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1.
J Craniofac Surg ; 29(1): 237-242, 2018 Jan.
Article in English | MEDLINE | ID: mdl-29065044

ABSTRACT

Crouzon syndrome is an autosomal-dominant congenital disease due to a mutation in the fibroblast growth factor receptor 2 protein. The purpose of this study is to evaluate wound-healing potential of Crouzon osteoblasts and adipose-derived stem cells (ADSCs) in a murine model. Parietal skull defects were created in Crouzon and mature wild-type (WT) CD-1 mice. One group of WT and Crouzon mice were left untreated. Another group was transplanted with both WT and Crouzon adipose-derived stem cells. Additional groups compared the use of a fibrin glue scaffold and periosteum removal. Skulls were harvested from each group and evaluated histologically at 8-week and/or 16-week periods. Mean areas of defect were quantified and compared via ANOVA F-test. The average area of defect after 8 and 16 weeks in untreated Crouzon mice was 15.37 ±â€Š1.08 cm and 16.69 ±â€Š1.51 cm, respectively. The average area of the defect in untreated WT mice after 8 and 16 weeks averaged 14.17 ±â€Š1.88 cm and 14.96 ±â€Š2.26 cm, respectively. WT mice with autologous ADSCs yielded an average area of 15.35 ±â€Š1.34 cm after 16 weeks while Crouzon mice with WT ADSCs healed to an average size of 12.98 ±â€Š1.89 cm. Crouzon ADSCs transplanted into WT mice yielded an average area of 15.47 ±â€Š1.29 cm while autologous Crouzon ADSCs yielded an area of 14.22 ±â€Š3.32 cm. ANOVA F-test yielded P = .415. The fibroblast growth factor receptor 2 mutation in Crouzon syndrome does not promote reossification of critical-sized defects in mature WT and Crouzon mice. Furthermore, Crouzon ADSCs do not possess osteogenic advantage over WT ADSCs.


Subject(s)
Craniofacial Dysostosis/genetics , Craniofacial Dysostosis/therapy , Osteoblasts/physiology , Osteogenesis/genetics , Stem Cells/physiology , Wound Healing/genetics , Adipose Tissue/cytology , Animals , Cells, Cultured , Disease Models, Animal , Fibrin Tissue Adhesive , Mice , Parietal Bone/injuries , Parietal Bone/physiology , Receptor, Fibroblast Growth Factor, Type 2/genetics , Stem Cell Transplantation
2.
Mol Med Rep ; 16(5): 5841-5846, 2017 Nov.
Article in English | MEDLINE | ID: mdl-28901406

ABSTRACT

The aim of the present study was to identify mutations in the fibroblast growth factor receptor 2 (FGFR2) gene in patients with Crouzon syndrome and characterize the associated clinical features. A total of two Chinese patients diagnosed with Crouzon syndrome underwent complete examinations, including best­corrected visual acuity, slit­lamp, examination, fundus examination, optical coherence tomography and computed tomography of the skull. Genomic DNA was extracted from peripheral blood samples collected from the patients, as well as their family members and 200 unrelated control subjects from the same population. Exons 8 and 10 in the FGFR2 gene were amplified by polymerase chain reaction and directly sequenced. Patient #1 had a heterozygous missense mutation (c.1025G>A, p.C342Y) in exon 10 of FGFR2. Patient #2 had a heterozygous mutation (c.1084+1 G>T; IVS10+1G>T) in intron 10. The mutations were not present in any of the unaffected family members or unrelated control subjects. These findings expand the mutation spectrum of FGFR2, and are valuable for genetic counseling in addition to prenatal diagnosis in patients with Crouzon syndrome.


