Clinical spectrum of fibroblast growth factor receptor mutations

Passos‐Bueno, Maria Rita; Wilcox, William R.; Jabs, Ethylin Wang; Sertié, Andréa L.; Alonso, Luís Garcia; Kitoh, Hiroshi

doi:10.1002/(sici)1098-1004(1999)14:2<115::aid-humu3>3.0.co;2-2

Cited by 267 publications

(70 citation statements)

References 84 publications

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“…Variable expression of the phenotype associated with the cathepsin C mutation may reflect the influence of other genetic or environmental factors. Identical mutations can give rise to multiple different phenotypes, such as has been shown for the craniosynostoses and fibroblast growth factor receptor mutations 45. Identical mutations in cathepsin C may also give rise to different phenotypes (PLS and PPP).…”

Section: Discussionmentioning

confidence: 93%

Localisation of a gene for prepubertal periodontitis to chromosome 11q14 and identification of a cathepsin C gene mutation

Hart

Michalec

et al. 2000

Journal of Medical Genetics

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Prepubertal periodontitis (PPP) is a rare and rapidly progressive disease of young children that results in destruction of the periodontal support of the primary dentition. The condition may occur as part of a recognised syndrome or may occur as an isolated finding. Both autosomal dominant and recessive forms of Mendelian transmission have been reported for PPP. We report a consanguineous Jordanian family with four members aVected by PPP in two nuclear sibships. The parents of the aVected subjects are first cousins. We have localised a gene of major eVect for PPP in this kindred (Zmax=3.55 for D11S901 at =0.00) to a 14 cM genetic interval on chromosome 11q14 flanked by D11S916 and D11S1367. This PPP candidate interval overlaps the region of chromosome 11q14 that contains the cathepsin C gene responsible for Papillon-Lefèvre and Haim-Munk syndromes. Sequence analysis of the cathepsin C gene from PPP aVected subjects from this Jordanian family indicated that all were homozygous for a missense mutation (1040A→G) that changes a tyrosine to a cysteine. All four parents were heterozygous carriers of this Tyr347Cys cathepsin C mutation. None of the family members who were heterozygous carriers for this mutation showed any clinical findings of PPP. None of the 50 controls tested were found to have this Tyr347Cys mutation. This is the first reported gene mutation for nonsyndromic periodontitis and shows that non-syndromic PPP is an allelic variant of the type IV palmoplantar ectodermal dysplasias. (J Med Genet 2000;37:95-101)

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Section: Discussionmentioning

confidence: 93%

Localisation of a gene for prepubertal periodontitis to chromosome 11q14 and identification of a cathepsin C gene mutation

Hart

Michalec

et al. 2000

Journal of Medical Genetics

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“…Activating mutations of FGFR2 can cause urogenital abnormalities in humans including hydroureter and solitary kidney (24, 25). Human studies have also shown that specific structural renal anomalies seen in Fgfr2 Mes-/- mice, such as renal agenesis, often occur in familial clusters (26, 27).…”

