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2. Mutations in the Kinesin-2 Motor KIF3B Cause an Autosomal-Dominant Ciliopathy.

Author

Cogné, Benjamin, Latypova, Xenia, Senaratne, Lokuliyanage Dona Samudita, Martin, Ludovic, Koboldt, Daniel C, Kellaris, Georgios, Fievet, Lorraine, Le Meur, Guylène, Caldari, Dominique, Debray, Dominique, Nizon, Mathilde, Frengen, Eirik, Bowne, Sara J, 99 Lives Consortium, Cadena, Elizabeth L, Daiger, Stephen P, Bujakowska, Kinga M, Pierce, Eric A, Gorin, Michael, Katsanis, Nicholas, Bézieau, Stéphane, Petersen-Jones, Simon M, Occelli, Laurence M, Lyons, Leslie A, Legeai-Mallet, Laurence, Sullivan, Lori S, Davis, Erica E, and Isidor, Bertrand

Subjects
Lives Consortium, Retina, Cilia, Animals, Zebrafish, Cats, Humans, Rhodopsin, Pedigree, Amino Acid Sequence, Larva, Heterozygote, Genes, Dominant, Phenotype, Mutation, Middle Aged, Child, Preschool, Female, Male, Photoreceptor Cells, Genome-Wide Association Study, Young Adult, Ciliopathies, Kinesins, KIF3B, feline genetics, hepatic fibrosis, kinesin, primary cilia, retinopathy, whole-exome sequencing, zebrafish, Neurosciences, Clinical Research, Genetics, Pediatric, Polycystic Kidney Disease, Eye Disease and Disorders of Vision, Congenital Structural Anomalies, Neurodegenerative, Kidney Disease, Rare Diseases, Aetiology, 2.1 Biological and endogenous factors, Eye, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Kinesin-2 enables ciliary assembly and maintenance as an anterograde intraflagellar transport (IFT) motor. Molecular motor activity is driven by a heterotrimeric complex comprised of KIF3A and KIF3B or KIF3C plus one non-motor subunit, KIFAP3. Using exome sequencing, we identified heterozygous KIF3B variants in two unrelated families with hallmark ciliopathy phenotypes. In the first family, the proband presents with hepatic fibrosis, retinitis pigmentosa, and postaxial polydactyly; he harbors a de novo c.748G>C (p.Glu250Gln) variant affecting the kinesin motor domain encoded by KIF3B. The second family is a six-generation pedigree affected predominantly by retinitis pigmentosa. Affected individuals carry a heterozygous c.1568T>C (p.Leu523Pro) KIF3B variant segregating in an autosomal-dominant pattern. We observed a significant increase in primary cilia length in vitro in the context of either of the two mutations while variant KIF3B proteins retained stability indistinguishable from wild type. Furthermore, we tested the effects of KIF3B mutant mRNA expression in the developing zebrafish retina. In the presence of either missense variant, rhodopsin was sequestered to the photoreceptor rod inner segment layer with a concomitant increase in photoreceptor cilia length. Notably, impaired rhodopsin trafficking is also characteristic of recessive KIF3B models as exemplified by an early-onset, autosomal-recessive, progressive retinal degeneration in Bengal cats; we identified a c.1000G>A (p.Ala334Thr) KIF3B variant by genome-wide association study and whole-genome sequencing. Together, our genetic, cell-based, and in vivo modeling data delineate an autosomal-dominant syndromic retinal ciliopathy in humans and suggest that multiple KIF3B pathomechanisms can impair kinesin-driven ciliary transport in the photoreceptor.

Published
2020

4. Theobroma cacao improves bone growth by modulating defective ciliogenesis in a mouse model of achondroplasia

Author

Martin, Ludovic, Kaci, Nabil, Benoist-Lasselin, Catherine, Mondoloni, Marine, Decaudaveine, Suzanne, Estibals, Valentin, Cornille, Maxence, Loisay, Léa, Flipo, Justine, Demuynck, Benoît, de la Luz Cádiz-Gurrea, Maria, Barbault, Florent, Fernández-Arroyo, Salvador, Schibler, Laurent, Segura-Carretero, Antonio, Dambroise, Emilie, and Legeai-Mallet, Laurence

Published
2022
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6. Craniosynostoses: Lessons Learned from Animal Models

