Article (Scientific journals)
A novel splice variant in the N-propeptide of COL5A1 causes an EDS phenotype with severe kyphoscoliosis and eye involvement.
Symoens, Sofie; Malfait, Fransiska; Vlummens, Philip et al.
2011In PLoS ONE, 6 (5), p. 20121
Peer Reviewed verified by ORBi
 

Files


Full Text
NOVEL SPLICE.pdf
Publisher postprint (1.03 MB)
Download

All documents in ORBi are protected by a user license.

Send to



Details



Keywords :
Adolescent; Alternative Splicing/genetics; Base Sequence; Child; Collagen Type V/genetics/secretion/ultrastructure; Ehlers-Danlos Syndrome/complications/genetics/radiography; Eye Abnormalities/complications; Female; HEK293 Cells; Humans; Infant, Newborn; Introns/genetics; Molecular Sequence Data; Mutant Proteins/secretion; Peptides/genetics; Phenotype; Pregnancy; Radiography, Thoracic; Scoliosis/complications
Abstract :
[en] BACKGROUND: The Ehlers-Danlos Syndrome (EDS) is a heritable connective tissue disorder characterized by hyperextensible skin, joint hypermobility and soft tissue fragility. The classic subtype of EDS is caused by mutations in one of the type V collagen genes (COL5A1 and COL5A2). Most mutations affect the type V collagen helical domain and lead to a diminished or structurally abnormal type V collagen protein. Remarkably, only two mutations were reported to affect the extended, highly conserved N-propeptide domain, which plays an important role in the regulation of the heterotypic collagen fibril diameter. We identified a novel COL5A1 N-propeptide mutation, resulting in an unusual but severe classic EDS phenotype and a remarkable splicing outcome. METHODOLOGY/PRINCIPAL FINDINGS: We identified a novel COL5A1 N-propeptide acceptor-splice site mutation (IVS6-2A>G, NM_000093.3_c.925-2A>G) in a patient with cutaneous features of EDS, severe progressive scoliosis and eye involvement. Two mutant transcripts were identified, one with an exon 7 skip and one in which exon 7 and the upstream exon 6 are deleted. Both transcripts are expressed and secreted into the extracellular matrix, where they can participate in and perturb collagen fibrillogenesis, as illustrated by the presence of dermal collagen cauliflowers. Determination of the order of intron removal and computational analysis showed that simultaneous skipping of exons 6 and 7 is due to the combined effect of delayed splicing of intron 7, altered pre-mRNA secondary structure, low splice site strength and possibly disturbed binding of splicing factors. CONCLUSIONS/SIGNIFICANCE: We report a novel COL5A1 N-propeptide acceptor-splice site mutation in intron 6, which not only affects splicing of the adjacent exon 7, but also causes a splicing error of the upstream exon 6. Our findings add further insights into the COL5A1 splicing order and show for the first time that a single COL5A1 acceptor-splice site mutation can perturb splicing of the upstream exon.
Disciplines :
Laboratory medicine & medical technology
Author, co-author :
Symoens, Sofie
Malfait, Fransiska
Vlummens, Philip
Hermanns-Lê, Trinh ;  Université de Liège - ULiège > Département des sciences cliniques > Dermatopathologie
Syx, Delfien
De Paepe, Anne
Language :
English
Title :
A novel splice variant in the N-propeptide of COL5A1 causes an EDS phenotype with severe kyphoscoliosis and eye involvement.
Publication date :
2011
Journal title :
PLoS ONE
eISSN :
1932-6203
Publisher :
Public Library of Science, United States - California
Volume :
6
Issue :
5
Pages :
e20121
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 21 January 2014

Statistics


Number of views
59 (4 by ULiège)
Number of downloads
108 (0 by ULiège)

Scopus citations®
 
31
Scopus citations®
without self-citations
25
OpenCitations
 
34

Bibliography


Similar publications



Contact ORBi