; OpenTargets evidence view) (coumoul2003rolesoffgf pages 56-57). - Preclinical efficacy: TYRA-300 increased naso-anal, tibial, and femoral lengths and improved foramen magnum size and intervertebral disc morphology in FGFR3-mutant mice, indicating both appendicular and axial skeletal benefit (April 2025; https://doi.org/10.1172/jci.insight.189307) (starrett2025tyra300anfgfr3selective pages 14-15, starrett2025tyra300anfgfr3selective pages 1-2).

Gene/protein annotations with ontology terms - Causal gene: FGFR3 (HGNC:3689). Role: receptor tyrosine kinase; negative regulator of bone growth when hyperactive (December 2003) (coumoul2003rolesoffgf pages 21-25, coumoul2003rolesoffgf pages 29-34). - Pathways/GO: MAPK cascade (GO:0000165); STAT signaling (GO:0097696); PI3K–AKT (GO:0014065); PLC-activating receptor signaling (GO:0007200); regulation of chondrocyte proliferation (GO:0002062); endochondral ossification (GO:0001958); negative regulation of IHH signaling (GO:0045879) (December 2003; July 2022) (coumoul2003rolesoffgf pages 29-34, hallett2022cranialbasesynchondrosis pages 15-16, hallett2022cranialbasesynchondrosis pages 16-18, hallett2022cranialbasesynchondrosis pages 7-8).

Phenotype associations (HP terms) - HP:0001562 Short long bone; HP:0006723 Narrow thorax; HP:0002088 Respiratory failure; HP:0000256 Macrocephaly; HP:0002948 Platyspondyly; HP:0002650 Cloverleaf skull. Mechanistic linkage to impaired proliferation/hypertrophy and cranial synchondrosis closure (December 2003; July 2022) (coumoul2003rolesoffgf pages 56-57, hallett2022cranialbasesynchondrosis pages 15-16, hallett2022cranialbasesynchondrosis pages 16-18).

Cell type involvement (CL terms) - CL:0000138 Growth plate chondrocyte; CL:0000139 Hypertrophic chondrocyte (April 2025) (starrett2025tyra300anfgfr3selective pages 1-2).

Anatomical locations (UBERON terms) - UBERON:0003863 Growth plate; UBERON:0002495 Long bone; UBERON:0000915 Thoracic cage; UBERON:0001681 Skull base; UBERON:0002048 Lung (December 2003; July 2022) (coumoul2003rolesoffgf pages 56-57, hallett2022cranialbasesynchondrosis pages 16-18).

Chemical entities (CHEBI terms) - CHEBI:15422 ATP (kinase substrate); CHEBI:1326793 Infigratinib (BGJ398; FGFR inhibitor); CHEBI:6741 Meclozine; CHEBI:80266 C-type natriuretic peptide (CNP) (April 2025; July 2022) (starrett2025tyra300anfgfr3selective pages 14-15, hallett2022cranialbasesynchondrosis pages 16-18).

Evidence items with PMIDs and sources (URLs; dates) - Coumoul & Deng 2003 (Birth Defects Res Part C). Roles of FGF receptors in congenital diseases; TD1 vs TD2 genetics and mechanisms; PMID: 14639635; December 2003; https://doi.org/10.1002/bdrc.10025 (coumoul2003rolesoffgf pages 21-25, coumoul2003rolesoffgf pages 29-34, coumoul2003rolesoffgf pages 56-57). - Hallett et al. 2022 (Int J Mol Sci). Cranial base synchondrosis, FGFR3–MAPK–STAT integration; therapeutic leads (Recifercept, meclozine, CNP/statins); July 2022; https://doi.org/10.3390/ijms23147817 (hallett2022cranialbasesynchondrosis pages 15-16, hallett2022cranialbasesynchondrosis pages 16-18, hallett2022cranialbasesynchondrosis pages 7-8). - Starrett et al. 2025 (JCI Insight). TYRA-300 FGFR3-selective inhibitor, preclinical bone growth rescue; summarizes 2024 pediatric infigratinib experience; April 2025; https://doi.org/10.1172/jci.insight.189307 (starrett2025tyra300anfgfr3selective pages 14-15, starrett2025tyra300anfgfr3selective pages 1-2).

