Syndrome of coronal craniosynostosis, Klippel-Feil anomaly, and sprengel shoulder with and without Pro250Arg mutation in the FGFR3 gene

Lowry, R. Brian; Jabs, Ethylin Wang; Graham, Gail E.; Gerritsen, Jennifer; Fleming, John R.

doi:10.1002/ajmg.10049

Cited by 30 publications

(15 citation statements)

References 15 publications

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“…Recent molecular genetic studies have suggested that Klippel-Feil syndrome may result from mutations or disruption of genes regulating segmentation, such as PAX1, 3 SGM1, 4 and FGFR3. 5 Vertebral segmentation occurs between the 4 th and 8 th weeks of gestation and any impairment in differentiation of the mesoderm may relate not only to cervical abnormalities but also to the combination of rare cardiovascular abnormalities such as ASV, single coronary artery, persistent left superior vena cava, patent foramen ovale and aortic valve fenestration observed in this patient. In fact, Klippel-Feil syndrome is associated with various cardiovascular abnormalities in 4-29% of patients.…”

Section: Discussionmentioning

confidence: 80%

Ruptured Aneurysm of the Sinus of Valsalva With Wildervanck Syndrome (Cervico-Oculo-Acoustic Syndrome), Blepharoptosis and Short Stature Case Report

Mori

Konno

et al. 2007

Circ J

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Section: Discussionmentioning

confidence: 80%

Ruptured Aneurysm of the Sinus of Valsalva With Wildervanck Syndrome (Cervico-Oculo-Acoustic Syndrome), Blepharoptosis and Short Stature Case Report

Mori

Konno

et al. 2007

Circ J

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“…Kallmann syndrome with hearing loss has also been reported in association with mutations in FGF8 (Falardeau et al, 2008). Moreover, a specific mutation in FGFR3 causes Muenke syndrome, consisting of coronal craniosynostosis and congenital sensorineural hearing loss (Muenke et al, 1997; Holloway et al, 1998; Lowry et al, 2001). Mutations in the tyrosine kinase domain of FGFR2 and 3 cause lacrimoauriculodentodigital syndrome (LADD), a component finding of which is mixed hearing loss (Milunsky et al, 2006; Rohmann et al, 2006).…”

Section: Resultsmentioning

confidence: 99%

Identification of differentially expressed genes in early inner ear development

Paxton

Bleyl

Chapman

et al. 2010

Gene Expression Patterns

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To understand the etiology of congenital hearing loss, a comprehensive understanding of the molecular genetic mechanisms underlying normal ear development is required. We are identifying genes involved in otogenesis, with the longer term goal of studying their mechanisms of action, leading to inner ear induction and patterning. Using Agilent microarrays, we compared the differential expression of a test domain (which consisted of the pre-otic placodal ectoderm with the adjacent hindbrain ectoderm and the underlying mesendodermal tissues) with a rostral control domain (which included tissue that is competent, but not specified, to express inner ear markers in explant assays). We identified 1,261 transcripts differentially expressed between the two domains at a 2-fold or greater change: 463 were upregulated and 798 were downregulated in the test domain. We validated the differential expression of several signaling molecules and transcription factors identified in this array using in situ hybridization. Furthermore, the expression patterns of the validated group of genes from the test domain were explored in detail to determine how the timing of their expression relates to specific events of otic induction and development. In conclusion, we identified a number of novel candidate genes for otic placode induction. KeywordsOtic induction; inner ear; Wnt; Fgf; Notch; Hox; otic placode; microarray; gene expression screen RESULTS AND DISCUSSIONCongenital hearing loss is among the most common birth defects, affecting approximately 3 out of every 1000 infants born each year in the United States. Genetic causes account for about 50% of all congenital hearing loss, but the roles of only a small number of genes directly linked to hearing loss are known. To better understand the mechanisms underlying congenital hearing Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptGene Expr Patterns. Author manuscript; available in PMC 2011 January 1. Through candidate gene approaches and subsequent gene mis-expression experiments, a small number of secreted proteins have been identified in the initiation and early patterning of the otic placode and vesicle, such that a rudimentary signaling network is beginning to be established. The signaling proteins thus far identified in this cascade belong mainly to the FGF, WNT, SHH, and Notch protein families (Ladher et al., 2000(Ladher et al., , 2005Vendrell et al., 2000;Adamska et al., 2001;Phillips et al., 2001Phillips et al., , 2004Leger and Brand, 2002;Maroon et al., 2002;Liu et al., 2002Liu et al., , 2003Riccoma...

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“…Muenke syndrome (OMIM 602849) is caused by a heterozygous 749C>G transversion in FGFR3 , which changes proline 250 to arginine (17,18). This is the most common individual mutation that occurs in a craniosynostosis syndrome (19), and several reports indicate that it can be variably associated with sensorineural hearing loss (HL) (20–24). In in vitro assays of the FGFR3c spliceform, the proline to arginine substitution, located in the linker between the extracellular IgII and IgIII domains of the receptor, resulted in significantly enhanced binding to two of nine tested FGFs, FGF2 and FGF9 (25).…”

Section: Introductionmentioning

confidence: 99%

Hearing loss in a mouse model of Muenke syndrome

Mansour

Twigg

Freeland

et al. 2008

Human Molecular Genetics

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The heterozygous Pro250Arg substitution mutation in fibroblast growth factor receptor 3 (FGFR3), which increases ligand-dependent signalling, is the most common genetic cause of craniosynostosis in humans and defines Muenke syndrome. Since FGF signalling plays dosage-sensitive roles in the differentiation of the auditory sensory epithelium, we evaluated hearing in a large group of Muenke syndrome subjects, as well as in the corresponding mouse model (Fgfr3P244R). The Muenke syndrome cohort showed significant, but incompletely penetrant, predominantly low-frequency sensorineural hearing loss, and the Fgfr3P244R mice showed dominant, fully penetrant hearing loss that was more severe than that in Muenke syndrome individuals, but had the same pattern of relative high-frequency sparing. The mouse hearing loss correlated with an alteration in the fate of supporting cells (Deiters'-to-pillar cells) along the entire length of the cochlear duct, with the most extreme abnormalities found at the apical or low-frequency end. In addition, there was excess outer hair cell development in the apical region. We conclude that low-frequency sensorineural hearing loss is a characteristic feature of Muenke syndrome and that the genetically equivalent mouse provides an excellent model that could be useful in testing hearing loss therapies aimed at manipulating the levels of FGF signalling in the inner ear.

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Syndrome of coronal craniosynostosis, Klippel-Feil anomaly, and sprengel shoulder with and without Pro250Arg mutation in the FGFR3 gene

Cited by 30 publications

References 15 publications

Ruptured Aneurysm of the Sinus of Valsalva With Wildervanck Syndrome (Cervico-Oculo-Acoustic Syndrome), Blepharoptosis and Short Stature Case Report

Ruptured Aneurysm of the Sinus of Valsalva With Wildervanck Syndrome (Cervico-Oculo-Acoustic Syndrome), Blepharoptosis and Short Stature Case Report

Identification of differentially expressed genes in early inner ear development

Hearing loss in a mouse model of Muenke syndrome

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