A Novel Skeletal Dysplasia with Developmental Delay and Acanthosis Nigricans Is Caused by a Lys650Met Mutation in the Fibroblast Growth Factor Receptor 3 Gene

Tavormina, Patricia L.; Bellus, Gary A.; Webster, Melanie K.; Bamshad, Michael J.; Fraley, Alexander E.; McIntosh, Iain; Szabo, Jinny; Jiang, Wen Guo; Jabs, Ethylin Wang; Wilcox, William R.; Wasmuth, John J.; Donoghue, Daniel J.; Thompson, Leslie M.; Francomano, Clair A.

doi:10.1086/302275

Cited by 151 publications

(136 citation statements)

References 33 publications

(46 reference statements)

Supporting

Mentioning

132

Contrasting

Unclassified

Order By: Relevance

“…Somatic FGFR3 mutations identical to those found in thanatophoric dysplasia (neonatal lethal dwarfism syndrome) and SADDAN have been associated with rare cases of human multiple myeloma. 12,13 We recently identified, in a series of 26 bladder and 12 cervix carcinomas, several FGFR3-activating mutations previously identified as associated with thanatophoric dysplasia. 8 To investigate further the role of FGFR3 mutations in bladder carcinogenesis, we assessed the incidence of FGFR3 mutations in a large series of 132 bladder tumors of various stages and grades.…”

Section: Discussionmentioning

confidence: 99%

“…These four regions contain the FGFR3 point mutations previously identified in thanatophoric dysplasia, SADDAN, achondroplasia, Crouzon syndrome with acanthosis nigricans, multiple myeloma, and bladder and cervical carcinomas. 8,12,13 For most of the samples (all pTa and pT1-4 tumors and 16 CIS), a single round of PCR was carried out, using the following primer pairs: exon 7, 5Ј-AGTGGCGGTGGT-GGTGAGGGAG-3Ј and 5Ј-TGTGCGTCACTGTACACCT-TGCAG-3Ј; exon 10, 5Ј-CAACGCCCATGTCTTTGCAG-3Ј and 5Ј-CGGGAAGCGGGAGATCTTG-3Ј; exon 15, 5Ј-GACCGAGGACAACGTGATG-3Ј and 5Ј-GTGTGGGAAG-GCGGTGTTG-3Ј; exon 19, 5Ј-TGTCGGCGCCTTTCGAG-CAGTA-3Ј and 5Ј-AGCAGCAGGGTGGGCTGCTA-3Ј. PCR was performed in a final volume of 50 l containing 50 ng genomic DNA or 1/20 th of the purified DNA from microdissected samples, 100 mol/L each of dATP, dCTP, dTTP, and dGTP, 1 mol/L forward and reverse primers, 1ϫ of amplification buffer provided with the polymerase and 1 Ci [␣ 33 P]dATP.…”

Section: Fgfr3 Mutation Analysismentioning

confidence: 99%

“…11 Specific point mutations in various domains of FGFR3 are associated with autosomal dominant human skeletal disorders such as hypochondroplasia, achondroplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), and thanatophoric dysplasia. 12,13 Several reports have demonstrated that these mutations lead to constitutive activation of the receptor. [12][13][14] The identification in multiple myeloma and, more recently, in bladder and cervical carcinomas of somatic mutations of FGFR3 identical to the activating mutations responsible for thanatophoric dysplasia and SADDAN 8,[15][16][17] suggested that FGFR3 plays an oncogenic role.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Frequent FGFR3 Mutations in Papillary Non-Invasive Bladder (pTa) Tumors

Billerey

Chopin

Aubriot-Lorton

et al. 2001

The American Journal of Pathology

428

339

View full text Add to dashboard Cite

We recently identified activating mutations of fibroblast growth factor receptor 3 (FGFR3) in bladder carcinoma. In this study we assessed the incidence of FGFR3 mutations in a series of 132 bladder carcinomas: 20 carcinoma in situ (CIS), 50 pTa, 19 pT1, and 43 pT2-4. All 48 mutations identified were identical to the germinal activating mutations that cause thanatophoric dysplasia, a lethal form of dwarfism. The S249C mutation, found in 33 of the 48 mutated tumors, was the most common. The frequency of mutations was higher in pTa tumors (37 of 50, 74%) than in CIS (0 of 20, 0%; P < 0.0001), pT1 (4 of 19, 21%; P < 0.0001) and pT2-4 tumors (7 of 43, 16%; P < 0.0001). Bladder cancer is the fourth most common malignancy in men and the ninth most common in women in the Western world. In these countries, more than 90% of bladder tumors are urothelial carcinomas. At the time of initial diagnosis, approximately 80% of urothelial carcinomas are confined to the epithelium (pTa, CIS) or lamina propria (pT1), whereas the remaining 20% invade the muscularis propria (pT2, pT3, pT4). pTa lesions, the most common form of bladder carcinoma, are papillary tumors. Carcinoma in situ (CIS) are flat, cytologically highgrade carcinomas. Primary isolated CIS is a very rare entity, CIS being more commonly associated with other malignant bladder lesions. 1 Clinical evidence and molecular studies suggest that there are two pathways in bladder carcinogenesis responsible for generating two types of urothelium-confined tumors (pTa and CIS) with very different behavior. 1-6 pTa tumors are associated with a high rate of recurrence (50 -75%) but a low probability (Ͻ5%) of progression to lamina propria-invasive (pT1) and muscleinvasive (pT2-4) tumors. CIS may be the most common precursor of invasive bladder cancer because CIS shows a strong tendency to progress (40 -50%), and because most muscle-invasive lesions arise with no history of a pTa precursor lesion. This clinical evidence is supported by various molecular studies showing that CIS and invasive tumors have many genetic alterations in common, such as specific chromosomal deletions and a high frequency of p53 mutations. 2,7 In our search for new markers of carcinoma progression, we recently reported specific missense mutations in a gene encoding a growth factor receptor, fibroblast

