Contribution of FGFR1 Variants to Craniofacial Variations in East Asians.

Mohamed Adel,Takatoshi Nakawaki,Soo-Byung Park,Abbadi A El-Kadi,Shugo Haga,Tetsutaro Yamaguchi,Akira Kawaguchi,Mutsumi Isa,Mohamed A Nadim,Walid H El-Kenany,Daisuke Tomita,Hajime Ishida,Yu Hikita,Masahiro Takahashi,Yong-Il Kim,Koutaro Maki,Ryosuke Kimura,Philip C Trackman

doi:10.1371/journal.pone.0170645

Abstract

FGFR1 plays an important role in the development of the nervous system as well as the regulation of the skeletal development and bone homeostasis. Mutations in FGFR1 genes affect skull development, specifically suture and synchondrosis, resulting in craniosynostosis and facial abnormalities. We examined subjects with normal skull morphology for genetic polymorphisms that might be associated with normal craniofacial variations. Genomic DNA was obtained from 216 Japanese and 227 Korean subjects. Four FGFR1 SNPs, namely, rs881301, rs6996321, rs4647905, and rs13317, were genotyped. These SNPs were tested for association with craniofacial measurements obtained from lateral and posteroanterior cephalometries, in which principle component analysis was performed to compress the data of the craniofacial measurements. We observed that SNPs rs13317 and rs6996321 were correlated with the overall head size and midfacial development, indicating that FGFR1 SNPs played crucial roles in the normal variation of human craniofacial morphology. Subjects with the derived alleles of SNPs rs13317 and rs6996321 had a small face and a facial pattern associated with a retruded midface and relatively wide-set eyes. These facial features were similar to but were milder than those of individuals with Pfeiffer syndrome, which is caused by a dysfunctional mutation in FGFR1.

Highlights

The human face hosts the most important sensory organs and is the main symbol of expression, appearance, communication, and identification
As the main role of the FGFR3 is the regulation of cell proliferation in epiphyseal plate chondrocytes, many FGFR3 mutations are characterized by short-limbed bone dysplasia of varying severity; craniosynostosis is rare in the first two of these disorders
Abnormalities resulting from mutations in FGFR2 and FGFR3 genes are a good example of a disorder that is better classified by mutation rather than phenotype [16,29]

Summary

Introduction

The human face hosts the most important sensory organs and is the main symbol of expression, appearance, communication, and identification. FGFR1 Variants and Craniofacial Variations in East Asians morphology is highly heritable; environmental factors play an important role in craniofacial development [3,4]. Mutations in genes involved in FGR/FGFR signaling are associated with craniosynostosis and related syndromes such as Jackson—Weiss, Muenke, Crouzon, Beare—Stevenson, Apert, and Pfeiffer syndromes, highlighting the role of these genes in skull development, especially suture and synchondrosis [10,11,12]. The role of FGFR1 in intramembranous bone development is important for understanding its association with craniofacial phenotypic variability. Patients with Pfeiffer syndrome show many characteristic features that affect the midface and the bones of the skull. These features result from coronal synostosis with or without sagittal synostosis. Abnormal growth of the skull bone in these patients leads to bulging and wide-set eyes, high and prominent forehead, underdeveloped upper jaw, and beaked nose [13,14,15]

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Results

Conclusion