The clinical features of Ehlers-Danlos syndrome type VIIB resulting from a base substitution at the splice acceptor site of intron 5 of the COL1A2 gene.

The features of a 32 year old woman with Ehlers-Danlos syndrome type VIIB and affected members of her family, resulting from a mutation in one COL1A2 allele, were studied. Her dermal type I collagen contained alpha 2(I) chains and mutant pN-alpha 2(I) chains in which the amino-terminal propeptide remained attached to the alpha 2(I) chain. She was heterozygous for an AG-->AC mutation at the splice acceptor site of intron 5 of the COL1A2 gene. The mutation activated a cryptic AG splice acceptor site corresponding to positions +14 and +15 of exon 6 of the COL1A2 gene. In contrast to previous reports only five, rather than all 18, amino acids encoded by exon 6 were deleted in the proband. The deleted peptide removed the amino-proteinase cleavage site, but not the nearby lysine cross linking site in the amino-telopeptide of the alpha 2(I) chain. She was born with bilateral hip dislocations, knee subluxations, and generalised joint hypermobility. Bilateral inguinal herniae and an umbilical hernia were present at birth. Facial features included a depressed nasal bridge with prominent paranasal folds. The skin was soft, moderately hyperelastic, and sagged over the face. Skin fragility and easy bruising were apparent from childhood. Skin wounds healed slowly and with broad, paper thin scars. Throughout her life, she had multiple fractures of the small bones of her hands and feet following moderate trauma. Electron microscopy of the proband's dermis as well as deep fascia and hip joint capsule from her affected brother showed that collagen fibrils in transverse section were nearly circular but with irregular margins. Light microscopy of bone from her affected brother and son showed normal Haversian systems and lamellar bone. All of these tissues contained approximately equal amounts of the normal and mutant alpha2(I) chains. The findings of this study confirm that loss of the amino-proteinase cleavage site of the pro alpha2(I) collagen chains, owing to anomalous splicing of exon 6 sequences in the conversion of pre-mRNA to mRNA, produces the clinical features of Ehlers-Danlos syndrome type VIIB. The history of frequent fractures found in this family is atypical and indicates an overlap with osteogenesis imperfecta.