© 1994 Oxford University Press
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Severe (type III) osteogenesis imperfecta due to glycine substitutions in the central domain of the collagen triple helix
Dipartimento di Biochimica, Università di Pavia 1lstituto di Biologia e Genetica, Strada Le Grazte 8, Universrtà di Verona 37134 Verona 2Ospedale dei Bambini ‘Umberto l°’ Brescia, Italy
*To whom correspondence should be addressed
Received August 11, 1994; Accepted September 28, 1994
The molecular defects responsible for three cases of severe (type III) osteogenesis Imperfecta (01) were investigated. The mutation sites were localized In pro
1(l) and pro2(1) mRNA molecules, respectively, by chemical cleavage of mismatch in heteroduplex nucleic acids. Mutation identification was achieved by reverse transcription - polymerase chain reaction - DNA amplification, followed by cloning and sequencing. Two unrelated patients were demonstrated to bear the same G-A transition at nucleotide 2418 of the pro 1(l) coding region, leading to G589S substitution and resulting in very similar clinical manifestations. In the latter patient, a G - T transversion at nucleotide 2166 was found In one pro 2(l) allele, which caused a G586V substitution and again severe Ol. Presumably all three mutations occurred de novo in the probands, since they were not found In their parents' DNA. The biochemical findings on type I collagen were very similar In all the probands: the mutations here described had little destabilizing effects on triple helix formation, secretion and stability. The half-life of the collagen incorporated Into the Insoluble matrix was comparable with that of controls. These mutations are localized in the gap zone of the fibrils where mineral nucleatlon occurs. This fact suggests that they probably do not exert destabilizing effects on the individual collagen molecules, but rather on the mineralization process, once the defective molecules are Incorporated into the fibrils, hence causing severe phenotypes.
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