Paediatric phenotype of Kallmann syndrome due to mutations of fibroblast growth factor receptor 1 (FGFR1)

Zénaty, Delphine; Bretones, Patricia; Lambe, Cécile; Guemas, Isabelle; Dávid, M; Léger, Juliane; Roux, Nicolas de

doi:10.1016/j.mce.2006.04.006

Cited by 51 publications

(56 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The physiological significance of the mechanism of transphosphorylation on Y769 revealed by our trans-phosphorylating kinases structure is also corroborated by a double pathogenic mutation (Q764H/D768Y) in the FGFR1 gene in a patient with isolated GnRH deficiency (idiopathic hypogonadotropic hypogonadism, IHH) (N.P., unpublished data). Approximately 10% of the Kallmann syndrome (IHH with anosmia) patients harbor FGFR1c mutations and structural and functional analysis of Ͼ15 of these mutations has documented that they impair FGFR1 function and signaling (17)(18)(19). Based on our structural data, the double mutation should affect trans-phosphorylation on Y766, which corresponds to Y769 of FGFR2, thus manifesting in reduced recruitment and phosphorylation of PLC␥ by FGFR1.…”

Section: Analysis Of Structure-based Mutations Support the Physiologicalmentioning

confidence: 87%

A crystallographic snapshot of tyrosine trans -phosphorylation in action

Chen¹,

Ma³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Tyrosine trans-phosphorylation is a key event in receptor tyrosine kinase signaling, yet, the structural basis for this process has eluded definition. Here, we present the crystal structure of the FGF receptor 2 kinases caught in the act of trans-phosphorylation of Y769, the major C-terminal phosphorylation site. The structure reveals that enzyme-and substrate-acting kinases engage each other through elaborate and specific interactions not only in the immediate vicinity of Y769 and the enzyme active site, but also in regions that are as much of 18 Å away from D626, the catalytic base in the enzyme active site. These interactions lead to an unprecedented level of specificity and precision during the trans-phosphorylation on Y769. Time-resolved mass spectrometry analysis supports the observed mechanism of trans-phosphorylation. Our data provide a molecular framework for understanding the mechanism of action of Kallmann syndrome mutations and the order of trans-phosphorylation reactions in FGFRs. We propose that the salient mechanistic features of Y769 transphosphorylation are applicable to trans-phosphorylation of the equivalent major phosphorylation sites in many other RTKs.crystal structure ͉ FGF receptor ͉ RTKs S ignaling by receptor tyrosine kinases (RTKs) plays ubiquitous roles throughout the human life cycle commencing at germ cell maturation and continuing throughout embryogenesis into adulthood (1). Ligand binding to the extracellular region of RTKs triggers activation of the intracellular tyrosine kinase domain through the universal process of trans-phosphorylation, whereby one kinase acts as a substrate for another one. Trans-phosphorylation has two major roles in RTK signaling: trans-phosphorylation on A-loop tyrosines elevates enzyme activity while trans-phosphorylation of juxtamembrane and C-terminal tyrosines generate platforms for recruitment and phosphorylation of target substrates (2-6).Structural studies of tyrosine kinase domains have been instrumental in shaping our current understanding of the mechanisms of tyrosine kinase regulation. Crystal structures of unphosphorylated tyrosine kinase domains have unveiled diverse tactics used by kinases to achieve self-inhibition (7-10). The crystal structures of phosphorylated kinases, however, reveal how tyrosine phosphorylation stabilizes the active conformation of the kinase, and how peptide substrates dock into the enzyme active site (7,(11)(12)(13). In contrast, the structural basis for tyrosine trans-phosphorylation has remained elusive. Here, we report the crystal structure of a phosphorylated FGF receptor 2 (FGFR2) kinase domain, which provides the first crystallographic snapshot of trans-phosphorylation in action. Our structural data supported by biochemical data show that trans-phosphorylation proceeds with a much higher degree of specificity than that currently perceived based on the crystal structures of kinases in complexes with short peptide substrates. Results and DiscussionWe recently reported the crystal structure of the A-loop phosphory...

