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Urothelial and Urethral Cancer
Published in Karl H. Pang, Nadir I. Osman, James W.F. Catto, Christopher R. Chapple, Basic Urological Sciences, 2021
Ibrahim Jubber, Karl H. Pang, James W.F. Catto
FGFR3 mutationsActivate the FGF growth pathway.Associated with a favourable clinical phenotype (fewer progression and recurrence events).FGF-targeting small molecules are now entering clinical practice (e.g., erdafitinib is FDA approved).
Craniofacial Regeneration—Bone
Published in Vincenzo Guarino, Marco Antonio Alvarez-Pérez, Current Advances in Oral and Craniofacial Tissue Engineering, 2020
Laura Guadalupe Hernandez, Lucia Pérez Sánchez, Rafael Hernández González, Janeth Serrano-Bello
Most recognizable craniofacial syndromes are monogenic Mendelian disorders, different mutations in the same gene. However, it is not a rule because, more than 7000 single-gene disorders have been identified in craniofacial disorders such as Stickler syndrome and the craniosynostosis syndromes involving different FGFR genes (FGFR1, FGFR2, FGFR3).
Genetics and metabolic disorders
Published in Jagdish M. Gupta, John Beveridge, MCQs in Paediatrics, 2020
Jagdish M. Gupta, John Beveridge
Achondroplasia is autosomal dominant (80% of cases represent new mutations). The risk to the offspring of an affected person will be 1 in 2 for each pregnancy. Consanguinity does not increase the risk in offspring unless both parents are affected. If both parents have achondroplasia, there is a 1 in 4 chance that an offspring will be unaffected. Complete penetrance implies that those who do not show the phenotype do not carry the mutation and therefore cannot pass it on. The gene responsible for the disorder has recently been identified as the fibroblast growth factor receptor-3 (FGFR-3), with almost all affected individuals carrying the same mutation. Prenatal diagnosis is now possible by DNA analysis.
Recent advances in the understanding of urothelial tumorigenesis
Published in Expert Review of Anticancer Therapy, 2023
Masato Yasui, Liam Cui, Hiroshi Miyamoto
Inactivation of mutant FGFR3 in bladder cancer cell lines has been associated with reduction of malignant potential. However, it should be further determined how FGFR3 could induce urothelial tumorigenesis. In a study [33], a transcription factor of the ETS family, ETV5, was suggested to function as a key mediator of the oncogenic activity of FGFR3 signaling in non-neoplastic urothelial cells. Specifically, FGFR3 up-regulated ETV5 expression via the MAPK/ERK pathway, resulting in induction of TAZ, a transcriptional coactivator and a downstream effector of Hippo signaling involving cell-contact inhibition. Knockdown of ETV5 in FGFR3 mutant bladder cancer cells was also associated with reduced proliferation and anchorage-independent growth. As pharmacological inhibition of Hippo in various non-urothelial cancer cell lines has shown promising results, the findings may indicate that TAZ is a therapeutic target in FGFR3-dependent bladder cancer.
Genetic variants of FGFR family associated with height, hypertension, and osteoporosis
Published in Annals of Human Biology, 2023
Hye-Won Cho, Hyun-Seok Jin, Yong-Bin Eom
Indeed, one study demonstrated that growth plate activity is deregulated in mice lacking Fgfr3, leading to overgrowth of the appendicular skeleton (Colvin et al. 1996; Deng et al. 1996; Eswarakumar and Schlessinger 2007). Researchers expected that functional mutations might occur in human FGFR3 since mice lacking FGFR3 are viable, and this expectation was validated by the discovery of a family with dominantly inherited camptodactyly, tall stature, and hearing loss (CATSHL) syndrome (Makrythanasis et al. 2014; Escobar et al. 2016). CATSHL syndrome results from a missense mutation in the human FGFR3 gene that can cause anomalies by inhibiting negative regulation of bone growth (Escobar et al. 2016). In the present study, we found that the minor allele of the genetic variant in FGFR3 increases both height and the risk of osteoporosis. Although FGFR3 mutations do not cause critical disability, they have an effect on the skeletal phenotype within the normal range. Notably, our finding that taller height is associated with minor alleles in three genetic variants of the FGFR3 gene is supported by the results of these other studies. Together, these findings highlight the potential value of the FGFR3 gene in the skeletal system.
Emerging drug targets for achondroplasia
Published in Expert Opinion on Therapeutic Targets, 2022
The period following on from this discovery has seen a slow but steady increase in our understanding of the molecular consequences of this FGFR3 mutation in growth plate chondrocytes. This has largely been achieved through development and detailed analysis of various transgenic and ‘knock-in’ mouse models of ACH that recapitulate the skeletal phenotype [5]. In these animal models, the gain-of-function mutation in FGFR3 leads to dysregulation of several downstream pathways resulting in inhibition of chondrocyte proliferation and differentiation (endochondral ossification) in the growth plate and decreased long bone growth [5]. Membranous ossification and axial skeletal development were also affected in these mice, leading to altered craniofacial morphology and spinal column development, comparable to the phenotype observed in humans with ACH. These models identified key downstream targets that were activated by the FGFR3 mutation, including MAP kinases such as ERK1, ERK2, and P38, protein phospholipases, and STAT1 (signal transducer and activation of transcription 1) [5]. In addition to providing a clearer understanding of the pathogenesis of ACH in humans, these models identified key molecules and pathways that might be amenable to therapeutic (drug) targeting and modulation.