Deletion of exon 8 from the EXT1 gene causes multiple osteochondromas (MO) in a family with three affected members.

Zhuang, Lei; Gerber, Simon D; Kuchen, Stefan; Villiger, Peter; Trueb, Beat (2016). Deletion of exon 8 from the EXT1 gene causes multiple osteochondromas (MO) in a family with three affected members. SpringerPlus, 5(71), p. 71. Springer 10.1186/s40064-016-1695-6

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Rheumatologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Rheumatologie

04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Rheumatology, Clinical Immunology and Allergology

UniBE Contributor:

Zhuang, Lei; Kuchen, Stefan; Villiger, Peter and Trueb, Beat

Subjects:

600 Technology > 610 Medicine & health

ISSN:

2193-1801

Publisher:

Springer

Language:

English

Submitter:

Stefan Kuchen

Date Deposited:

08 Jun 2016 08:47

Last Modified:

26 Jun 2016 02:15

Publisher DOI:

10.1186/s40064-016-1695-6

PubMed ID:

26839764

Uncontrolled Keywords:

Exostosin-1 (EXT1); Genomic deletion; Glycosyltransferase; Hereditary multiple exostoses (HME); Multiple osteochondromas (MO)

BORIS DOI:

10.7892/boris.80944

URI:

https://boris.unibe.ch/id/eprint/80944

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