Subject(s)
Craniofacial Dysostosis/genetics , Genetic Predisposition to Disease , Receptor, Fibroblast Growth Factor, Type 2/genetics , Adult , Asian People , Child, Preschool , Craniofacial Dysostosis/pathology , Exons/genetics , Female , Heterozygote , Humans , Mutation/genetics , Pedigree
3.
Mol Med Rep ; 16(4): 5333-5337, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28849010

ABSTRACT

The current study was performed with aim to investigate the fibroblast growth factor receptor 2 (FGFR2) gene in two Chinese families with two different forms of syndromic craniosynostosis, and to characterize their associated clinical features. Two families underwent complete ophthalmic examinations, and two patients from each family were diagnosed with craniosynostosis. Genomic DNA was extracted from leukocytes of peripheral blood collected from these two families and from 200 unrelated subjects within the same population as controls. Exons 8 and 10 of the FGFR2 gene were amplified by polymerase chain reaction and directly sequenced. Ophthalmic examinations of the two patients revealed shallow orbits and ocular proptosis, accompanied by midface hypoplasia and craniosynostosis. Case 1 had retinal detachment, abnormal limbs and hands, while case 2 exhibited normal hands and feet upon clinical examination. A heterozygous FGFR2 missense mutation c.833G>T (C278F) in exon 8 was identified in these two patients, but not in unaffected family members or the normal controls. Although FGFR2 gene mutations and polymorphisms have been studied in various ethnic groups, we report a mutation of FGFR2 in two different Chinese patients with two different types of syndromic craniosynostosis.


Subject(s)
Alleles , Amino Acid Substitution , Craniosynostoses/diagnosis , Craniosynostoses/genetics , Genetic Association Studies , Mutation , Receptor, Fibroblast Growth Factor, Type 2/genetics , Child , Codon , DNA Mutational Analysis , Exons , Facies , Female , Genotype , Humans , Male , Middle Aged , Phenotype , Radiography , Syndrome , Tomography, X-Ray Computed
4.
Mol Med Rep ; 14(3): 1941-6, 2016 Sep.
Article in English | MEDLINE | ID: mdl-27430617

ABSTRACT

Crouzon syndrome, a dominantly inherited disorder and the most common type of craniosynostosis syndrome, is caused by mutations in the fibroblast growth factor receptor 2 (FGFR 2) gene, and characterized by craniosynostosis, shallow orbits, ocular proptosis, midface hypoplasia and a curved, beak­like nose. The purpose of the present study was to investigate the fibroblast growth factor receptor 2 (FGFR 2) gene in two Chinese families with Crouzon syndrome and to characterize the associated clinical features. Two families underwent complete ophthalmic examination, and three patients in two families were diagnosed with Crouzon syndrome. Genomic DNA was extracted from leukocytes of peripheral blood samples, which were collected from the family members and 200 unrelated control subjects from the same population. Exons 8 and 10 of the FGFR 2 gene were amplified using polymerase chain reaction analysis and were directly sequenced. Ophthalmic examinations, including best­corrected visual acuity, slit­lamp examination, fundus examination and Computerized Tomography scans, and physical examinations were performed to exclude systemic diseases. These patients were affected with shallow orbits and ocular proptosis, accompanied by midface hypoplasia, craniosynostosis, strabismus or papilloedema, with clinically normal hands and feet. A heterozygous FGFR 2 missense mutation, c.811­812insGAG (p.273insGlu) in exon 8 was identified in the affected individual, but not in the unaffected family members or the normal control individuals in family 1. In family 2, another heterozygous FGFR 2 missense mutation, c.842A>G (P.Tyr281Cys or Y281C), in exon 8 was identified in the affected boy and his mother, but not in the unaffected family members or the normal control individuals. Although FGFR 2 gene mutations and polymorphisms have been reported in various ethnic groups, particularly in the area of osteology, the present study reported for the first time, to the best of our knowledge, the identification of two novel FGFR 2 gene mutations in Chinese patients with Crouzon syndrome.


Subject(s)
Craniofacial Dysostosis/metabolism , Heterozygote , Mutation, Missense , Receptor, Fibroblast Growth Factor, Type 2/genetics , Asian People/genetics , Child, Preschool , Craniofacial Dysostosis/genetics , DNA Mutational Analysis , Female , Humans , Infant , Male , Pedigree
5.
Dev Biol ; 415(2): 242-250, 2016 07 15.
Article in English | MEDLINE | ID: mdl-27034231