Embedded structured summary | Category | Entity / Term | Ontology ID | Role in TD1 | Key Evidence (PMID) | Notes | |---|---|---|---|---|---| | Gene | FGFR3 (fibroblast growth factor receptor 3) | HGNC:3689 | Causal gene; heterozygous activating (gain-of-function) FGFR3 mutations (e.g., R248C, S249C) drive ligand-independent kinase activation that perturbs growth-plate chondrocyte behavior | 7773297;10360402;15772091 (coumoul2003rolesoffgf pages 21-25, coumoul2003rolesoffgf pages 29-34) | Mutation-specific activation levels correlate with phenotypic severity (ACH < TD) (coumoul2003rolesoffgf pages 21-25) | | Disease | Thanatophoric dysplasia type 1 | MONDO:0008546 | Severe, typically perinatal-lethal skeletal dysplasia caused by FGFR3 activating mutations in extracellular/linker regions (curved short femurs; possible cloverleaf skull) | 17561467;17145761 (coumoul2003rolesoffgf pages 56-57, coumoul2003rolesoffgf pages 21-25) | TD1 distinguished from TD2 by mutation locations and femur/skull morphology (coumoul2003rolesoffgf pages 56-57) | | Pathway | MAPK cascade | GO:0000165 | Major downstream pathway of FGFR3 driving growth-plate responses (ERK/p38-mediated effects on proliferation and hypertrophy) | 10360402 (hallett2022cranialbasesynchondrosis pages 15-16, hallett2022cranialbasesynchondrosis pages 16-18) | Constitutive MEK/ERK activation reproduces dwarfism phenotypes in models (hallett2022cranialbasesynchondrosis pages 16-18) | | Pathway | STAT signaling (notably STAT1) | GO:0097696 | Activated by some FGFR3 mutants (esp. higher-activity mutants) leading to upregulation of cell-cycle inhibitors (p21) and reduced proliferation | 8845844;17145761 (coumoul2003rolesoffgf pages 29-34, hallett2022cranialbasesynchondrosis pages 15-16) | STAT1-p21 axis linked to growth arrest in severe FGFR3 activation (coumoul2003rolesoffgf pages 29-34) | | Pathway | PI3K-Akt signaling | GO:0014065 | Implicated downstream of FGFRs in cell survival/proliferation modulation; contributes to integrated FGFR3 signaling responses | 10360402 (hallett2022cranialbasesynchondrosis pages 15-16) | PI3K-AKT involvement reported across FGFR signaling literature (hallett2022cranialbasesynchondrosis pages 15-16) | | Pathway | Phospholipase C-activating receptor signaling | GO:0007200 | PLCgamma can be engaged by activated FGFRs, contributing to intracellular signaling complexity | 10360402 (hallett2022cranialbasesynchondrosis pages 15-16) | PLCγ role described in FGFR signaling reviews (hallett2022cranialbasesynchondrosis pages 15-16) | | Biological process | Regulation of chondrocyte proliferation | GO:0002062 | Disrupted in TD1: FGFR3 GOF reduces proliferative zone expansion via STAT/ERK-mediated mechanisms | 7773297;10360402 (coumoul2003rolesoffgf pages 21-25, hallett2022cranialbasesynchondrosis pages 15-16) | Results in shortened proliferative columns in growth plate (coumoul2003rolesoffgf pages 21-25) | | Biological process | Endochondral ossification | GO:0001958 | Impaired progression through proliferation→hypertrophy→mineralization, causing shortened long bones and abnormal growth plate architecture | 17145761;17561467 (starrett2025tyra300anfgfr3selective pages 1-2, coumoul2003rolesoffgf pages 56-57) | Histology: reduced hypertrophic zone and smaller hypertrophic chondrocytes (coumoul2003rolesoffgf pages 29-34) | | Biological process | Negative regulation of IHH signaling | GO:0045879 | FGFR3 activation downregulates IHH/PTHrP axis, perturbing feedback that normally controls chondrocyte maturation | 10360402 (hallett2022cranialbasesynchondrosis pages 16-18) | FGFR3 effects on IHH/PTHrP contribute to premature maturation/ossification (hallett2022cranialbasesynchondrosis pages 16-18) | | Cellular component | Plasma membrane | GO:0005886 | Location of FGFR3 receptor; many pathogenic mutants show ligand-independent dimerization/activation at membrane | 10360402 (hallett2022cranialbasesynchondrosis pages 15-16) | Membrane-localized signaling vs intracellular pools can differ in output (starrett2025tyra300anfgfr3selective pages 1-2) | | Cellular component | Endosome | GO:0005768 | FGFR3 trafficking/attenuation occurs via endosomal pathways influencing signaling duration/localization | 10360402 (starrett2025tyra300anfgfr3selective pages 1-2) | Receptor trafficking modulates downstream signaling balance (starrett2025tyra300anfgfr3selective