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Fgfr3 Mutation Analysismentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Frequent FGFR3 Mutations in Papillary Non-Invasive Bladder (pTa) Tumors

Billerey

Chopin

Aubriot-Lorton

et al. 2001

The American Journal of Pathology

428

339

View full text Add to dashboard Cite

show abstract

“…Mutations in the genes encoding the FGFRs confer several different disorders that affect skeletal development (20). Mutations and translocations of the FGFRs have also been associated with human cancers (21)(22)(23)(24)(25). In particular, mutations that result in aberrant activation of FGFR3 have been found in bladder carcinomas, cervical carcinomas, and multiple myeloma (26)(27)(28).…”

Section: Introductionmentioning

confidence: 99%

MUC1 Oncoprotein Functions in Activation of Fibroblast Growth Factor Receptor Signaling

Ren

Raina²,

Chen³

et al. 2006

Molecular Cancer Research

View full text Add to dashboard Cite

Activation of the fibroblast growth factor (FGF) receptor 3 (FGFR3) has been linked to the development of human cancers by mechanisms that are not well understood. The MUC1 oncoprotein is aberrantly overexpressed by certain hematologic malignancies and most human carcinomas. The present studies show that MUC1 associates with FGFR3. Stimulation of cells with FGF1 increased the interaction between MUC1 and FGFR3. FGF1 stimulation also induced c-Src-dependent tyrosine phosphorylation of the MUC1 cytoplasmic domain on a YEKV motif. FGF1-induced tyrosine phosphorylation of MUC1 was associated with increased binding of MUC1 to B-catenin and targeting of MUC1 and B-catenin to the nucleus. FGF1 also induced binding of MUC1 to the heat shock protein 90 (HSP90) chaperone by a mechanism dependent on phosphorylation of the YEKV motif. Notably, B-catenin and HSP90 compete for binding to the MUC1 cytoplasmic domain, indicating that MUC1 forms mutually exclusive complexes with these proteins. The results also show that inhibition of HSP90 with geldanamycin or 17-(allylamino)-17-demethoxygeldanamycin attenuates FGF1-induced binding of MUC1 to HSP90 and targeting of MUC1 to the mitochondrial outer membrane. These findings indicate that FGF1 induces phosphorylation of MUC1 on YEKV and thereby activates two distinct pathways: (a) nuclear localization of MUC1 and B-catenin and (b) delivery of MUC1 to mitochondria by HSP90. (Mol Cancer Res 2006;4(11):873 -83)

show abstract

“…Two phenotypes have been distinguished: 1) the above-described clinical signs plus curved femurs (TD-I) or 2) the less frequent, straight femurs and a cloverleaf skull (TD-II). There are several mutations described in TD-I that result from either a stop or missense mutation in different codons (mainly codons 248, 650, and 807), but in TD-II an exclusive mutation (Lys650Glu) has been associated with this phenotype [4,7,8].…”

Section: Introductionmentioning

confidence: 99%

Prenatal diagnosis of skeletal dysplasia due to FGFR3 gene mutations: a 9-year experience

Trujillo-Tiebas

Fenollar-Cortés

Lorda‐Sánchez

et al. 2009

J Assist Reprod Genet

View full text Add to dashboard Cite

Purpose Prenatal diagnosis with ultrasound findings compatible with skeletal dysplasia due to FGFR3 mutations over a 9 year period in pregnancies and abortuses. Methods 54 samples were studied. Aneuploidy studies were carried out on all samples. By sequencing analysis, we determined mutations for achondroplasia (ACH), hypochondroplasia (HCH), and type I and type II tanathophoric dysplasia (TD). Results 2 chorionic villi samples had a G380R mutation due to a mother with ACH; 4 amniotic fluid samples with TDs in which the foetuses had micromelia plus hypoplastic thoraces; 5 samples from abortuses with TDs. Neither ACH nor HCH occurred in sporadic cases. Conclusions Molecular studies in ongoing pregnancies are indicated in cases with an affected parent, a family history with positive molecular studies (maternal anxiety), and when the US finding demonstrates micromelia with a hypoplastic thorax. A protocol for tissues of abortuses should include an X-ray, pathologic anatomy, and genetic studies.

show abstract

A Novel Skeletal Dysplasia with Developmental Delay and Acanthosis Nigricans Is Caused by a Lys650Met Mutation in the Fibroblast Growth Factor Receptor 3 Gene

Cited by 151 publications

References 33 publications

Frequent FGFR3 Mutations in Papillary Non-Invasive Bladder (pTa) Tumors

Frequent FGFR3 Mutations in Papillary Non-Invasive Bladder (pTa) Tumors

MUC1 Oncoprotein Functions in Activation of Fibroblast Growth Factor Receptor Signaling

Prenatal diagnosis of skeletal dysplasia due to FGFR3 gene mutations: a 9-year experience

Contact Info

Product

Resources

About