Meyers GA, Orlow SJ, Munro IR, Przylepa KA, Jabs EW.. Fibroblast growth factor receptor 3 (FGFR3) transmembrane mutation in Crouzon syndrome with Acanthosis nigricans. Nat Genet 11: 462-464

Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, Maryland 21287-3914, USA.
Nature Genetics (Impact Factor: 29.35). 01/1996; 11(4):462-4. DOI: 10.1038/ng1295-462
Source: PubMed


Crouzon syndrome, an autosomal dominant condition characterized by craniosynostosis, ocular proptosis and midface hypoplasia, is associated with mutations in fibroblast growth factor receptor 2 (FGFR2) (refs 1-3). For example, we have identified 10 different mutations in the FGFR2 extracellular immunoglobulin III (IgIII) domain in 50% (16/32) of our Crouzon syndrome patients. All mutations described so far for other craniosynostotic syndromes with associated limb anomalies--Jackson-Weiss, Pfeiffer, and Apert--also occur in the extracellular domain of FGFR2, as well as FGFR1 for Pfeiffer syndrome. In contrast, only FGFR3 mutations have been reported in dwarfing conditions--achondroplasia, thanatophoric dysplasia, and hypochondroplasia. For achondroplasia, greater than 99% of mutations occur in the FGFR3 transmembrane domain. We now report the unexpected observation of a FGFR3 transmembrane domain mutation, Ala391Glu, in three unrelated families with Crouzon syndrome and acanthosis nigricans, a specific skin disorder of hyperkeratosis and hyperpigmentation. The association of non-dwarfing and even non-skeletal conditions with FGFR3 mutations reveals the potential for a wide range of FGFR pleiotropic effects as well as locus heterogeneity in Crouzon syndrome. Our study underscores the biologic complexity of the FGFR gene family.

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Available from: Ethylin Wang Jabs, Jun 19, 2014
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    • "Previously, we have characterized the dimerization of FGFR3 in the presence of the A391E mutation that causes a craniosynostosis, Crouzon syndrome with acanthosis nigricans [22]. We have shown that the mutation stabilizes the unliganded FGFR3 dimer by − 1.4 kcal/mol in plasma-membrane-derived vesicles produced with the DTT/formaldehyde vesiculation buffer [36]. "
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    ABSTRACT: Receptor Tyrosine Kinases (RTKs) conduct biochemical signals upon dimerization in the membrane plane. While RTKs are generally known to be activated in response to ligand binding, many of these receptors are capable of forming unliganded dimers that are likely important intermediates in the signaling process. All 58 RTKs consist of an extracellular domain, a transmembrane (TM) domain, and an intracellular domain which includes a juxtamembrane (JM) sequence and a kinase domain. Here we investigate directly the effect of the JM domain on unliganded dimer stability of FGFR3, a receptor that is critically important for skeletal development. The data suggest that FGFR3 unliganded dimers are stabilized by receptor-receptor contacts that involve the JM domains. The contribution is significant, as it is similar in magnitude to the stabilizing contribution of a pathogenic mutation and the repulsive contribution of the extracellular domain. Furthermore, we show that the effects of the JM domain and a TM pathogenic mutation on unliganded FGFR3 dimer stability are additive. We observe that the JM-mediated dimer stabilization occurs when the JM domain is linked to FGFR3 TM domain and not simply anchored to the plasma membrane. These results point to a coordinated stabilization of the unliganded dimeric state of FGFR3 by its JM and TM domains via a mechanism that is distinctly different from the case of another well studied receptor, EGFR. Copyright © 2015. Published by Elsevier Ltd.
    Full-text · Article · Feb 2015 · Journal of Molecular Biology
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    • "Additional recognizable syndromes such as Beare– Stevenson, Crouzon with acanthosis nigricans, and Antley‐Bixler (caused by mutations of FGFR2 and POR) have also been described [Beare et al., 1969; Stevenson et al., 1978; Meyers et al., 1995] "
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    ABSTRACT: Craniosynostosis is one of the most common craniofacial disorders encountered in clinical genetics practice, with an overall incidence of 1 in 2,500. Between 30% and 70% of syndromic craniosynostoses are caused by mutations in hotspots in the fibroblast growth factor receptor (FGFR) genes or in the TWIST1 gene with the difference in detection rates likely to be related to different study populations within craniofacial centers. Here we present results from molecular testing of an Australia and New Zealand cohort of 630 individuals with a diagnosis of craniosynostosis. Data were obtained by Sanger sequencing of FGFR1, FGFR2, and FGFR3 hotspot exons and the TWIST1 gene, as well as copy number detection of TWIST1. Of the 630 probands, there were 231 who had one of 80 distinct mutations (36%). Among the 80 mutations, 17 novel sequence variants were detected in three of the four genes screened. In addition to the proband cohort there were 96 individuals who underwent predictive or prenatal testing as part of family studies. Dysmorphic features consistent with the known FGFR1-3/TWIST1-associated syndromes were predictive for mutation detection. We also show a statistically significant association between splice site mutations in FGFR2 and a clinical diagnosis of Pfeiffer syndrome, more severe clinical phenotypes associated with FGFR2 exon 10 versus exon 8 mutations, and more frequent surgical procedures in the presence of a pathogenic mutation. Targeting gene hot spot areas for mutation analysis is a useful strategy to maximize the success of molecular diagnosis for individuals with craniosynostosis. © 2013 Wiley Periodicals, Inc.
    Full-text · Article · Oct 2013 · American Journal of Medical Genetics Part C Seminars in Medical Genetics
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    • "Mutation of the FGFR gene is also responsible for other craniosynostosis, such as Apert's, Pfeiffer's, Jackson-Weiss' and Saethe-Chotzen's syndromes.14 Rarely, acanthosis nigricans may coexist with CS in childhood and is caused by mutation in the FGFR3 gene (locus 4p16.3)15 "
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    ABSTRACT: Crouzon's syndrome (CS) is a rare autosomal dominant condition with multiple mutations of the fibroblast growth factor receptor (FGFR2) gene, which accounts for 4.8% of all cases of craniosynostosis. It is characterized by premature closure of cranial sutures, cranial deformities, midface hypoplasia, relative mandibular prognathism, hypertelorism, proptosis, strabismus and short upper lip, crowding of teeth, pseudocleft or sometimes cleft palate and other associated abnormalities. The CS can vary in severity from mild presentation to severe forms involving multiple cranial sutures. We report a case of CS in 11-year-old boy. How to cite this article: Kumar GR, Jyothsna M, Ahmed SB, Lakshmi KS, Crouzon's Syndrome: A Case Report. Int J Clin Pediatr Dent 2013;6(1):33-37.
    Full-text · Article · Apr 2013
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