Molecular mechanisms of classical Ehlers-Danlos syndrome (EDS).
Classical Ehlers-Danlos syndrome (EDS) is a heritable disorder characterized by joint hypermobility, skin hyperextensibility, and abnormal wound healing. The majority of affected individuals have alterations in 1 of the 2 type V collagen genes, COL5A1 and COL5A2. The most common mechanism is COL5A1 haploinsufficiency due to instability of the transcript of one allele. In dermal fibroblasts from our population of 76 individuals with clinical features of classical EDS, there were 21 (29.5%) with decreased expression of one COL5A1 allele, consistent with published estimates of the frequency of null alleles. We identified the causative mutation in nine of these cell strains (mutations for seven others had been previously described), and found two nonsense mutations, five splice mutations, and two insertion/deletions. The same type of genomic change at splice sites can have different effects at the RNA level and the outcome could not be predicted from the primary genomic DNA alteration.
Department of Pediatrics, Division of Genetics, University of Washington, Seattle, WA, USA. alm43@case.edu
Anna L
AL
Mitchell
Ulrike
U
Schwarze
Jessica F
JF
Jennings
Peter H
PH
Byers
D000483:Alleles; D024062:Collagen Type V / Q000235:genetics; D018076:DNA, Complementary / Q000032:analysis / Q000235:genetics; D004535:Ehlers-Danlos Syndrome / Q000235:genetics*; D004591:Electrophoresis, Polyacrylamide Gel; D005091:Exons / Q000235:genetics; D005787:Gene Frequency; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D009154:Mutation / Q000235:genetics; D022821:RNA Splice Sites / Q000235:genetics; D012326:RNA Splicing; D017422:Sequence Analysis, DNA
C530725:COL5A1 protein, human; D024062:Collagen Type V; D018076:DNA, Complementary; D022821:RNA Splice Sites