Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Effect of thanatophoric dysplasia type I mutations on FGFR3 dimerization.

ABSTRACT: Thanatophoric dysplasia type I (TDI) is a lethal human skeletal growth disorder with a prevalence of 1 in 20,000 to 1 in 50,000 births. TDI is known to arise because of five different mutations, all involving the substitution of an amino acid with a cysteine in fibroblast growth factor receptor 3 (FGFR3). Cysteine mutations in receptor tyrosine kinases (RTKs) have been previously proposed to induce constitutive dimerization in the absence of ligand, leading to receptor overactivation. However, their effect on RTK dimer stability has never been measured experimentally. In this study, we characterize the effect of three TDI mutations, Arg248Cys, Ser249Cys, and Tyr373Cys, on FGFR3 dimerization in mammalian membranes, in the absence of ligand. We demonstrate that the mutations lead to surprisingly modest dimer stabilization and to structural perturbations of the dimers, challenging the current understanding of the molecular interactions that underlie TDI.

SUBMITTER: Del Piccolo N

PROVIDER: S-EPMC4302202 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Effect of thanatophoric dysplasia type I mutations on FGFR3 dimerization.

Del Piccolo Nuala N Placone Jesse J Hristova Kalina K

Biophysical journal 20150101 2

Thanatophoric dysplasia type I (TDI) is a lethal human skeletal growth disorder with a prevalence of 1 in 20,000 to 1 in 50,000 births. TDI is known to arise because of five different mutations, all involving the substitution of an amino acid with a cysteine in fibroblast growth factor receptor 3 (FGFR3). Cysteine mutations in receptor tyrosine kinases (RTKs) have been previously proposed to induce constitutive dimerization in the absence of ligand, leading to receptor overactivation. However, t ...[more]

PMID: 25606676

Similar Datasets

Molecular Analysis of a Case of Thanatophoric Dysplasia Reveals Two de novo FGFR3 Missense Mutations located in cis.

Project description:OBJECTIVES:Thanatophoric dysplasia (TD) is the most common form of lethal skeletal dysplasia. It is primarily an autosomal dominant disorder and is characterised by macrocephaly, a narrow thorax, short ribs, brachydactyly, and hypotonia. In addition to these core phenotypic features, TD type I involves micromelia with bowed femurs, while TD type II is characterised by micromelia with straight femurs and a moderate to severe clover-leaf deformity of the skull. Mutations in the FGFR3 gene are responsible for all cases of TD reported to date. The objective of the study here was to delineate further the mutational spectrum responsible for TD. METHODS:Conventional polymerase chain reaction (PCR), allele-specific PCR, and sequence analysis were used to identify FGFR3 gene mutations in a fetus with a lethal skeletal dysplasia consistent with TD, which was detected during a routine antenatal ultrasound examination. RESULTS:In this report we describe the identification of two de novo missense mutations in cis in the FGFR3 gene (p.Asn540Lys and p.Val555Met) in a fetus displaying phenotypic features consistent with TD. CONCLUSION:This is the second description of a case of TD occurring as a result of double missense FGFR3 gene mutations, suggesting that the spectrum of mutations involved in the pathogenesis of TD may be broader than previously recognised.

| S-EPMC3616804 | biostudies-literature

Gene expressing profiling of PC12 cells expressing the FGFR3 mutation responsible for thanatophoric dysplasia type II

Project description:To investigate signaling pathways activated by FGFR3 mutations through an analysis of altered expression of downstream transcriptional targets, we performed gene expression profiling of stably transfected inducible PC12 cells expressing a chimeric receptor (PFR3) consisting of the extracellular domain of human platelet derived growth factor receptor (PDGFR) and the transmembrane and intracellular domains of human FGFR3 under the control of the zinc inducible metalliothionein promoter. Cells expressing the wildtype receptor (i.e. zinc induced) were compared to cells expressing the mutant receptor PFR3K650E, which contains the thanatophoric dysplasia type II mutation, K650E. See PubMed ID for further description of samples. Keywords = thanatophoric dysplasia Keywords = FGFR3 Keywords = PC12 Keywords = ERK1/2 Keywords: repeat sample

2005-05-06 | GSE2606 | GEO

Regulation of ciliary function by fibroblast growth factor signaling identifies FGFR3-related disorders achondroplasia and thanatophoric dysplasia as ciliopathies.

