A novel mutation in FGFR-3 disrupts a putative N-glycosylation site and results in hypochondroplasia

2000 ◽  
Vol 2 (1) ◽  
pp. 9-12 ◽  
Author(s):  
ANDREAS WINTERPACHT ◽  
KATJA HILBERT ◽  
CHRISTIANE STELZER ◽  
THORSTEN SCHWEIKARDT ◽  
HEINZ DECKER ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Novel Mutation ◽  
Hot Spot ◽  
Three Dimensional ◽  
Growth Factor Receptor ◽  
Kinase Domain ◽  
Glycosylation Site ◽  
Dimensional Structure ◽  
Tyrosine Kinase Domain ◽  
Common Mutation

Winterpacht, Andreas, Katja Hilbert, Christiane Stelzer, Thorsten Schweikardt, Heinz Decker, Hugo Segerer, Jürgen Spranger, and Bernhard Zabel. A novel mutation in FGFR-3 disrupts a putative N-glycosylation site and results in hypochondroplasia. Physiol. Genomics 2: 9–12, 2000.—Fibroblast growth factor receptor 3 (FGFR3) is a glycoprotein that belongs to the family of tyrosine kinase receptors. Specific mutations in the FGFR3 gene are associated with autosomal dominant human skeletal disorders such as hypochondroplasia, achondroplasia, and thanatophoric dysplasia. Hypochondroplasia (HCH), the mildest form of this group of short-limbed dwarfism disorders, results in ∼60% of cases from a mutation in the intracellular FGFR3-tyrosine kinase domain. The remaining cases may either be caused by defects in other FGFR gene regions or other yet unidentified genes. We describe a novel HCH mutation, the first found outside the common mutation hot spot of this condition. This point mutation, an N328I exchange in the extracellular Ig domain III of the receptor, seems to be unique as it affects a putative N-glycosylation site that is conserved between different FGFRs and species. The amino acid exchange itself most probably has no impact on the three-dimensional structure of the receptor domain, suggesting that the phenotype is the result of altered receptor glycosylation and its pathophysiological consequences.

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

1995 ◽  
Vol 10 (3) ◽  
pp. 357-359 ◽  
Author(s):  
Gary A. Bellus ◽  
Iain McIntosh ◽  
E. Anne Smith ◽  
Arthur S. Aylsworth ◽  
Ilkka Kaitila ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Kinase Domain ◽  
Recurrent Mutation ◽  
Tyrosine Kinase Domain ◽  
Fibroblast Growth

scholarly journals FLT4 Mutations Are Associated with Segmental Lymphatic Dysfunction and Initial Lymphatic Aplasia in Patients with Milroy Disease

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1611
Author(s):  
Ningfei Liu ◽  
Minzhe Gao
Keyword(s):  
Tyrosine Kinase ◽  
Protein Tyrosine Kinase ◽  
Clinical Signs ◽  
Lymphatic Vessels ◽  
Growth Factor Receptor ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Missense Mutations ◽  
History Of ◽  
Endothelial Growth Factor

This study explored mutations in the Fms-related tyrosine kinase 4/vascular endothelial growth factor receptor 3 gene (FLT4) and lymphatic defects in patients with Milroy disease (MD). Twenty-nine patients with lower limb lymphedema were enrolled. Sixteen patients had a familial history of MD, while 13 patients exhibited sporadic MD. Clinical signs, FLT4 mutations, indocyanine green (ICG) lymphography findings, and skin tissue immunohistochemical staining results were evaluated. Twenty-eight variants in FLT4 were identified. Twelve of these have previously been reported, while 16 are novel. Of the 28 variants, 26 are missense mutations, and the remaining two comprise a splicing mutation and a non-frame shift mutation. Twenty-five variants are located in the intracellular protein tyrosine kinase domain; three are located in the extracellular immunoglobulin domain. Substantially delayed contrast-enhanced tortuous lymphatic vessels were visualized to the ankle or knee level in 15 of 23 patients who underwent ICG lymphography. No initial lymphatic vessels were visualized in skin specimens from four patients who did not exhibit lymphatic vessels during imaging analyses. No specific variant was identified in relation to the unique clinical phenotype. Segmental dysfunction of lymphatic vessels and initial lymphatic aplasia are present in MD patients with FLT4 mutations.

Clinical Course and Significance of the Novel FLT3-Y842C Mutation in a Patient with AML Treated with PKC412 Monotherapy.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2537-2537
Author(s):  
T. Kindler ◽  
F. Breitenbuecher ◽  
S. Kasper ◽  
E. Estey ◽  
F. Giles ◽  
...  
Keyword(s):  
Sequence Analysis ◽  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
Clinical Course ◽  
Novel Mutation ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Activation Loop ◽  
The Novel ◽  
Constitutive Activation