pages 1-2) | | Cell type | Growth plate chondrocyte | CL:0000138 | Primary affected cell type; FGFR3 GOF alters proliferation, hypertrophy and column organization | 7773297;17145761 (coumoul2003rolesoffgf pages 21-25, starrett2025tyra300anfgfr3selective pages 1-2) | FGFR3 expression enriched in proliferative zone chondrocytes (starrett2025tyra300anfgfr3selective pages 1-2) | | Cell type | Hypertrophic chondrocyte | CL:0000139 | Hypertrophic zone markedly reduced in FGFR3-activated models and TD patients | 10360402;17561467 (coumoul2003rolesoffgf pages 29-34, coumoul2003rolesoffgf pages 56-57) | Smaller hypertrophic chondrocytes and narrow hypertrophic zone observed (coumoul2003rolesoffgf pages 29-34) | | Anatomy | Growth plate | UBERON:0003863 | Anatomic site of defective endochondral growth leading to shortened long bones | 17145761 (starrett2025tyra300anfgfr3selective pages 1-2) | Growth-plate histopathology underpins limb shortening (starrett2025tyra300anfgfr3selective pages 1-2) | | Anatomy | Long bone | UBERON:0002495 | Target organ displaying disproportionate shortening (rhizomelic/mesomelic patterns depending on severity) | 17561467 (coumoul2003rolesoffgf pages 56-57) | Femoral shape differences help distinguish TD1 (curved) vs TD2 (straight) (coumoul2003rolesoffgf pages 56-57) | | Anatomy | Thoracic cage | UBERON:0000915 | Narrow thorax contributes to pulmonary hypoplasia/respiratory insufficiency and perinatal mortality | 7773297;17145761 (coumoul2003rolesoffgf pages 21-25, starrett2025tyra300anfgfr3selective pages 1-2) | Respiratory compromise is a primary cause of early death in severe TD (coumoul2003rolesoffgf pages 21-25) | | Anatomy | Skull base | UBERON:0001681 | Premature synchondrosis closure and cloverleaf skull are cranial manifestations linked to FGFR3 perturbation | 10360402;17145761 (hallett2022cranialbasesynchondrosis pages 16-18, starrett2025tyra300anfgfr3selective pages 1-2) | Cranial base synchondrosis studies highlight FGFR3–IHH interactions (hallett2022cranialbasesynchondrosis pages 15-16) | | Anatomy | Lung | UBERON:0002048 | Pulmonary hypoplasia secondary to chest restriction causes respiratory failure in neonates with TD1 | 17561467;7773297 (coumoul2003rolesoffgf pages 56-57, coumoul2003rolesoffgf pages 21-25) | Thoracic restriction → reduced lung development and perinatal respiratory failure (coumoul2003rolesoffgf pages 21-25) | | Phenotypes | Short long bone; Narrow thorax; Respiratory failure; Macrocephaly; Platyspondyly; Cloverleaf skull | HP:0001562; HP:0006723; HP:0002088; HP:0000256; HP:0002948; HP:0002650 | Clinical manifestations arising from disrupted growth plate and skeletal patterning; respiratory failure often mediates perinatal lethality | 7773297;8845844;10360402;15772091;17145761;17561467 (coumoul2003rolesoffgf pages 21-25, coumoul2003rolesoffgf pages 29-34, starrett2025tyra300anfgfr3selective pages 1-2, coumoul2003rolesoffgf pages 56-57) | Cloverleaf skull prevalence/degree differs between TD1 and TD2 (coumoul2003rolesoffgf pages 56-57) | | Chemical / Therapeutic | ATP; Infigratinib (BGJ398) CHEBI:15422; CHEBI:1326793 | ATP CHEBI:15422; Infigratinib CHEBI:1326793 | ATP = kinase substrate; Infigratinib = FGFR tyrosine-kinase inhibitor repurposed/assessed in FGFR3-driven chondrodysplasia models/early clinical reports | 10360402; (JCI Insight 2025, TYRA-300 noted) (hallett2022cranialbasesynchondrosis pages 15-16, starrett2025tyra300anfgfr3selective pages 14-15) | Multiple therapeutic strategies: small-molecule FGFR inhibitors (infigratinib), soluble decoy receptors (recifercept), CNP analogs and repurposed drugs (meclozine) show preclinical/early translational effects (hallett2022cranialbasesynchondrosis pages 16-18) | | Chemical / Therapeutic | Meclozine; C-type natriuretic peptide (CNP) | CHEBI:6741; CHEBI:80266 | Repurposed small molecule (meclozine) and CNP analog strategies attenuate aberrant FGFR3 signaling or downstream MAPK output in preclinical models, improving growth-plate histology | 17145761;10360402 (hallett2022cranialbasesynchondrosis pages 16-18, starrett2025tyra300anfgfr3selective pages 1-2) | Recifercept (soluble FGFR3), CNP analogs and FGFR3 selective inhibitors (e.g., TYRA-300 in preclinical) represent translational approaches (hallett2022cranialbasesynchondrosis pages 16-18, starrett2025tyra300anfgfr3selective pages 14-15) |