Project description:Cilia project from almost every cell integrating extracellular cues with signaling pathways. Constitutive activation of FGFR3 signaling produces the skeletal disorders achondroplasia (ACH) and thanatophoric dysplasia (TD), but many of the molecular mechanisms underlying these phenotypes remain unresolved. Here, we report in vivo evidence for significantly shortened primary cilia in ACH and TD cartilage growth plates. Using in vivo and in vitro methodologies, our data demonstrate that transient versus sustained activation of FGF signaling correlated with different cilia consequences. Transient FGF pathway activation elongated cilia, while sustained activity shortened cilia. FGF signaling extended primary cilia via ERK MAP kinase and mTORC2 signaling, but not through mTORC1. Employing a GFP-tagged IFT20 construct to measure intraflagellar (IFT) speed in cilia, we showed that FGF signaling affected IFT velocities, as well as modulating cilia-based Hedgehog signaling. Our data integrate primary cilia into canonical FGF signal transduction and uncover a FGF-cilia pathway that needs consideration when elucidating the mechanisms of physiological and pathological FGFR function, or in the development of FGFR therapeutics.

| S-EPMC5886260 | biostudies-literature

Development of individuals with thanatophoric dysplasia surviving beyond infancy.

Project description:BackgroundThis study aimed to analyze the physical and psychosocial development of long-term survivors (age >1 year) of thanatophoric dysplasia (TD).MethodsThe participants were 20 long-term survivors recruited from a cohort obtained through a nationwide survey for TD conducted across 147 pediatric departments in Japan between 2012 and 2016. Their guardians consented to participate in this study. Medical and psychosocial information was collected through questionnaires and interviews with primary physicians and guardians.ResultsThe participants were 1.2-27.8 years old, and all showed marked growth deficiency. The mean length at birth was 36 cm (-3.4 SD to -7.9 SD). The adult height (age >16 years) was <-15.2 SD. All individuals showed severely delayed psychomotor development. The highest level of psychosocial development was equivalent to that at 2 years of age. Skin disorders (acanthosis nigricans and seborrheic keratoses) were common. Eleven subjects had been hospitalized or institutionalized consistently after birth, and nine had been moved to home care, and four were exclusively orally fed. All individuals required assisted ventilation.ConclusionsLong-term survival of TD individuals is common. Some individuals enjoy home-based lives; however, they are severely psychosocially and physically disabled and require meticulous respiratory and nutritional support.

| S-EPMC9305791 | biostudies-literature

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

Project description: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.

| S-EPMC2767486 | biostudies-literature

The prevalence of thanatophoric dysplasia and lethal osteogenesis imperfecta type II in Northern Ireland - a complete population study.

Project description:The minimum prevalence of lethal Osteogenesis imperfecta type II, thanatophoric dysplasia and achondroplasia were derived following detailed case note review of all perinatal lethal skeletal dysplasias (SD) in Northern Ireland over a 12 year period. Multiple sources of ascertainment, including genetic notes, radiological reports and post mortem findings, were used. 39 cases were identified. Thanatophoric dysplasia was the commonest diagnosis made (22), followed by osteogenesis imperfecta type II (four children) and achondroplasia (two children). Eleven other diagnoses each occurred once in the 12 year period. The minimum prevalence range, per live births, of each of the common skeletal dysplasias in Northern Ireland has been calculated; thanatophoric dysplasia 0.80/10,000, osteogenesis imperfecta type II 0.15/10,000 and achondroplasia 0.07/10,000. The prevalence range for thanatophoric dysplasia is much higher than reported in previous studies. We discuss reasons for the prevalence figures obtained.

| S-EPMC3284715 | biostudies-literature

XYLT1 mutations in Desbuquois dysplasia type 2.

Project description:Desbuquois dysplasia (DBQD) is a severe condition characterized by short stature, joint laxity, and advanced carpal ossification. Based on the presence of additional hand anomalies, we have previously distinguished DBQD type 1 and identified CANT1 (calcium activated nucleotidase 1) mutations as responsible for DBQD type 1. We report here the identification of five distinct homozygous xylosyltransferase 1 (XYLT1) mutations in seven DBQD type 2 subjects from six consanguineous families. Among the five mutations, four were expected to result in loss of function and a drastic reduction of XYLT1 cDNA level was demonstrated in two cultured individual fibroblasts. Because xylosyltransferase 1 (XT-I) catalyzes the very first step in proteoglycan (PG) biosynthesis, we further demonstrated in the two individual fibroblasts a significant reduction of cellular PG content. Our findings of XYLT1 mutations in DBQD type 2 further support a common physiological basis involving PG synthesis in the multiple dislocation group of disorders. This observation sheds light on the key role of the XT-I during the ossification process.

| S-EPMC3951945 | biostudies-literature

Effect of the achondroplasia mutation on FGFR3 dimerization and FGFR3 structural response to fgf1 and fgf2: A quantitative FRET study in osmotically derived plasma membrane vesicles.

