A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia

Bellus, Gary A.; McIntosh, Iain; Smith, Elizabeth A.; Aylsworth, Arthur S.; Kaitila, Ilkka; Horton, William A.; Greenhaw, Giselle A.; Hecht, Jacqueline; Francomano, Clair A.

doi:10.1038/ng0795-357

Cited by 432 publications

(248 citation statements)

References 22 publications

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“…6,24 In other words, possible hypochondroplasia mutations in other exons than 15 may have escaped their detection in bladder cancer. Among the 570 bladder tumours studied so far, only 89 have been studied for the hypochondroplasia mutations located in exon 13.…”

Section: Discussionmentioning

confidence: 99%

Novel fibroblast growth factor receptor 3 (FGFR3) mutations in bladder cancer previously identified in non-lethal skeletal disorders

et al. 2002

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Activating mutations in the fibroblast growth factor receptor 3 (FGFR3) gene are responsible for several autosomal dominant craniosynostosis syndromes and chondrodysplasias i.e. hypochondroplasia, achondroplasia, SADDAN and thanatophoric dysplasia -a neonatal lethal dwarfism syndrome. Recently, activating FGFR3 mutations have also been found to be present in cancer, i.e. at high frequency in carcinoma of the bladder and rarely in multiple myeloma and carcinoma of the cervix. Almost all reported mutations in carcinomas corresponded to the mutations identified in thanatophoric dysplasia. We here screened a series of 297 bladder tumours and found three FGFR3 somatic mutations (G380/ 382R; K650/652M and K650/652T) that were not previously identified in carcinomas or thanatophoric dysplasia. Another novel finding was the occurrence of two simultaneous FGFR3 mutations in four tumours. Two of the three new mutations in bladder cancer, the G380/382R and the K650/652M mutations, were previously reported in achondroplasia and SADDAN, respectively. These syndromes entail a longer life span than thanatophoric dysplasia. The K650/652T mutation has not previously been detected in patients with skeletal disorders, but affects a codon that has been shown to be affected in some cases of thanatophoric dysplasia, SADDAN and hypochondroplasia. From a clinical perspective, the patients with FGFR3-related, non-lethal skeletal disorders might be at a higher risk for development of bladder tumours than the general population.

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Section: Discussionmentioning

confidence: 99%

Novel fibroblast growth factor receptor 3 (FGFR3) mutations in bladder cancer previously identified in non-lethal skeletal disorders

et al. 2002

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“…Related autosomal dominant chondrodysplasia syndromes include the more severe and usually lethal thanatophoric dysplasia types I and II, which are attributed to two mutations in FGFR3 (K650E and R248C, respectively), and the milder form of dwarfism, hypochondroplasia, which is caused by an N540K or K650N mutation in FGFR3 (Bellus et al 1995(Bellus et al , 2000Tavormina et al 1995;Bonaventure et al 1996). A closely related disease, referred to as severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN) Tavormina et al 1999), and a very rare lethal chondrodysplasia, platyspondylic lethal skeletal dysplasia, San Diego type (Brodie et al 1999) are both caused by a K650M mutation in FGFR3.…”

Section: Chondrodysplasia Syndromesmentioning

confidence: 99%

Fibroblast growth factor signaling in skeletal development and disease

2015

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Fibroblast growth factor (FGF) signaling pathways are essential regulators of vertebrate skeletal development. FGF signaling regulates development of the limb bud and formation of the mesenchymal condensation and has key roles in regulating chondrogenesis, osteogenesis, and bone and mineral homeostasis. This review updates our review on FGFs in skeletal development published in Genes & Development in 2002, examines progress made on understanding the functions of the FGF signaling pathway during critical stages of skeletogenesis, and explores the mechanisms by which mutations in FGF signaling molecules cause skeletal malformations in humans. Links between FGF signaling pathways and other interacting pathways that are critical for skeletal development and could be exploited to treat genetic diseases and repair bone are also explored.

