title: Mutations of the alpha2(V) chain of type V collagen impair matrix assembly and produce ehlers-danlos syndrome type I.
abstract: Ehlers-Danlos syndrome (EDS) is a heterogeneous connective tissue disorder that severely impairs the structure and function of the skin, joints, eyes and blood vessels. We have identified mutations of the COL5A2 gene, which encodes the alpha2(V) chain of type V collagen, in two unrelated patients with the severe type I form of EDS. The first proband was heterozygous for a 7 bp deletion that resulted in skipping of exon 27 while the second proband was heterozygous for a single nucleotide substitution that resulted in skipping of exon 28. Cultured dermal fibroblasts from both probands produced about equal amounts of the normal and mutant alpha2(V) mRNAs and protein chains. The dermis from the first proband contained a sparse collagen fibrillar network with great variability in collagen fibril sizes and shapes. The dermal collagens were also abnormally soluble. Bone cells from the first proband also produced about equal amounts of the normal and mutant alpha2(V) mRNAs. However, the collagen fibrillar architecture and collagen solubility of the bone matrix were normal. Our findings show that heterozygous mutations of the COL5A2 gene can produce the EDS type I phenotype. They also suggest that type V collagen plays a more important role in collagen fibrillogenesis of dermis than that of bone.
authors.affiliation: Division of Orthopaedics, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Michalickova
authors.forename: M
authors.initials: M
authors.lastname: Susic
authors.forename: M C
authors.initials: MC
authors.lastname: Willing
authors.forename: R J
authors.initials: RJ
authors.lastname: Wenstrup
authors.forename: W G
authors.initials: WG
authors.lastname: Cole
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D001483:Base Sequence; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics* / Q000502:physiology; D004252:DNA Mutational Analysis; D004535:Ehlers-Danlos Syndrome / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D005091:Exons / Q000235:genetics; D005109:Extracellular Matrix / Q000378:metabolism*; D006579:Heterozygote; D006801:Humans; D008969:Molecular Sequence Data; D010641:Phenotype; D017354:Point Mutation; D017384:Sequence Deletion; D012867:Skin / Q000378:metabolism / Q000473:pathology
chemical_list: D003094:Collagen