Author

Dambroise, Emilie, Cornille, Maxence, Komla-Ebri, Davide, Kaci, Nabil, Biosse-Duplan, Martin, Di Rocco, Federico, Legeai-Mallet, Laurence, Di Rocco, Concezio, Section editor, Di Rocco, Concezio, editor, Pang, Dachling, editor, and Rutka, James T., editor

Published
2020
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12. Hypochondroplasia gain-of-function mutation in FGFR3 causes defective bone mineralization in mice

Author

Loisay, Léa, primary, Komla-Ebri, Davide, additional, Morice, Anne, additional, Heuzé, Yann, additional, Viaut, Camille, additional, de La Seiglière, Amélie, additional, Kaci, Nabil, additional, Chan, Danny, additional, Lamouroux, Audrey, additional, Baujat, Geneviève, additional, Bassett, J.H. Duncan, additional, Williams, Graham R., additional, and Legeai-Mallet, Laurence, additional

Published
2023
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15. Tyrosine kinase inhibitor NVP-BGJ398 functionally improves FGFR3-related dwarfism in mouse model

Author

Komla-Ebri, Davide, Dambroise, Emilie, Kramer, Ina, Benoist-Lasselin, Catherine, Kaci, Nabil, Gall, Cindy Le, Martin, Ludovic, Busca, Patricia, Barbault, Florent, Graus-Porta, Diana, Munnich, Arnold, Kneissel, Michaela, Rocco, Federico Di, Biosse-Duplan, Martin, and Legeai-Mallet, Laurence

Subjects
Tyrosine -- Health aspects, Embryonic development -- Health aspects, Phenols -- Health aspects, Bank clearinghouses -- Health aspects, Dwarfism -- Health aspects, Fibroblast growth factors -- Health aspects, Health care industry
Abstract

Achondroplasia (ACH) is the most frequent form of dwarfism and is caused by gain-of-function mutations in the fibroblast growth factor receptor 3-encoding (FGFR3-encoding) gene. Although potential therapeutic strategies for ACH, which aim to reduce excessive FGFR3 activation, have emerged over many years, the use of tyrosine kinase inhibitor (TKI) to counteract FGFR3 hyperactivity has yet to be evaluated. Here, we have reported that the pan-FGFR TKI, NVP-BGJ398, reduces FGFR3 phosphorylation and corrects the abnormal femoral growth plate and calvaria in organ cultures from embryos of the [Fgfr3.sup.Y367C/+] mouse model of ACH. Moreover, we demonstrated that a low dose of NVP-BGJ398, injected subcutaneously, was able to penetrate into the growth plate of [Fgfr3.sup.Y367C/+] mice and modify its organization. Improvements to the axial and appendicular skeletons were noticeable after 10 days of treatment and were more extensive after 15 days of treatment that started from postnatal day 1. Low-dose NVP-BGJ398 treatment reduced intervertebral disc defects of lumbar vertebrae, loss of synchondroses, and foramen-magnum shape anomalies. NVP-BGJ398 inhibited FGFR3 downstream signaling pathways, including MAPK, SOX9, STAT1, and PLCγ, in the growth plates of [Fgfr3.sup.Y367C/+] mice and in cultured chondrocyte models of ACH. Together, our data demonstrate that NVP-BGJ398 corrects pathological hallmarks of ACH and support TKIs as a potential therapeutic approach for ACH., Introduction Achondroplasia (ACH) is the most common form of dwarfism, which occurs with an estimated prevalence of between 1/16,000 and 1/25,000 live births (1, 2). ACH patients are characterized by [...]

Published
2016
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17. Craniofacial growth and function in achondroplasia: a multimodal 3D study on 15 patients

Author

Morice, Anne, primary, Taverne, Maxime, additional, Eché, Sophie, additional, Griffon, Lucie, additional, Fauroux, Brigitte, additional, Leboulanger, Nicolas, additional, Couloigner, Vincent, additional, Baujat, Geneviève, additional, Picard, Arnaud, additional, Legeai-Mallet, Laurence, additional, Kadlub, Natacha, additional, and Khonsari, Roman Hossein, additional

Published
2022
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18. FGFR3 overactivation in the brain is responsible for memory impairments in Crouzon syndrome mouse model