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“…Mutations in genes encoding extracellular matrix molecules, growth factors, receptors, and transcription factors have been identified as causes of several chondrodysplasias. For example, mutations in the genes for the parathyroid hormone (PTH)/PTH-related peptide receptor (PTHrP) (15,16), the fibroblast growth factor receptor 3 (17)(18)(19)(20), or the orphan receptor ROR2 (21)(22)(23)(24) are found in several skeletal dysplasias. In addition to PTHrP, fibroblast growth factors, and the currently unknown ligand(s) for ROR2, numerous other growth factors and hormones (such as transforming growth factor-␤ family members, growth hormone, insulin-like growth factors, Indian hedgehog, thyroid hormone, retinoic acid and vitamin D) (3,25) regulate growth plate biology.…”

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confidence: 99%

RhoA/ROCK Signaling Suppresses Hypertrophic Chondrocyte Differentiation

Wang

Woods

Sabari

et al. 2004

Journal of Biological Chemistry

117

118

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Coordinated proliferation and differentiation of growth plate chondrocytes is required for normal growth and development of the endochondral skeleton, but little is known about the intracellular signal transduction pathways regulating these processes. We have investigated the roles of the GTPase RhoA and its effector kinases ROCK1/2 in hypertrophic chondrocyte differentiation. RhoA, ROCK1, and ROCK2 are expressed throughout chondrogenic differentiation. RhoA overexpression in chondrogenic ATDC5 cells results in increased proliferation and a marked delay of hypertrophic differentiation, as shown by decreased induction of alkaline phosphatase activity, mineralization, and expression of the hypertrophic markers collagen X, bone sialoprotein, and matrix metalloproteinase 13. These effects are accompanied by activation of cyclin D1 transcription and repression of the collagen X promoter by RhoA. In contrast, inhibition of Rho/ROCK signaling by the pharmacological inhibitor Y27632 inhibits chondrocyte proliferation and accelerates hypertrophic differentiation. Dominant-negative RhoA also inhibits induction of the cyclin D1 promoter by parathyroid hormone-related peptide. Finally, Y27632 treatment partially rescues the effects of RhoA overexpression. In summary, we identify the RhoA/ROCK signaling pathway as a novel and important regulator of chondrocyte proliferation and differentiation.The development and growth of endochondral bones (such as ribs, vertebrae, and the long bones of vertebrate limbs) are regulated through the highly controlled rates of proliferation and hypertrophic differentiation of growth plate chondrocytes (1-3). In the growth plate, chondrocytes first undergo a series of cell divisions along the longitudinal axis of the growing bone, thereby forming characteristic columns of clonal cells. Chondrocytes then withdraw from the cell cycle and begin to increase their cell volume until reaching the fully differentiated state of hypertrophic chondrocytes. Transition from a proliferating to a hypertrophic phenotype involves numerous changes in gene expression, for example the induction of the collagen X (4, 5), matrix metalloproteinase 13 (6, 7), and bone sialoprotein (BSP) 1 (8 -10) genes. The latter two genes are also expressed by osteoblasts, suggesting similar biological properties of hypertrophic chondrocytes and osteoblasts. The fate of hypertrophic chondrocytes is still debated, but it appears that the majority of these cells undergo apoptosis and are replaced by bone tissue (11). Longitudinal growth of endochondral bones therefore requires both proliferation and differentiation-associated hypertrophy of growth plate chondrocytes.Disruption of chondrocyte proliferation and/or differentiation by gene mutations commonly results in chondrodysplasias that are characterized by skeletal deformities and reduced growth (12)(13)(14). Mutations in genes encoding extracellular matrix molecules, growth factors, receptors, and transcription factors have been identified as causes of several chondrodysplasias. Fo...

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A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia

Cited by 432 publications

References 22 publications

Novel fibroblast growth factor receptor 3 (FGFR3) mutations in bladder cancer previously identified in non-lethal skeletal disorders

Novel fibroblast growth factor receptor 3 (FGFR3) mutations in bladder cancer previously identified in non-lethal skeletal disorders

Fibroblast growth factor signaling in skeletal development and disease

RhoA/ROCK Signaling Suppresses Hypertrophic Chondrocyte Differentiation

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