title: A splice-site mutation leads to haploinsufficiency of EXT2 mRNA for a dominant trait in a large family with multiple osteochondromas.
abstract: Multiple osteochondromas (MO) is an autosomal-dominant disorder and mutations in EXT1 and EXT2 account up to 78% of the cases studied, including missense, nonsense, frameshift, and splice-site mutations. EXT1 and EXT2 encode glycosyltransferases required for the synthesis of heparan sulfate (HS) chains. The molecular pathogenesis underlying these mutations is still largely unknown. A heterozygous c.1173 + 1G > T (EXT2) mutation was identified in a three-generation 34-member MO family and is present in all 19 affected members. The consequence of this mutation is exon 7 being spliced out, and the result is a shift in the codon-reading frame from position 360 (R360) of the amino acid sequence leading to a premature termination codon, and the mutant mRNA is degraded to an undetectable level. Interestingly, HS glycosaminoglycans were also undetectable in the cartilage cap of the tumors by immunostaining. Full penetrance of this mutation in all affected members ranging from 5 to 70 years of age suggests this primary defect in EXT2 mRNA level, in conjunction with other cellular changes such as enhanced heparanase expression, can produce profound effect on the synthesis of HS chains in cartilage, the consequence of which impacts on the regulation of chondrocyte proliferation and differentiation.
authors.affiliation: Department of Biochemistry, University of Hong Kong, Pokfulam, Hong Kong, China.
authors.forename: Liu
authors.initials: L
authors.lastname: Yang
authors.forename: Wing Sum
authors.initials: WS
authors.lastname: Hui
authors.forename: Wilson C W
authors.initials: WC
authors.lastname: Chan
authors.forename: Vivian C W
authors.initials: VC
authors.lastname: Ng
authors.forename: Teresa H Y
authors.initials: TH
authors.lastname: Yam
authors.forename: Helen C M
authors.initials: HC
authors.lastname: Leung
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Huang
authors.forename: Daisy K Y
authors.initials: DK
authors.lastname: Shum
authors.forename: Qiang
authors.initials: Q
authors.lastname: Jie
authors.forename: Kenneth M C
authors.initials: KM
authors.lastname: Cheung
authors.forename: Kathryn S E
authors.initials: KS
authors.lastname: Cheah
authors.forename: Zhoujing
authors.initials: Z
authors.lastname: Luo
authors.forename: Danny
authors.initials: D
authors.lastname: Chan
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002454:Cell Differentiation; D002648:Child; D002675:Child, Preschool; D019902:Chondrocytes / Q000166:cytology; D005097:Exostoses, Multiple Hereditary / Q000235:genetics*; D005260:Female; D005966:Glucuronidase / Q000235:genetics; D006497:Heparan Sulfate / Q000032:analysis; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics*; D012326:RNA Splicing; D012333:RNA, Messenger / Q000378:metabolism*; D000099065:Exostosin 2; D000099175:Heparanase
chemical_list: D005966:Glucuronidase; D006497:Heparan Sulfate; D017351:N-Acetylglucosaminyltransferases; D012333:RNA, Messenger; D000099065:Exostosin 2; D000099175:Heparanase