Author

Legeai-Mallet L., Cornille, Maxence, Moriceau, Stephanie, Khonsari, Roman H., Heuzé, Yann, Loisay, Léa, Boitez, Valérie, Morice, Anne, Arnaud, Eric, Collet, Corinne, Bensidhoum, Morad, Kaci, Nabil, Boddaert, Nathalie, Paternoster, Giovanna, Rauschendorfer, Theresa, Werner, Sabine, Mansour, Suzanne L., Di Rocco, Federico, Oury, Franck, and Legeai-Mallet, Laurence

Subjects
musculoskeletal diseases
Abstract

Crouzon syndrome with acanthosis nigricans (CAN, a rare type of craniosynostosis characterized by premature suture fusion and neurological impairments) has been linked to a gain-of-function mutation (p.Ala391Glu) in fibroblast growth factor receptor 3 (FGFR3). To characterize the CAN mutation's impact on the skull and on brain functions, we developed the first mouse model (Fgfr3A385E/+) of this syndrome. Surprisingly, Fgfr3A385E/+ mice did not exhibit craniosynostosis but did show severe memory impairments, a structurally abnormal hippocampus, low activity-dependent synaptic plasticity, and overactivation of MAPK/ERK and Akt signaling pathways in the hippocampus. Systemic or brain-specific pharmacological inhibition of FGFR3 overactivation by BGJ398 injections rescued the memory impairments observed in Fgfr3A385E/+ mice. The present study is the first to have demonstrated cognitive impairments associated with brain FGFR3 overactivation, independently of skull abnormalities. Our results provide a better understanding of FGFR3's functional role and the impact of its gain-of-function mutation on brain functions. The modulation of FGFR3 signaling might be of value for treating the neurological disorders associated with craniosynostosis., Journal of Experimental Medicine, 219 (4), ISSN:0022-1007, ISSN:1540-0069, ISSN:1540-9538

Published
2022
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20. Meckel's and condylar cartilages anomalies in achondroplasia result in defective development and growth of the mandible

Author

Biosse Duplan, Martin, Komla-Ebri, Davide, Heuzé, Yann, Estibals, Valentin, Gaudas, Emilie, Kaci, Nabil, Benoist-Lasselin, Catherine, Zerah, Michel, Kramer, Ina, Kneissel, Michaela, Porta, Diana Grauss, Di Rocco, Federico, Legeai-Mallet, Laurence, Biosse Duplan, Martin, Komla-Ebri, Davide, Heuzé, Yann, Estibals, Valentin, Gaudas, Emilie, Kaci, Nabil, Benoist-Lasselin, Catherine, Zerah, Michel, Kramer, Ina, Kneissel, Michaela, Porta, Diana Grauss, Di Rocco, Federico, and Legeai-Mallet, Laurence

Abstract

Activating FGFR3 mutations in human result in achondroplasia (ACH), the most frequent form of dwarfism, where cartilages are severely disturbed causing long bones, cranial base and vertebrae defects. Because mandibular development and growth rely on cartilages that guide or directly participate to the ossification process, we investigated the impact of FGFR3 mutations on mandibular shape, size and position. By using CT scan imaging of ACH children and by analyzing Fgfr3Y367C/+ mice, a model of ACH, we show that FGFR3 gain-of-function mutations lead to structural anomalies of primary (Meckel's) and secondary (condylar) cartilages of the mandible, resulting in mandibular hypoplasia and dysmorphogenesis. These defects are likely related to a defective chondrocyte proliferation and differentiation and pan-FGFR tyrosine kinase inhibitor NVP-BGJ398 corrects Meckel's and condylar cartilages defects ex vivo. Moreover, we show that low dose of NVP-BGJ398 improves in vivo condyle growth and corrects dysmorphologies in Fgfr3Y367C/+ mice, suggesting that postnatal treatment with NVP-BGJ398 mice might offer a new therapeutic strategy to improve mandible anomalies in ACH and others FGFR3-related disorders.

Published
2021

22. Distinct effects of allelic NFIX mutations on nonsense-mediated mRNA decay engender either a Sotos-like or a Marshall-Smith syndrome

Author

Malan, Valerie, Rajan, Diana, Thomas, Sophie, Shaw, Adam C., dit Picard, Helene Louis, Layet, Valerie, Till, Marianne, van Haeringen, Arie, Mortier, Geert, Nampoothiri, Sheela, Puseljic, Silvija, Legeai-Mallet, Laurence, Carter, Nigel P., Vekemans, Michel, Munnich, Arnold, Hennekam, Raoul C., Colleaux, Laurence, and Cormier-Daire, Valerie

Subjects
Gene expression -- Analysis, Gene mutations -- Analysis, Messenger RNA -- Research, Skeleton -- Genetic aspects, Sotos syndrome -- Research, Biological sciences
Abstract

The study identifies nuclear factor I/X (NFIX) deletions or nonsense mutation in two human disorders, showing some resemblance to Sotos syndrome and Marshall-Smith syndrome. Findings show NFIX is normally expressed prenatally during human brain development and skeletogenesis, suggesting that allelic NFIX mutations elicit distinct phenotypes, depending specifically on their impact on mRNA decay (NMD).

