title: (G586V) substitutions in the alpha 1 and alpha 2 chains of collagen I: effect of alpha-chain stoichiometry on the phenotype of osteogenesis imperfecta?
abstract: Osteogenesis imperfecta (OI) is a congenital disease of connective tissue, most often caused by single amino acid substitutions of glycine residues within the triple helical region of collagen I. Collagen I consists of two alpha 1 chains and one alpha 2 chain. Thus, a substitution in the alpha 1(I) chain is thought to affect the function of the collagen molecule more than would a similar substitution in the alpha 2(I) chain, thereby causing more severe OI. Theoretically this hypothesis may be tested by comparing patients with identical substitutions in different alpha-chains. We present a Gly586Val substitution in the alpha 1(I) chain, and compare our findings to those resulting from Gly586Val substitutions in the alpha 2(I) chain (Forlino et al., 1994; Bateman et al., 1991). Our proband had lethal OI type II. Most alpha-chains of collagen I produced by his cultured fibroblasts were overmodified. The denaturation temperature of the abnormal collagen was 1.5 degrees C below normal. Cyanogen bromide cleavage and subsequent sequencing revealed a G-to-T base substitution at nucleotide 2420 of COL1A1, resulting in a Gly586Val substitution. The collagen findings were almost identical to those reported by Bateman et al. (1991) and Forlino et al. (1994), but the clinical phenotypes were different: the patients with the alpha 2(I) substitutions had OI type IV and III and not the lethal OI type II of our proband. It is known that identical biochemical aberrations in the same chain may have different phenotypic effects, both within families and between non-related patients. This must be taken into account in our cautious proposal that substitutions in the alpha 1(I) chain may have more serious consequences than similar substitutions in the alpha 2(I) chain.
authors.affiliation: Department of Clinical Genetics, Rigshopitalet 4062, Copenhagen.
authors.forename: A M
authors.initials: AM
authors.lastname: Lund
authors.forename: F
authors.initials: F
authors.lastname: Skovby
authors.forename: M
authors.initials: M
authors.lastname: Schwartz
mesh_terms: D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D010013:Osteogenesis Imperfecta / Q000235:genetics*; D010641:Phenotype
chemical_list: D003094:Collagen