title: Exome sequencing and functional analysis identifies a novel mutation in EXT1 gene that causes multiple osteochondromas.
abstract: Multiple osteochondromas (MO) is an inherited skeletal disorder, and the molecular mechanism of MO remains elusive. Exome sequencing has high chromosomal coverage and accuracy, and has recently been successfully used to identify pathogenic gene mutations. In this study, exome sequencing followed by Sanger sequencing validation was first used to screen gene mutations in two representative MO patients from a Chinese family. After filtering the data from the 1000 Genome Project and the dbSNP database (build 132), the detected candidate gene mutations were further validated via Sanger sequencing of four other members of the same MO family and 200 unrelated healthy subjects. Immunohistochemisty and multiple sequence alignment were performed to evaluate the importance of the identified causal mutation. A novel frameshift mutation, c.1457insG at codon 486 of exon 6 of EXT1 gene, was identified, which truncated the glycosyltransferase domain of EXT1 gene. Multiple sequence alignment showed that codon 486 of EXT1 gene was highly conserved across various vertebrates. Immunohistochemisty demonstrated that the chondrocytes with functional EXT1 in MO were less than those in extragenetic solitary chondromas. The novel c.1457insG deleterious mutation of EXT1 gene reported in this study expands the causal mutation spectrum of MO, and may be helpful for prenatal genetic screening and early diagnosis of MO.
authors.affiliation: Key Laboratory of Environment and Gene Related Diseases of Ministry Education, Faculty of Public Health, College of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.forename: Jinlong
authors.initials: J
authors.lastname: Liang
authors.forename: Xiong
authors.initials: X
authors.lastname: Guo
authors.forename: Yingang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yan
authors.initials: Y
authors.lastname: Wen
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.forename: Zengtie
authors.initials: Z
authors.lastname: Zhang
authors.forename: Weijuan
authors.initials: W
authors.lastname: Ma
authors.forename: Lanlan
authors.initials: L
authors.lastname: Dai
authors.forename: Xuanzhu
authors.initials: X
authors.lastname: Liu
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
mesh_terms: D000293:Adolescent; D000328:Adult; D003062:Codon; D059472:Exome; D005091:Exons; D005097:Exostoses, Multiple Hereditary / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D016368:Frameshift Mutation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007719:Knee Joint / Q000000981:diagnostic imaging / Q000473:pathology; D008297:Male; D009154:Mutation; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011859:Radiography; D055815:Young Adult; D000099058:Exostosin 1
chemical_list: D003062:Codon; D017351:N-Acetylglucosaminyltransferases; D000099058:Exostosin 1