Published
2010

25. Phosphatase inhibition by LB-100 enhances BMN-111 stimulation of bone growth

Author

Shuhaibar, Leia C., primary, Kaci, Nabil, additional, Egbert, Jeremy R., additional, Horville, Thibault, additional, Loisay, Léa, additional, Vigone, Giulia, additional, Uliasz, Tracy F., additional, Dambroise, Emilie, additional, Swingle, Mark R., additional, Honkanen, Richard E., additional, Duplan, Martin Biosse, additional, Jaffe, Laurinda A., additional, and Legeai-Mallet, Laurence, additional

Published
2021
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28. FGFR3 in Periosteal Cells Drives Cartilage-to-Bone Transformation in Bone Repair

Author

Julien, Anais, Perrin, Simon, Duchamp de Lageneste, Oriane, Carvalho, Caroline, Bensidhoum, Morad, Legeai-Mallet, Laurence, Colnot, Céline, Biologie, Bioingénierie et Bioimagerie Ostéo-articulaires (B3OA (UMR_7052)), Institut National de la Santé et de la Recherche Médicale (INSERM)-École nationale vétérinaire d'Alfort (ENVA)-Université de Paris (UP)-Centre National de la Recherche Scientifique (CNRS), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), and Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Fracture Healing, Homeodomain Proteins, Bone Regeneration, Integrases, Tibia, [SDV.BA]Life Sciences [q-bio]/Animal biology, periosteum, pseudarthrosis, Cell Differentiation, bone repair, Article, Bone and Bones, Mice, Inbred C57BL, endochondral ossification, Cartilage, Phenotype, FGFR3, Animals, Receptor, Fibroblast Growth Factor, Type 3, Bony Callus, skeletal stem/progenitor cell, ComputingMilieux_MISCELLANEOUS
Abstract

Summary Most organs and tissues in the body, including bone, can repair after an injury due to the activation of endogenous adult stem/progenitor cells to replace the damaged tissue. Inherent dysfunctions of the endogenous stem/progenitor cells in skeletal repair disorders are still poorly understood. Here, we report that Fgfr3Y637C/+ over-activating mutation in Prx1-derived skeletal stem/progenitor cells leads to failure of fracture consolidation. We show that periosteal cells (PCs) carrying the Fgfr3Y637C/+ mutation can engage in osteogenic and chondrogenic lineages, but following transplantation do not undergo terminal chondrocyte hypertrophy and transformation into bone causing pseudarthrosis. Instead, Prx1Cre;Fgfr3Y637C/+ PCs give rise to fibrocartilage and fibrosis. Conversely, wild-type PCs transplanted at the fracture site of Prx1Cre;Fgfr3Y637C/+ mice allow hypertrophic cartilage transition to bone and permit fracture consolidation. The results thus highlight cartilage-to-bone transformation as a necessary step for bone repair and FGFR3 signaling within PCs as a key regulator of this transformation., Graphical Abstract, Highlights • Fgfr3Y367C activating mutation in skeletal stem/progenitor cells prevents bone healing • Intrinsic deficiencies in transplanted Prx1Cre;Fgfr3Y637C/+ PCs cause pseudarthrosis • Prx1Cre;Fgfr3Y637C/+ PCs cannot support cartilage-to-bone transformation • Wild-type PCs can rescue the Prx1Cre;Fgfr3Y637C/+ pseudarthrosis phenotype, Julien et al. report a severe bone repair phenotype associated with pseudarthrosis and functional impairment of periosteal cells (PCs) in Prx1Cre;Fgfr3Y637C/+ mice. PCs carrying the Fgfr3Y367C activating mutation cannot undergo cartilage-to-bone transformation thus uncovering an essential role of this transformation step in bone healing.

