A splice-site mutation leads to haploinsufficiency of EXT2 mRNA for a dominant trait in a large family with multiple osteochondromas

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) cha...

Full description

Saved in:
Bibliographic Details
Published in:Journal of orthopaedic research 2010-11, Vol.28 (11), p.1522-1530
Main Authors: Yang, Liu, Hui, Wing Sum, Chan, Wilson C. W., Ng, Vivian C. W., Yam, Teresa H. Y., Leung, Helen C. M., Huang, Jian-Dong, Shum, Daisy K. Y., Jie, Qiang, Cheung, Kenneth M. C., Cheah, Kathryn S. E., Luo, Zhoujing, Chan, Danny
Format: Article
Language:English
Subjects:
Adolescent
Adult
Aged
Cell Differentiation
Child
Child, Preschool
Chondrocytes - cytology
Exostoses, Multiple Hereditary - genetics
exostosis
EXT2
Female
Glucuronidase - genetics
glycosyltransferases
Heparitin Sulfate - analysis
Humans
Male
Middle Aged
multiple osteochondromas
Mutation
N-Acetylglucosaminyltransferases - genetics
RNA Splicing
RNA, Messenger - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:1522–1530, 2010
ISSN:0736-0266
1554-527X
DOI:10.1002/jor.21162