Section: Discussionmentioning

confidence: 99%

Role of Fibroblast Growth Factor Receptor 2 in Kidney Mesenchyme

et al. 2008

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Conditional deletion of murine fibroblast growth factor receptors (Fgfrs) 1 and 2 in metanephric mesenchyme leads to renal agenesis with unbranched ureteric buds; however, there are occasionally two buds per nephric duct. Our goal was to determine whether conditional deletion of Fgfr1 or Fgfr2 alone resulted in multiple ureteric bud induction sites. Although deletion of Fgfr1 alone results in no abnormalities, loss of Fgfr2 often leads to multiple ureteric buds and anomalies including renal aplasia, misshaped kidneys, partially duplicated kidneys, duplicated ureters, and obstructed hydroureter. Deletion of Fgfr2 did not change expression domains of glial cell line-derived neurotrophic factor (GDNF), Robo2, bone morphogenetic protein 4, or Sprouty1, all of which regulate ureteric bud induction. Cultured Fgfr2 mutant nephric ducts were also not more sensitive to exogenous GDNF than controls. Whole mount in situ hybridization revealed that in mutant embryos, Fgfr2 was deleted from stromal cells around the nephric duct and ureteric bud base, which correlates well with the ureteric bud induction abnormalities. Thus, Fgfr2 is critical in ensuring that there is a single ureteric bud from the nephric duct. The plethora of later stage defects in Fgfr2 conditional knockouts is reminiscent of many human cases of genetic urogenital anomalies. (Pediatr Res 64: 592-598, 2008) F ibroblast growth factor receptors (Fgfrs) are receptor tyrosine kinases with four known signaling members and 22 ligands in mammals (1). Fgfrs are expressed throughout embryogenesis in many tissues, including the kidney (1).The metanephric kidney arises from two embryonic tissues, the metanephric mesenchyme and ureteric bud. At embryonic day (E) 10.5 in the mouse and the 5th week of gestation in humans, the metanephric mesenchyme induces a single ureteric bud from the Wolffian (nephric) duct near the hind limb (2). Subsequently, the ureteric bud elongates and branches within the metanephric mesenchyme, giving rise to the collecting ducts, pelvis, and ureter (2). At its tips, the ureteric bud induces local metanephric mesenchyme to condense and differentiate into nephron epithelia. Regions of stromal mesenchyme also surround the developing nephrons.Many studies have documented diverse actions of Fgfrs in developing kidneys. Addition of Fgf2 to isolated rat metanephric mesenchymal tissues prevented apoptosis (3,4) and promoted condensation (4). Transgenic mice with a dominant negative Fgfr fragment developed renal agenesis/severe dysgenesis (5). Mice null for Fgf7, Fgf10, or Fgfr2-IIIb (the receptor isoform for Fgf7 and Fgf10), have small kidneys with normal-appearing nephrons (6 -8). Mice with conditional deletion of Fgf8 from the metanephric mesenchyme, however, have interrupted nephron development (9,10).Although Fgfr1 and Fgfr2 null mice are early embryonic lethal (11-14), conditional knockout approaches have revealed roles for these receptors in kidney development. We observed that deletion of Fgfr2 from the ureteric bud results in aberran...

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“…Activating mutations in FGFR3 result in several human skeletal dysplasias such as thanatophoric dysplasia (TD) and achondroplasia (ACH), the most common genetic forms of lethal and non-lethal dwarfism, respectively [1]. Despite recent progress in unraveling the mechanisms of FGFR3 signaling in cartilage, many aspects of this signaling still remain elusive.…”

Section: Introductionmentioning

confidence: 99%

FGFR3 signaling induces a reversible senescence phenotype in chondrocytes similar to oncogene-induced premature senescence

Krejčı́

Procházková

Smutny

et al. 2010

Bone

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Oncogenic activation of the RAS-ERK MAP kinase signaling pathway can lead to uncontrolled proliferation but can also result in apoptosis or premature cellular senescence, both regarded as natural protective barriers to cell immortalization and transformation. In FGFR3-related skeletal dyplasias, oncogenic mutations in the FGFR3 receptor tyrosine kinase cause profound inhibition of cartilage growth resulting in severe dwarfism, although many of the precise mechanisms of FGFR3 action remain unclear. Mutated FGFR3 induces constitutive activation of the ERK pathway in chondrocytes and, remarkably, can also cause both increased proliferation and apoptosis in growing cartilage, depending on the gestational age. Here, we demonstrate that FGFR3 signaling is also capable of inducing premature senescence in chondrocytes, manifested as reversible, ERK-dependent growth arrest accompanied by alteration of cellular shape, loss of the extracellular matrix, upregulation of senescence markers (α-GLUCOSIDASE, FIBRONECTIN, CAVEOLIN 1, LAMIN A, SM22α and TIMP 1), and induction of senescence-associated β-GALACTOSIDASE activity. Our data support a model whereby FGFR3 signaling inhibits cartilage growth via exploiting cellular responses originally designed to eliminate cells harbouring activated oncogenes.

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Clinical spectrum of fibroblast growth factor receptor mutations

Cited by 267 publications

References 84 publications

Localisation of a gene for prepubertal periodontitis to chromosome 11q14 and identification of a cathepsin C gene mutation

Localisation of a gene for prepubertal periodontitis to chromosome 11q14 and identification of a cathepsin C gene mutation

Role of Fibroblast Growth Factor Receptor 2 in Kidney Mesenchyme

FGFR3 signaling induces a reversible senescence phenotype in chondrocytes similar to oncogene-induced premature senescence

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