Published
2020

29. FGFR3 overactivation in the brain is responsible for memory impairments in Crouzon syndrome mouse model

Author

Cornille, Maxence, Moriceau, Stéphanie, Khonsari, Roman, Heuzé, Yann, Loisay, Léa, Boitez, Valérie, Morice, Anne, Arnaud, Eric, Collet, Corinne, Bensidhoum, Morad, Kaci, Nabil, Boddaert, Nathalie, Paternoster, Giovanna, Rauschendorfer, Theresa, Werner, Sabine, Mansour, Suzanne, Di Rocco, Federico, Oury, Franck, Legeai-Mallet, Laurence, Heuzé, Yann, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), National Cystic Fibrosis Reference Center [CHU Necker] (CNR - INSERM U1151), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de chirurgie plastique et maxillofaciale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), De la Préhistoire à l'Actuel : Culture, Environnement et Anthropologie (PACEA), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Service de neurochirurgie pédiatrique [CHU Necker], Hôpital Lariboisière-Fernand-Widal [APHP], Laboratoire de Biomécanique et Biomatériaux Ostéo-Articulaires (B2OA), Université Paris Diderot - Paris 7 (UPD7), Service de radiologie pédiatrique [CHU Necker], Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), University of Utah, Hôpital Femme Mère Enfant [CHU - HCL] (HFME), and Hospices Civils de Lyon (HCL)

Subjects
[SDV] Life Sciences [q-bio], Craniosynostoses, Disease Models, Animal, Memory Disorders, Mice, [SDV]Life Sciences [q-bio], Craniofacial Dysostosis, Animals, Brain, Receptor, Fibroblast Growth Factor, Type 3, Acanthosis Nigricans
Abstract

International audience; Crouzon syndrome with acanthosis nigricans (CAN, a rare type of craniosynostosis characterized by premature suture fusion and neurological impairments) has been linked to a gain-of-function mutation (p.Ala391Glu) in fibroblast growth factor receptor 3 (FGFR3). To characterize the CAN mutation's impact on the skull and on brain functions, we developed the first mouse model (Fgfr3 A385E/+) of this syndrome. Surprisingly, Fgfr3 A385E/+ mice did not exhibit craniosynostosis but did show severe memory impairments, a structurally abnormal hippocampus, low activity-dependent synaptic plasticity, and overactivation of MAPK/ERK and Akt signaling pathways in the hippocampus. Systemic or brain-specific pharmacological inhibition of FGFR3 overactivation by BGJ398 injections rescued the memory impairments observed in Fgfr3 A385E/+ mice. The present study is the first to have demonstrated cognitive impairments associated with brain FGFR3 overactivation, independently of skull abnormalities. Our results provide a better understanding of FGFR3's functional role and the impact of its gain-of-function mutation on brain functions. The modulation of FGFR3 signaling might be of value for treating the neurological disorders associated with craniosynostosis.

Published
2020

30. ADAMTS10 mutations in autosomal recessive Weill-Marchesani syndrome

Author

Dagoneau, Nathalie, Benoist-Lasselin, Catherine, Huber, Celine, Faivre, Laurence, Megarbane, Andre, Alswaid, Abdulrahman, Dollfus, Helene, Alembik, Yves, Munnich, Arnold, Legeai-Mallet, Laurence, and Cormier-Daire, Valerie

Subjects
Syndromes -- Research, Syndromes -- Identification and classification, Chromosome abnormalities -- Research, Syndromes in children -- Research, Children -- Diseases, Children -- Research, Biological sciences
Published
2004

31. Null leukemia inhibitory factor receptor (LIFR) mutations in Stuve-Wiedemann/Schwartz-Jampel type 2 syndrome

Author

Dagoneau, Nathalie, Scheffer, Deborah, Huber, Celine, Al-Gazali, Lihadh I., Di Rocco, Maja, Godard, Anne, Martinovic, Jelena, Raas-Rothschild, Annick, Sigaudy, Sabine, Unger, Sheila, Nicole, Sophie, Fontaine, Bertrand, Taupin, Jean-Luc, Moreau, Jean-Francois, Superti-Furga, Andrea, Le Merrer, Martine, Bonaventure, Jacky, Munnich, Arnold, Legeai-Mallet, Laurence, and Cormier-Daire, Valerie

