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(G586V) substitutions in the α1 and α2 chains of collagen I: Effect of α‐chain stoichiometry on the phenotype of osteogenesis imperfecta?
Author(s) -
Lund Allan M.,
Skovby Flemming,
Schwartz Marianne
Publication year - 1997
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/(sici)1098-1004(1997)9:5<431::aid-humu9>3.0.co;2-6
Subject(s) - osteogenesis imperfecta , cyanogen bromide , type i collagen , dentinogenesis imperfecta , biology , proband , phenotype , connective tissue , genetics , microbiology and biotechnology , peptide sequence , mutation , gene , endocrinology , anatomy
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 α1 chains and one α2 chain. Thus, a substitution in the α1(I) chain is thought to affect the function of the collagen molecule more than would a similar substitution in the α2(I) chain, thereby causing more severe OI. Theoretically this hypothesis may be tested by comparing patients with identical substitutions in different α‐chains. We present a Gly586Val substitution in the α1(I) chain, and compare our findings to those resulting from Gly586Val substitutions in the α2(I) chain (Forlino et al., 1994; Bateman et al., 1991). Our proband had lethal OI type II. Most α‐chains of collagen I produced by his cultured fibroblasts were overmodified. The denaturation temperature of the abnormal collagen was 1.5°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 α2(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 α1(I) chain may have more serious consequences than similar substitutions in the α2(I) chain. Hum Mutat 9:431–436, 1997. © 1997 Wiley‐Liss, Inc.