Project description:The G380R mutation in the transmembrane domain of FGFR3 is a germline mutation responsible for most cases of Achondroplasia, a common form of human dwarfism. Here we use quantitative F?ster Resonance Energy Transfer (FRET) and osmotically derived plasma membrane vesicles to study the effect of the achondroplasia mutation on the early stages of FGFR3 signaling in response to the ligands fgf1 and fgf2. Using a methodology that allows us to capture structural changes on the cytoplasmic side of the membrane in response to ligand binding to the extracellular domain of FGFR3, we observe no measurable effects of the G380R mutation on FGFR3 ligand-bound dimer configurations. Instead, the most notable effect of the achondroplasia mutation is increased propensity for FGFR3 dimerization in the absence of ligand. This work reveals new information about the molecular events that underlie the achondroplasia phenotype, and highlights differences in FGFR3 activation due to different single amino-acid pathogenic mutations.

| S-EPMC4870120 | biostudies-literature

Distinct missense mutations of the FGFR3 lys650 codon modulate receptor kinase activation and the severity of the skeletal dysplasia phenotype.

Project description:The fibroblast growth factor-receptor 3 (FGFR3) Lys650 codon is located within a critical region of the tyrosine kinase-domain activation loop. Two missense mutations in this codon are known to result in strong constitutive activation of the FGFR3 tyrosine kinase and cause three different skeletal dysplasia syndromes-thanatophoric dysplasia type II (TD2) (A1948G [Lys650Glu]) and SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans) syndrome and thanatophoric dysplasia type I (TD1) (both due to A1949T [Lys650Met]). Other mutations within the FGFR3 tyrosine kinase domain (e.g., C1620A or C1620G [both resulting in Asn540Lys]) are known to cause hypochondroplasia, a relatively common but milder skeletal dysplasia. In 90 individuals with suspected clinical diagnoses of hypochondroplasia who do not have Asn540Lys mutations, we screened for mutations, in FGFR3 exon 15, that would disrupt a unique BbsI restriction site that includes the Lys650 codon. We report here the discovery of three novel mutations (G1950T and G1950C [both resulting in Lys650Asn] and A1948C [Lys650Gln]) occurring in six individuals from five families. Several physical and radiological features of these individuals were significantly milder than those in individuals with the Asn540Lys mutations. The Lys650Asn/Gln mutations result in constitutive activation of the FGFR3 tyrosine kinase but to a lesser degree than that observed with the Lys540Glu and Lys650Met mutations. These results demonstrate that different amino acid substitutions at the FGFR3 Lys650 codon can result in several different skeletal dysplasia phenotypes.

| S-EPMC1287918 | biostudies-literature

Novel and Recurrent Mutations in the FGFR3 Gene and Double Heterozygosity Cases in a Cohort of Brazilian Patients with Skeletal Dysplasia.

Project description:Mutations in the fibroblast growth factor receptor 3 gene (FGFR3) cause achondroplasia (ACH), hypochondroplasia (HCH), and thanatophoric dysplasia types I and II (TDI/TDII). In this study, we performed a genetic study of 123 Brazilian patients with these phenotypes. Mutation hotspots of the FGFR3 gene were PCR amplified and sequenced. All cases had recurrent mutations related to ACH, HCH, TDI or TDII, except for 2 patients. One of them had a classical TDI phenotype but a typical ACH mutation (c.1138G>A) in combination with a novel c.1130T>C mutation predicted as being pathogenic. The presence of the second c.1130T>C mutation likely explained the more severe phenotype. Another atypical patient presented with a compound phenotype that resulted from a combination of ACH and X-linked spondyloepiphyseal dysplasia tarda (OMIM 313400). Next-generation sequencing of this patient's DNA showed double heterozygosity for a typical de novo ACH c.1138G>A mutation and a maternally inherited TRAPPC2 c.6del mutation. All mutations were confirmed by Sanger sequencing. A pilot study using high-resolution melting (HRM) technique was also performed to confirm several mutations identified through sequencing. We concluded that for recurrent FGFR3 mutations, HRM can be used as a faster, reliable, and less expensive genotyping test than Sanger sequencing.

| S-EPMC5836216 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data