Identification and characterization of an inhibitory fibroblast growth factor receptor 2 (FGFR2) molecule, up-regulated in an Apert Syndrome mouse model

Wheldon, Lee M.; Khodabukus, Naila; Patey, Susannah J.; Smith, Terence Gordon; Heath, John K.; Hajihosseini, Mohammad K.

doi:10.1042/bj20100884

Cited by 13 publications

(12 citation statements)

References 47 publications

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“…59 These mutations are thought to result in sustained FGFR2 signaling due to increased affinity of the ligand to the receptor in the absence of sustained FGF2 expression. 60,61 Although the effects of these changes have been studied in bone formation, little is known about the effects on the EOMs specifically. It is important to note that an examination of fetal orbital tissues showed that the EOMs specifically express FGFR2.…”

Section: Discussionmentioning

confidence: 99%

Morphological Differences in the Inferior Oblique Muscles from Subjects with Over-elevation in Adduction

Rudell

Felius

McLoon

2020

Invest. Ophthalmol. Vis. Sci.

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We examined inferior oblique muscles from subjects with over-elevation in adduction for characteristics that might shed light on the potential mechanisms for their abnormal eye position. METHODS. The inferior oblique muscles were obtained at the time of surgery in subjects diagnosed with either primary inferior oblique overaction or Apert syndrome. The muscles were frozen and processed for morphometric analysis of myofiber size, central nucleation, myosin heavy chain (MyHC) isoform expression, nerve density, and numbers of neuromuscular junctions per muscle section. RESULTS. The inferior oblique muscles from subjects with Apert Syndrome were smaller, and had a much more heterogeneous profile relative to myofiber cross-sectional area compared to controls. Increased central nucleation in the Apert syndrome muscles suggested ongoing myofiber regeneration or reinnervation over time. Complex changes were seen in the MyHC isoform patterns that would predict slower and more sustained contractions than in the control muscles. Nerve fiber densities were significantly increased compared to controls for the muscles with primary inferior oblique overaction and Apert syndrome that had no prior surgery. The muscles from Apert syndrome subjects as well as those with primary inferior oblique overaction with no prior surgery had significantly elevated numbers of neuromuscular junctions relative to the whole muscle area. CONCLUSIONS. The muscles from both sets of subjects were significantly different from control muscles in a number of properties examined. These data support the view that despite similar manifestations of eye misalignment, the potential mechanism behind the strabismus in these subjects is significantly different.

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Section: Discussionmentioning

confidence: 99%

Morphological Differences in the Inferior Oblique Muscles from Subjects with Over-elevation in Adduction

Rudell

Felius

McLoon

2020

Invest. Ophthalmol. Vis. Sci.

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“…For example, soluble FGFR1s were mapped and found to be the two and three Ig-like domain isoforms of FGFR1 IIIc and a carboxyl-terminal cleavage peptide from the two and three Ig-like domain isoforms of FGFR1IIIb. Secreted receptors truncated after either IgI or IgIII by the introduction of early stop or premature termination codons have also been identified in other studies (Johnson and Williams, 1993;Wheldon et al, 2011). For example, a secreted receptor, FGFR1IIIa, is the IIIa splice form that contains intronic sequence upstream of exons 8 and 9, terminating within the IgIII domain and with no known signaling ability .…”

Section: Soluble Receptorsmentioning

confidence: 97%

Isoforms of Receptors of Fibroblast Growth Factors

Gong

2014

Journal Cellular Physiology

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The breadth and scope of Fibroblast Growth Factor signaling is immense, with documentation of its role in almost every organism and system studied so far. FGF ligands signal through a family of four distinct tyrosine kinase receptors, the FGF receptors (FGFRs). One contribution to the diversity of function and signaling of FGFs and their receptors arises from the numerous alternative splicing variants that have been documented in the FGFR literature. The present review discusses the types and roles of alternatively spliced variants of the FGFR family members and the significant impact of alternative splicing on the physiological functions of five broad classes of FGFR isoforms. Some characterized known regulatory mechanisms of alternative splicing and future directions in studies of FGFR alternative splicing are also discussed. Presence, absence, and/or the combination of specific exons within each FGFR protein impart upon each individual isoform its unique function and expression pattern during normal function and in diseased states (e.g., in cancers and birth defects). A better understanding of the diversity of FGF signaling in different developmental contexts and diseased states can be achieved through increased knowledge of the presence of specific FGFR isoforms and their impact on downstream signaling and functions. Modern high-throughput techniques afford an opportunity to explore the distribution and function of isoforms of FGFR during development and in diseases.

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“…The deletion described here removes the entire intron between exons IIIb and IIIc, and therefore all known regulatory elements within this intron, as well as an ESS from each exon. It is difficult to predict exactly how the chimeric exon would be processed in vivo , but the AS phenotype of the child, which implies a gain-of-function mechanism, does indicate that production of FGFR2 containing the in-frame chimeric exon is likely to occur in critical target tissues; by contrast, skipping of both exons IIIb and IIIc would generate an isoform with loss-of-function properties [22]. …”

Section: Discussionmentioning

confidence: 99%

A deletion of FGFR2 creating a chimeric IIIb/IIIc exon in a child with Apert syndrome

et al. 2011

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BackgroundSignalling by fibroblast growth factor receptor type 2 (FGFR2) normally involves a tissue-specific alternative splice choice between two exons (IIIb and IIIc), which generates two receptor isoforms (FGFR2b and FGFR2c respectively) with differing repertoires of FGF-binding specificity. Here we describe a unique chimeric IIIb/c exon in a patient with Apert syndrome, generated by a non-allelic homologous recombination event.Case PresentationWe present a child with Apert syndrome in whom routine genetic testing had excluded the FGFR2 missense mutations commonly associated with this disorder. The patient was found to harbour a heterozygous 1372 bp deletion between FGFR2 exons IIIb and IIIc, apparently originating from recombination between 13 bp of identical DNA sequence present in both exons. The rearrangement was not present in the unaffected parents.ConclusionsBased on the known pathogenesis of Apert syndrome, the chimeric FGFR2 protein is predicted to act in a dominant gain-of-function manner. This is likely to result from its expression in mesenchymal tissues, where retention of most of the residues essential for FGFR2b binding activity would result in autocrine activation. This report adds to the repertoire of rare cases of Apert syndrome for which a pathogenesis based on atypical FGFR2 rearrangements can be demonstrated.

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Identification and characterization of an inhibitory fibroblast growth factor receptor 2 (FGFR2) molecule, up-regulated in an Apert Syndrome mouse model

Cited by 13 publications

References 47 publications

Morphological Differences in the Inferior Oblique Muscles from Subjects with Over-elevation in Adduction

Morphological Differences in the Inferior Oblique Muscles from Subjects with Over-elevation in Adduction

Isoforms of Receptors of Fibroblast Growth Factors

A deletion of FGFR2 creating a chimeric IIIb/IIIc exon in a child with Apert syndrome

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