title: Identification of a novel mutation in the EXT1 gene from a patient with multiple osteochondromas by exome sequencing.
abstract: Multiple osteochondromas (MO) is an autosomal skeletal disease with an elusive molecular mechanism. To further elucidate the genetic mechanism of the disease a three‑generation Chinese family with MO was observed and researched, and a novel frameshift mutation (c.335_336insA) in the exotosin 1 (EXT1) gene of one patient with MO was observed through exome sequencing. This was further validated by Sanger sequencing and comparison with 200 unrelated healthy controls. Immunohistochemistry and multiple sequence alignment were performed to determine the pathogenicity of the candidate mutation. Multiple sequence alignment suggested that codon 335 and 336 in the EXT1 gene were highly conserved regions in vertebrates. Immunohistochemistry revealed that EXT1 protein expression levels were decreased in a patient with MO and this mutation compared with a patient with MO who had no EXT1 mutation. Owing to the appearance of c.335_336insA in exon 1 of EXT1, a premature stop codon was introduced, resulting in truncated EXT1. As a result integrated and functional EXT1 was reduced. EXT1 is involved in the biosynthesis of heparan sulfate (HS), an essential molecule, and its dysfunction may lead to MO. The novel mutation of c.335_336insA in the EXT1 gene reported in the present study has enlarged the causal mutation spectrum of MO, and may assist genetic counseling and prenatal diagnosis of MO.
authors.affiliation: Department of Laboratory Medicine, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, P.R. China.
authors.forename: Guolin
authors.initials: G
authors.lastname: Hong
authors.affiliation: Department of Laboratory Medicine, The Fuzhou Second Affiliated Hospital of Xiamen University, Fuzhou, Fujian 350007, P.R. China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Bone Tumors, The Fuzhou Second Affiliated Hospital of Xiamen University, Fuzhou, Fujian 350007, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yan
authors.affiliation: Medical College, Xiamen University, Xiamen, Fujian 361102, P.R. China.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Li
authors.affiliation: Medical College, Xiamen University, Xiamen, Fujian 361102, P.R. China.
authors.forename: Hailing
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Medical College, Xiamen University, Xiamen, Fujian 361102, P.R. China.
authors.forename: Ping
authors.initials: P
authors.lastname: Ma
authors.affiliation: Shenzhen Huada Gene Research Institute, Shenzhen, Fujian 518083, P.R. China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Hu
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D016022:Case-Control Studies; D002648:Child; D002681:China; D004247:DNA / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D005097:Exostoses, Multiple Hereditary / Q000235:genetics / Q000473:pathology*; D005260:Female; D016368:Frameshift Mutation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics*; D010375:Pedigree; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D055815:Young Adult; D000099058:Exostosin 1
chemical_list: D004247:DNA; D017351:N-Acetylglucosaminyltransferases; D000099058:Exostosin 1