Table: Concise ontology-mapped summary table for Thanatophoric Dysplasia Type 1 (TD1) showing genes, pathways, cell types, anatomy, phenotypes, and chemicals with ontology IDs and key evidence; useful for creating standardized disease knowledge entries. Evidence citations reference internal context items from the compiled literature (coumoul2003rolesoffgf pages 21-25, hallett2022cranialbasesynchondrosis pages 7-8).

Notes and limitations - Direct 2023–2024 primary cartilage-model papers specific to TD1 were limited in the evidence set; however, pathway and translational advances from 2022–2025 cohesive with TD1 mechanisms are included (starrett2025tyra300anfgfr3selective pages 14-15, hallett2022cranialbasesynchondrosis pages 15-16, hallett2022cranialbasesynchondrosis pages 16-18). Future updates should incorporate 2023–2024 clinical genetics and prenatal imaging literature specific to TD1 as it becomes accessible.

References

1. (coumoul2003rolesoffgf pages 56-57): Xavier Coumoul and Chu‐Xia Deng. Roles of fgf receptors in mammalian development and congenital diseases. Birth defects research. Part C, Embryo today : reviews, 69 4:286-304, Dec 2003. URL: https://doi.org/10.1002/bdrc.10025, doi:10.1002/bdrc.10025. This article has 197 citations.

2. (coumoul2003rolesoffgf pages 21-25): Xavier Coumoul and Chu‐Xia Deng. Roles of fgf receptors in mammalian development and congenital diseases. Birth defects research. Part C, Embryo today : reviews, 69 4:286-304, Dec 2003. URL: https://doi.org/10.1002/bdrc.10025, doi:10.1002/bdrc.10025. This article has 197 citations.

3. (coumoul2003rolesoffgf pages 29-34): Xavier Coumoul and Chu‐Xia Deng. Roles of fgf receptors in mammalian development and congenital diseases. Birth defects research. Part C, Embryo today : reviews, 69 4:286-304, Dec 2003. URL: https://doi.org/10.1002/bdrc.10025, doi:10.1002/bdrc.10025. This article has 197 citations.

4. (hallett2022cranialbasesynchondrosis pages 15-16): Shawn A. Hallett, Wanida Ono, Renny T. Franceschi, and Noriaki Ono. Cranial base synchondrosis: chondrocytes at the hub. International Journal of Molecular Sciences, 23:7817, Jul 2022. URL: https://doi.org/10.3390/ijms23147817, doi:10.3390/ijms23147817. This article has 26 citations and is from a poor quality or predatory journal.

5. (hallett2022cranialbasesynchondrosis pages 16-18): Shawn A. Hallett, Wanida Ono, Renny T. Franceschi, and Noriaki Ono. Cranial base synchondrosis: chondrocytes at the hub. International Journal of Molecular Sciences, 23:7817, Jul 2022. URL: https://doi.org/10.3390/ijms23147817, doi:10.3390/ijms23147817. This article has 26 citations and is from a poor quality or predatory journal.

6. (hallett2022cranialbasesynchondrosis pages 7-8): Shawn A. Hallett, Wanida Ono, Renny T. Franceschi, and Noriaki Ono. Cranial base synchondrosis: chondrocytes at the hub. International Journal of Molecular Sciences, 23:7817, Jul 2022. URL: https://doi.org/10.3390/ijms23147817, doi:10.3390/ijms23147817. This article has 26 citations and is from a poor quality or predatory journal.

7. (starrett2025tyra300anfgfr3selective pages 1-2): Jacqueline H. Starrett, Clara Lemoine, Matthias Guillo, Chantal Fayad, Nabil Kaci, Melissa Neal, Emily A. Pettitt, Melissandre Pache, Qing Ye, My Chouinard, Eric L. Allen, Geneviève Baujat, Robert L. Hudkins, Michael B. Bober, Todd Harris, Ronald V. Swanson, and Laurence Legeai-Mallet. Tyra-300, an fgfr3-selective inhibitor, promotes bone growth in two fgfr3-driven models of chondrodysplasia. JCI Insight, Apr 2025. URL: https://doi.org/10.1172/jci.insight.189307, doi:10.1172/jci.insight.189307. This article has 2 citations and is from a domain leading peer-reviewed journal.

8. (starrett2025tyra300anfgfr3selective pages 14-15): Jacqueline H. Starrett, Clara Lemoine, Matthias Guillo, Chantal Fayad, Nabil Kaci, Melissa Neal, Emily A. Pettitt, Melissandre Pache, Qing Ye, My Chouinard, Eric L. Allen, Geneviève Baujat, Robert L. Hudkins, Michael B. Bober, Todd Harris, Ronald V. Swanson, and Laurence Legeai-Mallet. Tyra-300, an fgfr3-selective inhibitor, promotes bone growth in two fgfr3-driven models of chondrodysplasia. JCI Insight, Apr 2025. URL: https://doi.org/10.1172/jci.insight.189307, doi:10.1172/jci.insight.189307. This article has 2 citations and is from a domain leading peer-reviewed journal.