Abstract We recently identified a novel mutation (Y842C) within the tyrosine kinase domain of FLT3 in a patient treated with PKC410 monotherapy (ASH 2003, # 4681). Here, we present follow up studies including the clinical course of the patient and frequency analysis in 110 patients with AML. In addition, we characterized the novel mutation using overexpression of FLT3-Y842C in 32D cells. AML M2 was diagnosed in a 63 year old, male patient in 1993. After having experienced his second relapse upon standard therapy the patient was refractory to alemtuzumab treatment. Due to reduced performance status the patient was not eligible to standard chemotherapy and was enrolled into a phase II trial investigating PKC412. On conventional FLT3 mutation analysis the patient was considered to be FLT3 wild-type. Upon 8 and 29 days of treatment complete clearance of PB blast counts and BM blast infiltration was observed, respectively. Daily substitution of G-CSF resulted in transient recovery or the patients ANC′s. Since the patient showed an excellent clinical responsiveness, we reasoned whether the patient may have a yet unidentified FLT3 mutation. Sequence analysis revealed a novel point mutation in exon 21 of FLT3 (Y842C). Protein analysis of primary AML blasts showed constitutive FLT3 tyrosine-phosphorylation, ex vivo treatment with PKC412 caused significant inhibition of FLT3 and STAT5 activation. Further, in vivo analysis of FLT3 tyrosine-phosphorylation during the course of PKC412 treatment showed complete suppression of FLT3 activation within 8 days. Overexpression of FLT3-Y842C in 32D cells resulted in constitutive activation of FLT3 and STAT5 as well as in factor independent proliferation. Treatment with PKC412 caused inhibition of FLT3 tyrosine-phosphorylation, factor independent growth and apoptotic cell death. To further investigate the clinical significance of the novel Y842C mutation, the tyrosine kinase domain of FLT3 was investigated in 110 patients with AML using sequence analysis. Altogether, the novel mutation Y842C was identified in 2 patients, FLT-ITD in 22 patients and D835 in 7 patients, respectively. It is interesting to note that the recently described crystal structure of FLT3 reveals a critical role for Y842 in regulating the switch from the closed to the open (=active) conformation of the FLT3 activation loop. Since our data is consistent with the concept that the Y842C mutation results in constitutive activation of FLT3, it is tempting to speculate that the exchange of tyrosine for cysteine at position 842 disrupts the autoinhibited state of the FLT3 activation loop. Given that the novel mutation described here could only be identified by direct sequencing, it is likely that the number of mutations in this region of FLT3 is currently underestimated. Thus, extended sequence analysis of this mutational hotspot may be helpful in further defining the spectrum of TKI-sensitive FLT3 mutations in AML.

scholarly journals In VitroActivation and Inhibition of Recombinant EGFR Tyrosine Kinase Expressed inEscherichia coli

2013 ◽  
Vol 2013 ◽  
pp. 1-5 ◽  
Author(s):  
Jihene Elloumi-Mseddi ◽  
Karim Jellali ◽  
Sami Aifa
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Activity ◽  
Growth Factor Receptor ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Glutathione S Transferase ◽  
Amino Acid Peptide ◽  
Juxtamembrane Region ◽  
Exogenous Substrate ◽  
Epidermal Growth

The present work concerns the heterologous expression of the intracellular domain harbouring the tyrosine kinase activity of the epidermal growth factor receptor (EGFR). Protein expression was improved thanks to the deletion of a 13-amino acid peptide of the juxtamembrane region (JM). The recombinant proteins were produced as a glutathione S-transferase (GST) fusion inEscherichia coli, and the solubilisation was performed by sarkosyl addition during extraction. The produced proteins spontaneously dimerize allowing the activation of the tyrosine kinase domain in the presence of[γ-32P]ATP. The activity assay has revealed the autophosphorylation of EGFR proteins which was decreased in the presence of genistein. Our system could facilitate the screening of EGFR inhibitors without the need of adding an exogenous substrate.

scholarly journals Large-cell neuroendocrine carcinoma of lung with epidermal growth factor receptor (EGFR) gene mutation and co-expression of adenocarcinoma markers: a case report and review of the literature

2013 ◽  
Vol 8 ◽  
Author(s):  
Yasuhiro Sakai ◽  
Takashi Yamasaki ◽  
Yoshito Kusakabe ◽  
Daisuke Kasai ◽  
Yoshikazu Kotani ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Neuroendocrine Carcinoma ◽  
Growth Factor Receptor ◽  
Large Cell ◽  
Kinase Domain ◽  
Large Cell Neuroendocrine Carcinoma ◽  
Tyrosine Kinase Domain ◽  
High Grade ◽  
Epidermal Growth ◽  
L858r Mutation

Purpose: A high rate of response to treatment with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) has been observed in certain patients (women, of East Asian ethnicity, with non-smoking history and adenocarcinoma histology) with mutations in exons 18 to 21 of the tyrosine kinase domain of EGFR. Some cases of high-grade neuroendocrine carcinoma of the lung harboring mutations have been sporadically reported. Methods: We describe the case of a 78-year-old woman with large-cell neuroendocrine carcinoma of the lung, with mutation in exon 21 L858R and co-expression of adenocarcinoma markers. Results: A mass (3.0 cm in diameter) was identified in the inferior lobe of the left lung, accompanied by metastases into ipsilateral mediastinal lymph nodes and elevations of serum pro-gastrin-releasing peptide and carcinoembryonic antigen. Initial transbronchial brushing cytology suggested high-grade neuroendocrine carcinoma favoring small-cell carcinoma in poorly smeared and degenerated preparations, and revealed exon 21 L858R mutation. Re-enlargement of the cancer and bone metastases was observed after chemotherapy, and further testing suggested large-cell neuroendocrine carcinoma with immunoreactivity to markers of primary lung adenocarcinoma and L858R mutation. High-grade neuroendocrine carcinoma with mutations in the tyrosine kinase domain of EGFR may be associated with adenocarcinoma, as reviewed from the literature and may also apply to our case. Conclusions: EGFR-TKI could provide better quality of life and survival in patients with advanced or relapsed high-grade neuroendocrine carcinoma with EGFR gene mutations. Further studies in this respect are warranted.

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