Subjects
Biological sciences
Published
2004

40. Fgfr3 Is a Positive Regulator of Osteoblast Expansion and Differentiation During Zebrafish Skull Vault Development

Author

Dambroise, Emilie, primary, Ktorza, Ivan, additional, Brombin, Alessandro, additional, Abdessalem, Ghaith, additional, Edouard, Joanne, additional, Luka, Marine, additional, Fiedler, Imke, additional, Binder, Olivia, additional, Pelle, Olivier, additional, Patton, E Elizabeth, additional, Busse, Björn, additional, Menager, Mickaël, additional, Sohm, Frederic, additional, and Legeai‐Mallet, Laurence, additional

Published
2020
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46. Tyrosine kinases regulate chondrocyte hypertrophy: promising drug targets for Osteoarthritis.

Author

Ferrao Blanco, M.N., Domenech Garcia, H., Legeai-Mallet, L., van Osch, G.J.V.M., Ferrao Blanco, Mauricio N, Garcia, Heura Domenech, Legeai-Mallet, Laurence, van Osch, Gerjo J V M, and Garcia, H D

Abstract

Osteoarthritis (OA) is a major health problem worldwide that affects the joints and causes severe disability. It is characterized by pain and low-grade inflammation. However, the exact pathogenesis remains unknown and the therapeutic options are limited. In OA articular chondrocytes undergo a phenotypic transition becoming hypertrophic, which leads to cartilage damage, aggravating the disease. Therefore, a therapeutic agent inhibiting hypertrophy would be a promising disease-modifying drug. The therapeutic use of tyrosine kinase inhibitors has been mainly focused on oncology, but the Food and Drug Administration (FDA) approval of the Janus kinase inhibitor Tofacitinib in Rheumatoid Arthritis has broadened the applicability of these compounds to other diseases. Interestingly, tyrosine kinases have been associated with chondrocyte hypertrophy. In this review, we discuss the experimental evidence that implicates specific tyrosine kinases in signaling pathways promoting chondrocyte hypertrophy, highlighting their potential as therapeutic targets for OA. [ABSTRACT FROM AUTHOR]

Published
2021
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49. Achondroplasia: Development, Pathogenesis, and Therapy

Author

Ornitz, David M. and Legeai-Mallet, Laurence

Subjects
musculoskeletal diseases, congenital, hereditary, and neonatal diseases and abnormalities, Chondrocytes, Animals, Humans, Receptor, Fibroblast Growth Factor, Type 3, Growth Plate, Article, Achondroplasia, Signal Transduction
Abstract

Autosomal dominant mutations in fibroblast growth factor receptor 3 (FGFR3) cause achondroplasia (Ach), the most common form of dwarfism in humans, and related chondrodysplasia syndromes that include hypochondroplasia (Hch), severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), and thanatophoric dysplasia (TD). FGFR3 is expressed in chondrocytes and mature osteoblasts where it functions to regulate bone growth. Analysis of the mutations in FGFR3 revealed increased signaling through a combination of mechanisms that include stabilization of the receptor, enhanced dimerization, and enhanced tyrosine kinase activity. Paradoxically, increased FGFR3 signaling profoundly suppresses proliferation and maturation of growth plate chondrocytes resulting in decreased growth plate size, reduced trabecular bone volume, and resulting decreased bone elongation. In this review, we discuss the molecular mechanisms that regulate growth plate chondrocytes, the pathogenesis of Ach, and therapeutic approaches that are being evaluated to improve endochondral bone growth in people with Ach and related conditions. Developmental Dynamics 246:291-309, 2017. © 2016 Wiley Periodicals, Inc.

Published
2017

50. Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia

Author

Rousseau, Francis, Bonaventure, Jacky, Legeai-Mallet, Laurence, Pelet, Anna, Rozet, Jean-Michel, Maroteaux, Pierre, Merrer, Martine Le, and Munnich, Arnold

Subjects
Achondroplasia -- Genetic aspects, Mutation (Biology) -- Observations, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Genetic mutations and subsequent studies of the genes that cause achondroplasia in individuals reveal recurring missense mutations in a CpG doublet of the transmembrane region of the fibroblast-growth factor receptor-3 (FGFR3) in 17 sporadic and 6 unassociated familial types of achondroplasia. The mutant genotype separately groups with the disease in the observed families. The FGFR3 gene is responsible for achondroplasia, as a mutation of a single amino acid in the transmembrane region of FGFR3 initiates a skeletal growth defect.

Published
1994

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