show abstract

Section: Analysis Of Structure-based Mutations Support the Physiologicalmentioning

confidence: 87%

A crystallographic snapshot of tyrosine trans -phosphorylation in action

Chen¹,

Ma³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…14,15 The PROKR2 and PROK2 mutations have also been reported to be the cause of isolated congenital anosmia. 16 The 2 patients with suspected Kallmann syndrome did not have a chromosomal microarray.…”

Section: Discussionmentioning

confidence: 99%

Spectrum of Clinical and Associated MR Imaging Findings in Children with Olfactory Anomalies

Booth

Rollins

2016

American Journal of Neuroradiology

View full text Add to dashboard Cite

show abstract

“…Mutations in KAL1 are mainly nonsense mutations, frameshift mutations, or large gene deletions, whereas the majority of mutations in FGFR1 (ie, approximately 70%) or FGF8 (all six mutations reported so far) are missense mutations. Notably, as many as 30% of the FGFR1 mutations found in the patients could be de novo mutations 13,48,66 (C Dodé, unpublished results). Putative lossof-function mutations in PROKR2 or PROK2, encoding prokineticin receptor-2 and prokineticin-2, respectively, have been detected in approximately 9% of the KS patients (see Supplementary Table S4 for a list of the mutations).…”

Section: The Complex Genetics Of Ksmentioning

confidence: 99%

“…Consequently, previously reported KS cases associated with congenital heart disease 44 or choanal atresia 45 could in fact represent unrecognised mild CHARGE cases. 46 CHARGE syndrome shares additional traits with the KAL2 genetic form of KS (see below), including cleft lip or palate, present in 20 -35% of KAL2 7,11 -13 and CHARGE 47 patients, external ear malformation, noted in virtually all CHARGE patients 47 and a few KAL2 patients, 48 agenesis of the corpus callosum, reported in several CHARGE 47 and KAL2 patients, 7,13 and coloboma that is highly prevalent in CHARGE patients 47 and has been reported in at least one KAL2 patient too. 7 Most individuals with CHARGE syndrome are heterozygous for loss-of-function mutations in CHD7 that encodes a chromodomain (chromatin organisation modifier domain) helicase DNA-binding protein.…”

Section: Differential Diagnosis: Normosmic Idiopathic Hh and Charge Smentioning

confidence: 99%

“…On the other hand, the loss of nasal cartilage, external ear hypoplasia, and skeletal anomalies of the hands or feet, have only been reported in KAL2 patients. 7,13,48 By contrast, hearing impairment is common to several genetic forms of KS, 7,8,13,23,24,29,65 although it should be noted that the underlying defect (conductive, perceptive, or mixed) is likely to vary between different genetic forms. Palate defects should also be considered as one of these shared traits, even though the severity differs between KAL1 (high arched palate) and KAL2 (cleft palate).…”

Section: Genotype -Phenotype Correlationmentioning

confidence: 99%

See 1 more Smart Citation

Kallmann syndrome

2008

View full text Add to dashboard Cite

The Kallmann syndrome (KS) combines hypogonadotropic hypogonadism (HH) with anosmia. This is a clinically and genetically heterogeneous disease. KAL1, encoding the extracellular glycoprotein anosmin-1, is responsible for the X chromosome-linked recessive form of the disease. Mutations in FGFR1 or FGF8, encoding fibroblast growth factor receptor-1 and fibroblast growth factor-8, respectively, underlie an autosomal dominant form with incomplete penetrance. Finally, mutations in PROKR2 and PROK2, encoding prokineticin receptor-2 and prokineticin-2, have been found in heterozygous, homozygous, and compound heterozygous states. These two genes are likely to be involved both in monogenic recessive and digenic/oligogenic KS transmission modes. Notably, mutations in any of the above-mentioned KS genes have been found in less than 30% of the KS patients, which indicates that other genes involved in the disease remain to be discovered.

show abstract

Paediatric phenotype of Kallmann syndrome due to mutations of fibroblast growth factor receptor 1 (FGFR1)

Cited by 51 publications

References 19 publications

A crystallographic snapshot of tyrosine trans -phosphorylation in action

A crystallographic snapshot of tyrosine trans -phosphorylation in action

Spectrum of Clinical and Associated MR Imaging Findings in Children with Olfactory Anomalies

Kallmann syndrome

Contact Info

Product

Resources

About