ABSTRACT

Fibroblast growth factor receptor 2 (FGFR2) signaling is critical for proper craniofacial development. A gain-of-function mutation in the 2c splice variant of the receptor's gene is associated with Crouzon syndrome, which is characterized by craniosynostosis, the premature fusion of one or more of the cranial vault sutures, leading to craniofacial maldevelopment. Insight into the molecular mechanism of craniosynostosis has identified the ERK-MAPK signaling cascade as a critical regulator of suture patency. The aim of this study is to investigate the role of FGFR2c-induced ERK-MAPK activation in the regulation of coronal suture development. Loss-of-function and gain-of-function Fgfr2c mutant mice have overlapping phenotypes, including coronal synostosis and craniofacial dysmorphia. In vivo analysis of coronal sutures in loss-of-function and gain-of-function models demonstrated fundamentally different pathogenesis underlying coronal suture synostosis. Calvarial osteoblasts from gain-of-function mice demonstrated enhanced osteoblastic function and maturation with concomitant increase in ERK-MAPK activation. In vitro inhibition with the ERK protein inhibitor U0126 mitigated ERK protein activation levels with a concomitant reduction in alkaline phosphatase activity. This study identifies FGFR2c-mediated ERK-MAPK signaling as a key mediator of craniofacial growth and coronal suture development. Furthermore, our results solve the apparent paradox between loss-of-function and gain-of-function FGFR2c mutants with respect to coronal suture synostosis.


Subject(s)
Cranial Sutures/embryology , Craniofacial Dysostosis/embryology , MAP Kinase Signaling System/physiology , Receptor, Fibroblast Growth Factor, Type 2/physiology , Alkaline Phosphatase/biosynthesis , Alkaline Phosphatase/genetics , Animals , Butadienes/pharmacology , Cells, Cultured , Cranial Sutures/abnormalities , Enzyme Activation/drug effects , Mice , Mice, Knockout , Mutation , Nitriles/pharmacology , Osteoblasts/metabolism , Osteoblasts/pathology , Osteoclasts/metabolism , Osteogenesis/physiology , Phenotype , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/physiology , Receptor, Fibroblast Growth Factor, Type 2/antagonists & inhibitors , Receptor, Fibroblast Growth Factor, Type 2/deficiency , Receptor, Fibroblast Growth Factor, Type 2/genetics , Synostosis/genetics , Synostosis/pathology
6.
Hum Mol Genet ; 24(23): 6699-710, 2015 Dec 01.
Article in English | MEDLINE | ID: mdl-26362256

ABSTRACT

Patients with 46,XY gonadal dysgenesis (GD) exhibit genital anomalies, which range from hypospadias to complete male-to-female sex reversal. However, a molecular diagnosis is made in only 30% of cases. Heterozygous mutations in the human FGFR2 gene cause various craniosynostosis syndromes including Crouzon and Pfeiffer, but testicular defects were not reported. Here, we describe a patient whose features we would suggest represent a new FGFR2-related syndrome, craniosynostosis with XY male-to-female sex reversal or CSR. The craniosynostosis patient was chromosomally XY, but presented as a phenotypic female due to complete GD. DNA sequencing identified the FGFR2c heterozygous missense mutation, c.1025G>C (p.Cys342Ser). Substitution of Cys342 by Ser or other amino acids (Arg/Phe/Try/Tyr) has been previously reported in Crouzon and Pfeiffer syndrome. We show that the 'knock-in' Crouzon mouse model Fgfr2c(C342Y/C342Y) carrying a Cys342Tyr substitution displays XY gonadal sex reversal with variable expressivity. We also show that despite FGFR2c-Cys342Tyr being widely considered a gain-of-function mutation, Cys342Tyr substitution in the gonad leads to loss of function, as demonstrated by sex reversal in Fgfr2c(C342Y/-) mice carrying the knock-in allele on a null background. The rarity of our patient suggests the influence of modifier genes which exacerbated the testicular phenotype. Indeed, patient whole exome analysis revealed several potential modifiers expressed in Sertoli cells at the time of testis determination in mice. In summary, this study identifies the first FGFR2 mutation in a 46,XY GD patient. We conclude that, in certain rare genetic contexts, maintaining normal levels of FGFR2 signaling is important for human testis determination.


Subject(s)
Craniosynostoses/genetics , Gonadal Dysgenesis, 46,XY/genetics , Mutation, Missense , Receptor, Fibroblast Growth Factor, Type 2/genetics , Adolescent , Animals , Craniosynostoses/metabolism , DNA Mutational Analysis , Disease Models, Animal , Female , Gene Knock-In Techniques , Humans , Male , Mice , Mice, Mutant Strains , Syndrome
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