Hereditary multiple exostoses (HME) is a rare skeletal disorder characterized by
the formation of multiple benign cartilage-capped tumors, usually in the
metaphyseal region of the long bones. Over 70% of HME cases arise from
monoallelic mutations in either of the two genes encoding the heparan sulfate
(HS) synthesis enzymes,
ext1
and
ext2
. To
identify more HME-associated mutations, genomic DNA from members of five
independent consanguineous families with HME was sequenced with whole exome
sequencing (WES). A novel heterozygous splice site mutation (c.1173+2T>A) in
ext2
was detected in all three affected members of family
V. Further study showed that the novel mutation caused exon 7 of
ext2
mRNA to be skipped during splicing and caused a
frameshift after the codon for Arg360, which results in the appearance of new 43
codons, followed by a termination codon. Although the resulting truncated
protein was still localized to the Golgi, similar to the full-length EXT2, its
HS synthesis activity decreased by 40%. In this study, a novel splice site
mutation in
ext2
was identified and suggested to be a
pathogenic mutation of HME, which may expand the genetic etiology spectrum of
HME and may be helpful for clinical genetic counseling and prenatal
diagnosis.
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