title: Deletion of exon 8 from the EXT1 gene causes multiple osteochondromas (MO) in a family with three affected members.
abstract: Multiple osteochondromas (also called hereditary multiple exostoses) is an autosomal dominant disorder characterized by multiple cartilaginous tumors, which are caused by mutations in the genes for exostosin-1 (EXT1) and exostosin-2 (EXT2). The goal of this study was to elucidate the genetic alterations in a family with three affected members. Isolation of RNA from the patients' blood followed by reverse transcription and PCR amplification of selected fragments showed that the three patients lack a specific region of 90 bp from their EXT1 mRNA. This region corresponds to the sequence of exon 8 from the EXT1 gene. No splice site mutation was found around exon 8. However, long-range PCR amplification of the region from intron 7 to intron 8 indicated that the three patients contain a deletion of 4318 bp, which includes exon 8 and part of the flanking introns. There is evidence that the deletion was caused by non-homologous end joining because the breakpoints are not located within a repetitive element, but contain multiple copies of the deletion hotspot sequence TGRRKM. Exon 8 encodes part of the active site of the EXT1 enzyme, including the DXD signature of all UDP-sugar glycosyltransferases. It is conceivable that the mutant protein exerts a dominant negative effect on the activity of the EXT glycosyltransferase since it might interact with normal copies of the enzyme to form an inactive hetero-oligomeric complex. We suggest that sequencing of RNA might be superior to exome sequencing to detect short deletions of a single exon.
authors.affiliation: Department of Clinical Research, University of Bern, Murtenstrasse 35, 3008 Bern, Switzerland.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhuang
authors.affiliation: Institut IMAGINE, 75015 Paris, France.
authors.forename: Simon D
authors.initials: SD
authors.lastname: Gerber
authors.affiliation: Department of Rheumatology, University Hospital, 3010 Bern, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kuchen
authors.affiliation: Department of Rheumatology, University Hospital, 3010 Bern, Switzerland.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Villiger
authors.affiliation: Department of Clinical Research, University of Bern, Murtenstrasse 35, 3008 Bern, Switzerland ; Department of Rheumatology, University Hospital, 3010 Bern, Switzerland.
authors.forename: Beat
authors.initials: B
authors.lastname: Trueb
keywords: Exostosin-1 (EXT1); Genomic deletion; Glycosyltransferase; Hereditary multiple exostoses (HME); Multiple osteochondromas (MO)
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