Abstract

// Hongbo He 1 , Qing Liu 1 , Can Zhang 1 , Zhan Liao 1 , Yupeng Liu 1 , Jun Wan 1 , Jian Tian 1 , Xiaopeng Tong 1 , Lichun Sun 1,2,3 and Wei Luo 1 1 Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan, China 2 Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy & Pharmacology, University of South China, Hengyang, China 3 Department of Medicine, School of Medicine, Tulane Health Sciences Center, New Orleans, LA, USA Correspondence to: Wei Luo, email: luowei0928@126.com Keywords : fibrous dysplasia; whole-exome sequencing (WES); transcriptome sequencing (RNAseq); single gene sequencing; SNV/InDel Received: May 07, 2017 Accepted: November 13, 2017 Epub: January 03, 2018 Abstract Fibrous dysplasia (FD) of bone is a rare and non-inheritable bone disease. Its precise molecular mechanisms remain unclear. We collected FD patient samples and applied the innovative technology of whole-exome sequencing (WES) and transcriptome sequencing (RNAseq) to analyze the gene mutations and expression profiles. By comparing gene mutations with both WES and RNAseq, and further filtering these mutations with gene expressional significance (average > 1TPM), we eventually identified 20 genes with non-synonymous single nucleotide variations (SNVs) occurring in the exonic regions of all FD samples. About 40 genes with SNVs were mutated in 50% of the FD samples, including GNAS (Guanine Nucleotide Binding Protein Alpha) and RTN4 (Reticulon 4). Particularly, in three of these patients (Patient 1, 3 and 4), GNAS were identified as having SNVs, with the nucleotide changed in exon 8 and the amino acid residue changed in position 201 (GNAS: NM_000516: exon8: c.G602A: p.R201H; or c.C601T: p.R201C). We only observed 2 genes, FAM21B (mutation type: deletion) and GAGE2A (mutation type: amplification), with copy number variations (CNVs) occurred in FD patients. When analyzing signaling pathways and biological functions, we predicted some key genes, such as GPCRs, G proteins, chemokine and ANK-associated genes, and their associated signaling networks might play critical roles in FD development. We further confirmed these observations via single gene sequencing and Q-PCR. Thus, the mutations of these genes may be connected with fibroblast and bone development disorders. These findings may provide a clue for our next investigation of FD pathogenesis and its molecular mechanisms.

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