Identification of a Mutation in FGF23 Involved in Mandibular Prognathism.

Fengshan Chen,Xin Li,Qin Li,Jun Yu,Mingliang Gu,Yong-Biao Zhang

doi:10.1038/srep11250

Abstract

Mandibular prognathism (MP) is a severe maxillofacial disorder with undetermined genetic background. We collected a Chinese pedigree with MP which involved in 23 living members of 4 generations. Genome-wide linkage analysis were carried out to obtain the information in this family and a new MP-susceptibility locus, 12pter-p12.3 was identified. Whole-exome sequencing identified a novel heterozygous mutation in fibroblast growth factor (FGF) 23 (; p.A12D) which well segregated with MP in this pedigree within the locus. The mutation was also detected in 3 cases out of 65 sporadic MP patients, but not in any of the 342 control subjects. The p.A12D mutation may disrupt signal peptide function and inhibit secretory in FGF23. Furthermore, mutant FGF23 was overexpressed in 293T cells, increased cytoplasmic accumulation was observed compared with the wild type. We have discovered that c.35C>A mutation in FGF23 strongly associated with MP, which expand our understanding of the genetic contribution to MP pathogenesis.

Highlights

Mandibular prognathism (MP; MIM 176700) is a dentofacial deformity characterized by overgrowth of the lower jaw with or without undergrowth of the upper jaw[1]
We focus on simple mandibular prognathism without maxillary retrognathism
Genome Project, or NHLBI GO Exome Sequencing Project) heterozygous mutation in FGF23 (c.35C> A; p.A12D) that was strongly associated with MP

Summary

Introduction

Mandibular prognathism (MP; MIM 176700) is a dentofacial deformity characterized by overgrowth of the lower jaw with or without undergrowth of the upper jaw[1]. 1p22.3 and 1q32.2 have been reported to be associated with MP using genome-wide association study (GWAS)[6] Among these studies, Yamaguchi et al and Li et al investigated largely on the mandibular prognathic subtype[8,9,10], whereas Frazier-Bowers et al found that affected individuals were mostly maxillary deficient[7]. Nikopensius et al[15] performed whole-exome sequencing on five siblings from an Estonian family affected by class III malocclusion and identified a mutation of DUSP6, c.545C> T (p.Ser182Phe), which is likely a causal variant of class III malocclusion The family members they studied exhibited maxillary retrusion or mandibular protrusion.

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